Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial.

Background: Pegmolesatide, a synthetic peptide-based erythropoietin (EPO) receptor agonist, is being evaluated as an alternative to epoetin alfa for treating anemia of chronic kidney disease (CKD) in Chinese dialysis patients. There is a critical need for a long-acting, cost-effective erythropoiesis-stimulating agent that does not produce EPO antibodies. Methods: A randomized, open-label, active-comparator, non-inferiority phase three trial was conducted at 43 dialysis centers in China between May 17th, 2019, and March 28th, 2022. Eligible patients aged 18-70 years were randomly assigned (2:1) to receive pegmolesatide once every four weeks or epoetin alfa one to three times per week, with doses adjusted to maintain a hemoglobin level between 10.0 and 12.0 g/dL. The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the efficacy evaluation period in the per-protocol set (PPS) population. Non-inferiority of pegmolesatide to epoetin alfa was established if the lower limit of the two-sided 95% confidence interval for the between-group difference was ≥ -1.0 g/dL. Safety assessment included adverse events and potential anaphylaxis reactions. This trial is registered at ClinicalTrials.gov, NCT03902691. Findings: Three hundreds and seventy-two patients were randomly assigned to the pegmolesatide group (248 patients) or the epoetin alfa group (124 patients). A total of 347 patients (233 in the pegmolesatide group and 114 in the epoetin alfa group) were included in the PPS population. In the PPS, the mean change (standard deviation, SD) in hemoglobin level from baseline to the efficacy evaluation period was 0.07 (0.92) g/dL in the pegmolesatide group and -0.22 (0.97) g/dL in the epoetin alfa group. The between-group difference was 0.29 g/dL (95% confidence interval: 0.11-0.47), verifying non-inferiority of pegmolesatide to epoetin alfa. Adverse events occurred in 231 (94%) participants in the pegmolesatide group and in 110 (89%) in the epoetin alfa group. Hypertension was the most common treatment-related adverse event. No fatal cases of anaphylaxis or hypotension were reported. Interpretation: Monthly subcutaneously injection of pegmolesatide was as effective and safe as conventional epoetin alfa administrated one to three times a week in treating anemia in Chinese dialysis patients. Funding: The study was supported by Hansoh Medical Development Group.

Efficacy and Safety of Ferric Citrate on Hyperphosphatemia among Chinese Patients with Chronic Kidney Disease Undergoing Hemodialysis: A Phase III Multicenter Randomized Open-Label Active-Drug-Controlled Study.

INTRODUCTION: Hyperphosphatemia in chronic kidney disease (CKD) patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis. METHODS: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio, receiving either ferric citrate or sevelamer carbonate, respectively, for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated every 2 weeks. Frequency and severity of adverse events were recorded. RESULTS: 217 (90.4%) patients completed the study with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59 ± 0.54 mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (p > 0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group was significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) patients in the sevelamer carbonate group experienced drug-related treatment emergent adverse events (TEAEs); most were mild and tolerable. Common drug-related TEAEs were gastrointestinal disorders, including diarrhea (12.9 vs. 2.5%), fecal discoloration (14.7 vs. 0%), and constipation (1.7 vs. 7.4%) in ferric citrate and sevelamer carbonate group. CONCLUSION: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.

A Mendelian randomization study on causal effects of 25(OH) vitamin D levels on diabetic nephropathy.

BACKGROUND: Vitamin D supplementation is associated with a lower incidence of diabetic nephropathy (DN); however, whether this association is causative is uncertain. METHODS: We used two-sample Mendelian randomization to examine the causal influence of vitamin D on diabetic nephropathy in 7,751 individuals with type I diabetes-related nephropathy (T1DN) and 9,933 individuals with type II diabetes-related nephropathy (T2DN). Meanwhile, we repeated some previous studies on the influence of KIM-1 (kidney injury molecule 1) and body mass index (BMI) on DN. Additionally, to test the validity of the instruments variable for vitamin D, we conducted two negative controls Mendelian randomization (MR) on breast and prostate cancer, and a positive control MR on multiple sclerosis. RESULTS: Results of the MR analysis showed that there was no causal association between 25(OH)D with the early/later stage of T1DN (early: OR = 0.903, 95%CI: 0.229 to 3.555; later: OR = 1.213, 95%CI: 0.367 to 4.010) and T2DN (early: OR = 0.588, 95%CI: 0.182 to 1.904; later: OR = 0.904, 95%CI: 0.376 to 2.173), nor with the kidney function of patients with diabetes mellitus: eGFRcyea (creatinine-based estimated GFR) (Beta = 0.007, 95%CI: -0.355 to 0.369)) or UACR (urinary albumin creatinine ratio) (Beta = 0.186, 95%CI: -0.961 to 1.333)). CONCLUSIONS: We found no evidence that Vitamin D was causally associated with DN or kidney function in diabetic patients.

MiR-3646 accelerates inflammatory response of Ang II-induced hVSMCs via CYP2J2/EETs axis in hypertension model.

