Multitarget therapy with a corticosteroid, cyclosporine and mycophenolate mofetil for idiopathic membranous nephropathy: a prospective randomized controlled trial.

BACKGROUND: The effectiveness of multitarget combination therapy with a corticosteroid, cyclosporine and mycophenolate mofetil for idiopathic membranous nephropathy (IMN) is unclear. In the present study, we aimed to compare the efficacy and safety of multitarget therapy with a cyclical corticosteroid-cyclophosphamide regimen in patients with IMN. METHODS: This was a single-centre, prospective, randomized, controlled trial. We randomly assigned patients with IMN to receive multitarget therapy (a combination of prednisone, cyclosporine and mycophenolate mofetil) or 6-month cyclical treatment with a corticosteroid and cyclophosphamide. The study patients were followed up for 12 months. The primary outcome was a composite of complete or partial remissions at 12 months. Adverse events were also assessed. RESULTS: The study cohort comprised 78 patients, 39 of whom received multitarget therapy and the other 39 cyclical alternating treatment with a corticosteroid and cyclophosphamide. At 12 months, 31 of 39 patients (79%) in the multitarget therapy group and 34 of 39 (87%) in the corticosteroid-cyclophosphamide group had achieved complete or partial remissions (relative risk 0.93; 95% confidence interval 0.72-1.21; P = .85; log-rank test). The prevalence of adverse events was significantly lower in the multitarget therapy group than in the corticosteroid-cyclophosphamide group [46% (18 of 39) vs 74% (29 of 39); P < .05]. CONCLUSIONS: Multitarget therapy for IMN patients is noninferior to cyclical alternating treatment with corticosteroid and cyclophosphamide in inducing proteinuria remission and has a better safety profile than the corticosteroid-cyclophosphamide combination.

Renalase Prevents Renal Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Down-Regulating GSK-3ß/Snail Signaling.

Background: Treating renal fibrosis is crucial to delaying chronic kidney disease. The glycogen synthase kinase-3ß (GSK-3ß)/Snail pathway regulates renal fibrosis and Renalase can ameliorate renal interstitial fibrosis. However, it is not clear whether GSK-3ß/Snail signaling affects Renalase action. Here, we explored the role and mechanism of GSK-3ß/Snail in the anti-fibrosis action of Renalase. Materials and methods: We used mice with complete unilateral ureteral obstruction (UUO) and human proximal renal tubular epithelial (HK-2) cells with transforming growth factor-ß1 (TGF-ß1)-induced fibrosis to explore the role and regulatory mechanism of the GSK-3ß/Snail pathway in the amelioration of renal fibrosis by Renalase. Results: In UUO mice and TGF-ß1-induced fibrotic HK-2 cells, the expression of p-GSK-3ß-Tyr216/p-GSK-3ß-Ser9, GSK-3ß and Snail was significantly increased, and endoplasmic reticulum (ER) stress was activated. After Renalase supplementation, fibrosis was alleviated, ER stress was inhibited and p-GSK-3ß-Tyr216/p-GSK-3ß-Ser9, GSK-3ß and Snail were significantly down-regulated. The amelioration of renal fibrosis by Renalase and its inhibitory effect on GSK-3ß/Snail were reversed by an ER stress agonist. Furthermore, when an adeno-associated virus or plasmid was used to overexpress GSK-3ß, the effect of Renalase on delaying renal fibrosis was counteracted, although ER stress markers did not change. Conclusion: Renalase prevents renal fibrosis by down-regulating GSK-3ß/Snail signaling through inhibition of ER stress. Exogenous Renalase may be an effective method of slowing or stopping chronic kidney disease progression.

Effect of dialytic phosphate reduction rate on mortality in maintenance hemodialysis patients: a matched case-control study.

BACKGROUND: Phosphates, similar to urea, are small molecular substances that can be cleared during dialysis. Dialytic phosphate reduction rate (PRR) may, to some extent, be related to the relative amount of phosphates cleared during dialysis. However, few studies have evaluated the associations between PRR and mortality in maintenance hemodialysis (MHD) patients. In this study, we investigated the association between PRR and clinical outcomes in MHD patients. METHODS: This was a retrospective, matched case-control study. Data were collected from the Beijing Hemodialysis Quality Control and Improvement Center. Patients were divided into four groups according to PRR quartile. Age, sex, and diabetes were matched between the groups. The primary outcome was all-cause death, and the secondary outcome was cardiocerebrovascular death. RESULTS: The study cohort comprised 4063 patients who were divided into four groups according to the PRR quartile: group PRR1 (< 48.35%), group PRR2 (48.35% - 54.14%), group PRR3 (54.14% - 59.14%), and group PRR4 (≥ 59.14%). We enrolled 2172 patients (543 in each study group) by case-control matching. The all-cause death rates were as follows: group PRR1: 22.5% (122/543), group PRR2: 20.1% (109/543), group PRR3: 19.3% (105/543), and group PRR4: 19.3% (105/543). No significant differences in all-cause and cardiocerebrovascular death rates according to the Kaplan-Meier survival curves were found between the groups (log-rank test, P > 0.05). Multivariable Cox regression analysis revealed no significant differences in all-cause and cardiocerebrovascular death rates between the four groups (P = 0.461; adjusted hazard ratio, 0.99; 95% confidence interval, 0.97 - 1.02 versus P = 0.068; adjusted hazard ratio, 0.99; 95% confidence interval, 0.97 - 1.00, respectively). CONCLUSIONS: Dialytic PRR was not significantly associated with all-cause death and cardiocerebrovascular death in MHD patients.

Exosomes from high glucose-treated macrophages promote epithelial-mesenchymal transition of renal tubular epithelial cells via long non-coding RNAs.

BACKGROUND: Macrophages contribute to epithelial-mesenchymal transition (EMT) in diabetic nephropathy (DN). Exosomal long non-coding RNAs (lncRNAs) derived from macrophages play a major role in transmitting biological information, whereas related studies on DN are rare. Here we investigated the effects of exosomal lncRNAs from high glucose-treated macrophages on EMT. METHODS: High glucose-treated macrophage exosomes (HG-exos) were extracted by coprecipitation and stabilized. Then, mouse renal tubular epithelial cells were treated with HG-exos for 24 h. Expression of E-cadherin, α-smooth muscle actin (α-SMA), and fibronectin was detected by western blotting, qPCR, and immunofluorescence. High-throughput sequencing was then applied to analyze the bioinformatics of HG-exos. RESULTS: HG-exos inhibited the proliferation of tubular epithelial cells. Additionally, HG-exos markedly upregulated α-SMA and fibronectin expression and downregulated E-cadherin expression in tubular epithelial cells, indicating EMT induction. A total of 378 differentially expressed lncRNAs and 674 differentially expressed mRNAs were identified by high-throughput sequencing of HG-exos. Bioinformatics analysis and subsequent qPCR validation suggested 27 lncRNAs were enriched in the EMT-related MAPK pathway. Among them, ENSMUST00000181751.1, XR_001778608.1, and XR_880236.2 showed high homology with humans. CONCLUSION: Exosomes from macrophages induce EMT in DN and lncRNAs in exosomes enriched in the MAPK signaling pathway may be the possible mechanism.

Epidemiological analysis of death among patients on maintenance hemodialysis: results from the beijing blood purification quality Control and Improvement Center.