BACKGROUND: Inflammatory response of human vascular smooth muscle cells (hVSMCs) is a driving factor in hypertension progression. It has been reported that miR-3646 was significantly up-regulated in serum samples from patients with coronary artery disease and acute myocardial infarction mice. However, its role and underlying molecular mechanism related to inflammatory response of angiotensin II (Ang II)-induced hVSMCs remain unclear. OBJECTIVE: We aimed to explore the potential molecular mechanisms related to inflammatory response of angiotensin II (Ang II)-induced hVSMCs. METHODS: Ang II-induced hypertension model was established after hVSMCs treated with 1 µM Ang II at 24 h. The interaction between microRNA 3646 (miR-3646) and cytochrome P450 2J2 (CYP2J2) was assessed by dual-luciferase reporter gene assay. MTS assay, Lipid Peroxidation MDA Assay Kit, ELISA, Western blot, and qRT-PCR were performed to examine viability, malondialdehyde (MDA) level, inflammatory cytokine levels, and the level of genes and proteins. RESULTS: Our findings illustrated that miR-3646 was up-regulated but CYP2J2 was down-regulated in Ang II-induced hVSMCs. Mechanically, miR-3646 negatively targeted to CYP2J2 in Ang II-induced hVSMCs. These findings indicated that miR-3646 regulated inflammatory response of Ang II-induced hVSMCs via targeting CYP2J2. Moreover, functional researches showed that CYP2J2 overexpression alleviated inflammatory response of Ang II-induced hVSMCs via epoxyeicosatrienoic acids/peroxisome proliferator-activated receptor-γ (EETs/PPARγ) axis, and miR-3646 aggravated inflammatory response of Ang II-induced hVSMCs via mediating CYP2J2/EETs axis. CONCLUSION: MiR-3646 accelerated inflammatory response of Ang II-induced hVSMCs via CYP2J2/EETs axis. Our findings illustrated the specific molecular mechanism of miR-3646 regulating hypertension.

LncRNA HOX transcript antisense RNA mediates hyperglycemic-induced injury in the renal tubular epithelial cell via the miR-126-5pAkt axis.

OBJECTIVE: To investigate the involvement of HOX transcript antisense RNA (HOTAIR) in the injury of renal tubular epithelial cells induced by high glucose. Results: In high glucose-induced HK-2 cells, the expression of HOTAIR was upregulated, resulting in suppressed cell proliferation. Meanwhile, HOTAIR upregulates the expression of pro-apoptotic proteins Bax and cleaved caspase-3, while downregulating the expression of the anti-apoptotic protein Bcl-2. Luciferase reporter assays revealed that HOTAIR could target miR-126-5p. Additionally, it was found that the PI3K/Akt signaling pathway serves as a downstream target of miR-126-5p. Knockdown of HOTAIR relieved apoptosis, whereas further inhibition of miR-126-5p led to apoptosis in HK-2 cells. Conclusions: HOTAIR plays a regulatory role in mediating high glucose-induced injuries in HK-2 cells, specifically affecting apoptosis and cell viability, via the miR-126-5p/PI3K/Akt signaling pathway.

Relationship between Acute Respiratory Tract Infection and the Serum 25(OH) D3 Level in Chronic Kidney Disease Patients and Its Prevention and Treatment.

Observational studies and randomized controlled studies propose that vitamin D plays a significant role in preventing acute respiratory tract infection (RTI); however, results are inconsistent and the optimal serum 25-hydroxyvitamin D (25-OH-D3) concentration remains unknown. This study explores the risk factors associated with acute RTI in patients with chronic kidney disease (CKD) and analyzes its correlation with serum 25-OH-D3 levels, to provide appropriate preventive treatment measures for CKD patients complicated with acute RTI. Seventy cases of CKD patients treated in the department of nephrology of Jiangxi Provincial People's Hospital are recruited as the research objects and divided into a control group (CKD without RTI) and an observation group (CKD with RTI), with 35 cases in each group. The laboratory indexes and serum 25-OH-D3 levels are compared between the two groups. The area under the receiver operating characteristic curve (ROC) of 25-OH-D3 in the diagnosis of CKD patients complicated with RTI is 0.892, and the standard error is 0.038. The glomerular filtration rates (GFR) are 48.32 ± 9.87 mL/min and 50.18 ± 20.71 mL/min in the control group and the experimental group, respectively, with no statistical significance between the two groups (P > 0.05). The serum 25-OH-D3 content in the control group (35.08 ± 6.2 nmol/L) is dramatically higher than that in the observation group (20.71 ± 5.87 nmol/L) (P < 0.05). The proportion of patients with diabetes mellitus (DM) in the control group and observation group is 25.71% and 68.57%, respectively, with a considerable difference (P < 0.05). In the control group and the experimental group, the proportion of patients with oral vitamin D receptor agonists is 54.29% and 11.43%, respectively, and the difference is significant (P < 0.05). Results show that the serum 25-OH-D3 level is highly correlated with the occurrence of RTI in CKD patients. In addition, it is related to patients' age, DM, and vitamin D receptor agonists.