BACKGROUND: China has the largest number of patients on maintenance hemodialysis (MHD) worldwide. Despite continuous improvements in hemodialysis techniques, patients on MHD have a higher mortality rate than the general population. Understanding the characteristics of death in this population can better promote clinical practice, thereby improving patients' survival. METHODS: We collected demographic and clinical data for patients on MHD registered in the Beijing Blood Purification Quality Control and Improvement Center database from 2014 to 2020. The annual mortality rate was calculatedand the primary cause of end-stage renal disease (ESRD), dialysis vintage, and cause of death among deceased patients were analyzed. RESULTS: (1) 24,363 patients on MHD were included, of which 6,065 patients died from 2014 to 2020. The annual mortality rate fluctuated between 7.4% and 8.0%. The median age of death was 70.0 (60.8-79.0) years and the male to female ratio was 1.27:1 (2). The top three primary causes of ESRD in deceased patients were chronic glomerulonephritis (CGN), diabetic nephropathy (DN), and hypertensive nephropathy (HN). Comparison of the annual mortality rate showed DN > HN > CGN (3). The median dialysis vintage of deceased patients was 3.7 (1.8-6.9) years, which slowly increased annually. Patients with diabetes had a shorter dialysis vintage than patients without diabetes (3.4 vs. 4.1 years, Z = 8.3, P < 0.001) (4). The major causes of death were cardiovascular disease (20.2%), sudden death (18.1%), infection (17.9%), and cerebrovascular disease (12.6%). Proportions of death from cardiovascular disease, infection, and sudden death were higher in patients with diabetes (22.2%, 20.2%, and 20.0%) than patients without diabetes (18.4%, 15.8%, and 16.3%). Sudden death was the leading cause of death in young (18-44 years; 27.0%) and middle aged (45-64 years; 20.8%) patients, whereas infection was the leading cause of death in patients aged ≥ 75 years (24.5%). CONCLUSION: The annual mortality rate of patients on MHD in Beijing was relatively stable from 2014 to 2020. Sudden death was more likely to occur in young and middle-aged patients, and more patients aged ≥ 75 years died from infections.

Title: Bioinformatic Identification of Genes Involved in Diabetic Nephropathy Fibrosis and their Clinical Relevance.

Tubulointerstitial fibrosis is an important pathological feature of diabetic nephropathy that is associated with impaired renal function. However, the mechanism by which fibrosis occurs in diabetic nephropathy is unclear. Differentially expressed genes were identified from transcriptome profiles of renal tissue from diabetic patients and unilateral ureteral obstruction mice and intersected to obtain genes that may be involved in diabetic fibrosis. Biological function analysis and protein-protein interaction network analysis were performed. ROC curve and Pearson correlation analysis between hub genes were performed and glomerular filtration rate estimated. Finally, the RNA levels of hub genes were measured using real-time PCR. A total of 283 genes were identified as potentially involved in diabetic nephropathy fibrosis. TYROBP, CTSS, LCP2, LUM and TLR7 were identified as aberrantly expressed hub genes. Immune cell infiltration analysis demonstrated higher numbers of cytotoxic lymphocytes, B lineage cells, monocyte lineage cells, myeloid dendritic cells, neutrophils, and fibroblasts in the diabetic nephropathy group. The areas under ROC curves for TYROBP, CTSS, LCP2, LUM and TLR7 were 0.9167, 0.9583, 0.9917, 0.93333, and 0.9583, respectively (P < 0.001), and their correlation coefficients with estimated glomerular filtration rate were - 0.8332, - 0.752, - 0.7875, - 0.7567, and - 0.7136, respectively (P < 0.001). The RNA levels of TYROBP, CTSS, LUM and TLR7 were upregulated in high-glucose-treated human renal tubular epithelial cells (P < 0.005). Our study identified TYROBP, CTSS, LCP2, LUM and TLR7 as potentially involved in diabetic nephropathy fibrosis. Furthermore, TYROBP, CTSS, LUM and TLR7 may be associated with epithelial-mesenchymal transition of tubular epithelial cells.

Bioinformatics analysis of potential key ferroptosis-related genes involved in tubulointerstitial injury in patients with diabetic nephropathy.

Diabetic nephropathy (DN) is the primary complication of diabetes mellitus. Ferroptosis is a form of cell death that plays an important role in DN tubulointerstitial injury, but the specific molecular mechanism remains unclear. Here, we downloaded the DN tubulointerstitial datasets GSE104954 and GSE30529 from the Gene Expression Omnibus database. We examined the differentially expressed genes (DEGs) between DN patients and healthy controls, and 36 ferroptosis-related DEGs were selected. Pathway-enrichment analyses showed that many of these genes are involved in metabolic pathways, phosphoinositide 3-kinase/Akt signaling, and hypoxia-inducible factor-1 signaling. Ten of the 36 ferroptosis-related DEGs (CD44, PTEN, CDKN1A, DPP4, DUSP1, CYBB, DDIT3, ALOX5, VEGFA, and NCF2) were identified as key genes. Expression patterns for six of these (CD44, PTEN, DDIT3, ALOX5, VEGFA, and NCF2) were validated in the GSE30529 dataset. Nephroseq data indicated that the mRNA expression levels of CD44, PTEN, ALOX5, and NCF2 were negatively correlated with the glomerular filtration rate (GFR), while VEGFA and DDIT3 mRNA expression levels were positively correlated with GFR. Immune infiltration analysis demonstrated altered immunity in DN patients. Real-time quantitative PCR (qPCR) analysis showed that ALOX5, PTEN, and NCF2 mRNA levels were significantly upregulated in high-glucose-treated human proximal tubular (HK-2) cells, while DDIT3 and VEGFA mRNA levels were significantly downregulated. Immunohistochemistry analysis of human renal biopsies showed positive staining for ALOX5 and NCF2 protein in DN samples but not the controls. These key genes may be involved in the molecular mechanisms underlying ferroptosis in patients with DN, potentially through specific metabolic pathways and immune/inflammatory mechanisms.

Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria.

Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in acute kidney injury (AKI), which is a risk factor for the development of chronic kidney disease (CKD). Apelin is a bioactive peptide that protects against AKI by alleviating inflammation, inhibiting apoptosis, and preventing lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of apelin on mitochondria in cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in cisplatin-induced AKI mice. In vitro, apelin inhibited the cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting protein optic atrophy 1 (OPA1) downregulation. Apelin co-treatment reversed the decreased levels of the deacetylase, Sirt3, and the increased levels of protein acetylation in mitochondria of cisplatin-stimulated cells. Overall, apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model, apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of Sirt3 and OPA1 expression in apelin-treated AKI mice was also observed. Finally, exogenous administration of apelin normalized the serum level of creatinine and urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and Sirt3. In conclusion, we demonstrated that apelin ameliorates renal functions by protecting tubular mitochondria through Sirt3 upregulation, which is a novel protective mechanism of apelin in AKI. These results suggest that apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.

Secreted Frizzled-Related Protein 5 Ameliorates Vascular Calcification in a Rat Model of Chronic Kidney Disease through the Wnt/ß-Catenin Pathway.

INTRODUCTION: Vascular calcification (VC) is highly prevalent and a major cardiovascular risk factor in chronic kidney disease (CKD) patients. Secreted frizzled-related protein 5 (SFRP5), an inhibitor of the Wnt pathway, is an adipokine with a positive effect on metabolic and cardiovascular diseases. Our previous in vitro study showed that SFRP5 attenuates high phosphate-induced calcification in vascular smooth muscle cells by inhibiting the Wnt/ß-catenin pathway. Therefore, we hypothesized that SFRP5 may protect against CKD-associated VC (CKD-VC) through the same signalling. METHODS: The rat model of CKD with VC was induced by 0.75% adenine combined with 1.8% high phosphate diet, which were administered with adenovirus vectors of SFRP5. We evaluated the SFRP5 effect on VC by von Kossa staining and calcium content analysis and osteogenic markers by immunohistochemistry and Western blot. The components of Wnt/ß-catenin signalling were also evaluated. RESULTS: SFRP5 local and serum levels were significantly decreased in the CKD-VC rat model compared with the control group. Adenovirus-mediated overexpression of SFRP5 significantly inhibited VC, which was due to suppression of CKD-induced expression of calcification and osteoblastic markers. Additionally, SFRP5 abrogated activation of the Wnt/ß-catenin pathway that plays a major role in the pathogenesis of VC. The specificity of SFRP5 for inhibition of VC was confirmed using an empty adenovirus as a control. CONCLUSION: Our results suggest that SFRP5 ameliorates VC of CKD rats by inhibiting the expression of calcification and osteoblastic markers as well as the Wnt/ß-catenin pathway. Collectively, this study suggests that SFRP5 is a potential therapeutic target in CKD-VC.