Transforming growth factor beta (TGF-ß) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure.

Chronic renal failure (CRF), also known as chronic kidney disease (CKD), is a common renal disorder characterized by gradual kidney dysfunction. Molecular dissection reveals that transforming growth factor beta (TGF-ß) plays a central role in the pathogenesis of CRF. However, the mechanism underlying TGF-ß upregulation has not been demonstrated. Here, we verified that the elevated level of TGF-ß was associated with the severity of CRF stages and the activation of TGF-ß-mediated signaling in 120 renal biopsies from CRF patients. By analyzing the promoter region of the TGFB1 gene, we identified one AP-1 (activator protein 1) and four NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) binding sites. Knockdown of two AP-1 subunits (c-Jun and c-FOS) or blockage of AP-1 signaling with two inhibitors T-5224 and SR11302 could cause the downregulation of TGFB1, whereas knockdown of two NF-κB subunits (p65 and p50) or blockage of NF-κB signaling with two inhibitors TPCA1 and BOT-64 could not change the expression of TGFB1. Using mass spectrometry and coimmunoprecipitation analyses, we found that both c-Jun and c-FOS formed a complex with CtBP2 (C-terminal binding protein 2) and histone acetyltransferase p300. Our in vitro data demonstrated that induction of CtBP2 by recombinant IL-1ß (interleukin-1 beta) led to the upregulation of TGFB1 and the activation of TGF-ß downstream signaling, while knockdown of CtBP2 resulted in the reversed effects. Using chromatin immunoprecipitation assays, we revealed that the CtBP2-p300-AP1 complex specifically bound to the promoter of TGFB and that knockdown or blockage of CtBP2 significantly decreased the occupancies of the p300 and AP-1 subunits. Our results support a model in which the CtBP2-p300-AP1 transcriptional complex activates the expression of TGFB1, increasing its production and extracellular secretion. The secreted TGF-ß binds to its receptors and initiates downstream signaling.

Acid mine drainage affects the diversity and metal resistance gene profile of sediment bacterial community along a river.

Acid mine drainage (AMD) is one of the most hazardous byproducts of some types of mining. However, research on how AMD affects the bacterial community structure of downstream riverine ecosystems and the distribution of metal resistance genes (MRGs) along pollution gradient is limited. Comprehensive geochemical and high-throughput next-generation sequencing analyses can be integrated to characterize spatial distributions and MRG profiles of sediment bacteria communities along the AMD-contaminated Hengshi River. We found that (1) diversities of bacterial communities significantly and gradually increased along the river with decreasing contamination, suggesting community composition reflected changes in geochemical conditions; (2) relative abundances of phyla Proteobacteria and genus Halomonas and Planococcaceae that function in metal reduction decreased along the AMD gradient; (3) low levels of sediment salinity, sulfate, aquatic lead (Pb), and cadmium (Cd) were negatively correlated with bacterial diversity despite pH was in a positive manner with diversity; and (4) arsenic (As) and copper (Cu) resistance genes corresponded to sediment concentrations of As and Cu, respectively. Altogether, our findings offer initial insight into the distribution patterns of sediment bacterial community structure, diversity and MRGs along a lotic ecosystem contaminated by AMD, and the factors that affect them.

Structures and spectroscopic properties of nonperipherally and peripherally substituted metal-free phthalocyanines: a substitution effect study based on density functional theory calculations.

The molecular structures, molecular orbitals, atomic charges, electronic absorption spectra, and infrared (IR) and Raman spectra of a series of substituted metal-free phthalocyanine compounds with four (1, 3, 5, 7) or eight (2, 4, 6, 8) methoxyl (1, 2, 5, 6) or methylthio groups (3, 4, 7, 8) on the nonperipheral (1-4) or peripheral positions (5-8) of the phthalocyanine ring are studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. The calculated structural parameters and simulated electronic absorption and IR spectra are compared with the X-ray crystallography structures and the experimentally observed electronic absorption and IR spectra of the similar molecules, and good agreement between the calculated and experimental results is found. The substitution of the methoxyl or methylthio groups at the nonperipheral positions of the phthalocyanine ring has obvious effects on the molecular structure and spectroscopic properties of the metal-free phthalocyanine. Nonperipheral substitution has a more significant influence than peripheral substitution. The substitution effect increases with an increase in the number of substituents. The methylthio group shows more significant influence than the methoxyl group, despite the stronger electron-donating property of the methoxyl group than the methylthio group. The octa-methylthio-substituted metal-free phthalocyanine compounds have nonplanar structures whose low-lying occupied molecular orbitals and electronic absorption spectra are significantly changed by the substituents. The present systematical study will be helpful for understanding the relationship between structures and properties in phthalocyanine compounds and designing phthalocyanines with typical properties.