Microwave ablation versus parathyroidectomy for severe secondary hyperparathyroidism in patients on hemodialysis: a retrospective multicenter study.

BACKGROUND: Microwave ablation is effective for severe secondary hyperparathyroidism, but the difference in efficacy between microwave ablation and parathyroidectomy remains unclear. In this multicenter retrospective cohort study, we compared the long-term clinical efficacy of microwave ablation and parathyroidectomy for severe secondary hyperparathyroidism undergoing hemodialysis. MATERIALS AND METHODS: The patients were divided into microwave ablation and parathyroidectomy groups. The primary endpoint was the proportion of patients with intact parathyroid hormone (iPTH) concentrations within the target range (100-600 pg/mL) during the efficacy assessment phase. The secondary endpoints were (i) differences in iPTH concentrations over time between the two groups, and (ii) decreases in iPTH concentrations over time in the two groups. RESULTS: Microwave ablation was performed in 47/92 patients and parathyroidectomy in 45/92. Primary endpoint: iPTH concentrations within the target range were achieved during the efficacy assessment phase in 26/47 patients (55.3%) and in 14/45 (31.1%) patients in the microwave ablation and parathyroidectomy groups, respectively (p = .02). Secondary endpoints: (i) Mean iPTH concentrations during the efficacy assessment phase were significantly higher in the microwave ablation versus parathyroidectomy groups (649 ± 519 pg/mL versus 136 ± 228 pg/mL, respectively; p < .01). (ii) Mean decrease in iPTH concentration from baseline was 725 ± 605 pg/mL versus 1369 ± 478 pg/mL in the MWA versus parathyroidectomy groups, respectively (p < .01). CONCLUSIONS: Ultrasound-guided percutaneous microwave ablation provides higher iPTH target-achieving rates than parathyroidectomy in patients with severe secondary hyperparathyroidism undergoing hemodialysis.

Long-Term Effect of Microwave Ablation on Patients Undergoing Hemodialysis for Moderate Secondary Hyperparathyroidism: A Retrospective Cohort Study.

OBJECTIVES: A previous 12-month study confirmed that microwave ablation (MWA) was effective for moderate secondary hyperparathyroidism (SHPT). A further analysis was performed in this study to evaluate the efficacy of MWA for moderate SHPT over an observational follow-up period of up to 60 months. METHODS: This was a retrospective cohort study of patients involved in a previous randomized controlled trial. Patients were divided into an MWA group (those who underwent MWA followed by drug therapy according to the patient's clinical situation) and a control group (those who received drug therapy only). The primary outcome was the composite endpoint. During the efficacy assessment phase, the two groups were compared in terms of the proportion of patients with intact parathyroid hormone (iPTH) levels <300 pg/ml and the differences in iPTH levels. RESULTS: Twenty-seven patients were included in this study: 13 in the MWA group and 14 in the control group. The median (interquartile range) follow-up periods of the MWA and control groups were 58 (54-60) and 58 (49-60) months, respectively. The proportion of patients with iPTH levels <300 pg/ml in the MWA group was slightly higher than that in the control group (6/13 [46.2%] versus 2/14 [14.3%], respectively; p = .08). Furthermore, iPTH levels in the MWA group were lower than in the control group during the efficacy assessment phase (411 ± 299 pg/ml versus 516 ± 369 pg/ml, respectively; p <.01). CONCLUSIONS: MWA helped to contain the necessary iPTH levels in patients undergoing hemodialysis for moderate SHPT in a 60-month timeframe.

Genome-wide identification of lncRNAs and mRNAs differentially expressed in human vascular smooth muscle cells stimulated by high phosphorus.

Background: Cardiovascular events are the primary cause of death for chronic kidney disease patients, which occurred via vascular calcification evolving pathogenically. Although a high level of phosphorus contributes to the induction of osteogenic differentiation of vascular smooth muscle cells (VSMCs), the role of lncRNA in this process awaits further study.Methods: In this study, we systematically investigated the variation of gene expression in human VSMCs induced by high phosphorus. LncRNAs and mRNAs expression were revealed by microarray analyses of the control group and high-phosphorus (HP) group. LncRNA-mRNA co-expression network was established based on the specific lncRNA-mRNA relationships. Hierarchical clustering was used to identify a common set of regulated genes. In addition, Gene Ontology enrichment, Kyoto Gene-Encyclopedia and genomic analyses were conducted for the mRNAs differentially expressed under high phosphorus.Result: RT-qPCR results confirmed that the expression of RUNX2, BMP2 and osteocalcin in HP group exhibited significant increases than in control group (p < .05). VSMC in HP group also showed higher intracellular calcium content. Volcano plots results show that 379 mRNAs and 728 lncRNAs different expressed in HP group. LncRNA-mRNA co-expression networks analysis revealed that 8 lncRNAs were the most highly connected lncRNAs. Quantitative analysis indicated that two lncRNAs were confirmed to increase significantly in the HP group. The mRNA expression of NT5E and ICAM1 were higher in group HP, while MAP3K7CL was lower than CON group (p < .05).Conclusion: This study provided a working list of lncRNAs that may be relevant to osteogenic differentiation, which presents a new insights into the mechanism of vascular calcification induced by high phosphorus in VSMCs.

C1q/tumor necrosis factor-related protein-3 improves renal fibrosis via inhibiting notch signaling pathways.

C1q/tumor necrosis factor-related protein-3 (CTRP3) has been extensively reported as an important role involved in antifibrosis, antiapoptosis, and anti-inflammation. However, the role of CTRP3 involved in renal fibrosis remains unclear. Our current study explored the role of CTRP3 in renal fibrosis and its underlying mechanisms by using serums and renal biopsy specimens from renal fibrosis patients and control subjects, rats models with the surgery of unilateral ureteral obstruction (UUO) and human renal proximal tubular epithelial cells (HRPTEpiCs). We found that circulating levels of CTRP3 had no significant difference between renal fibrosis patients and healthy subjects; however, renal CTRP3 expression was markedly downregulated in the fibrotic region with an abundant expression of collagen-I. In UUO rat models, circulating levels of CTRP3 have not changed with the prolonged obstruction of the kidney; renal CTRP3 expression was decreased with the severity of renal fibrosis; adenovirus-mediated CTRP3 treatment inhibited renal interstitial fibrosis. In vitro experiments revealed that CTRP3 attenuates TGF-ß1 induced tubular epithelial cells fibrotic changes; CTRP3 knockdown facilitates the expression of fibrotic markers in TGF-ß1-induced HRPTEpiCs; recombinant CTRP3 or adenovirus-mediated CTRP3 overexpression significantly inhibited the Notch signaling pathway-associated factors, and knockdown of CTRP3 increased TGF-ß1-mediated activation of the Notch signaling pathways. Collectively, our current study found that CTRP3 could improve renal fibrosis, to some extent, through inhibiting the Notch pathway.

Bone marrow mesenchymal stem cell-derived exosomes alleviate high phosphorus-induced vascular smooth muscle cells calcification by modifying microRNA profiles.

Vascular calcification is a common complication in patients with chronic kidney disease (CKD). It is an important predictor of cardiovascular disease and all-cause mortality. Previous studies have confirmed that bone marrow mesenchymal stem cell (BMSC) therapy can reduce vascular calcification, but the specific mechanism is still controversial. In this study, we aimed to investigate the mechanisms of BMSC-derived exosomes (EXO) in improving vascular calcification. BMSCs were cultured and EXO were isolated using the Total Exosome Isolation Reagent. Human aortic vascular smooth muscle cells (HA-VSMCs) were cultured into three groups: control group, high phosphorus group, and high phosphorus plus EXO group. Then, indicators related to smooth muscle cell calcification and microRNA profiles were analyzed. BMSC-derived exosomes inhibited high phosphorus-induced calcification in HA-VSMCs. Besides, EXO treatment reduced calcium content and decreased the alkaline phosphatase (AKP) activity in high phosphorus co-incubated HA-VSMCs. MicroRNA (miRNA) and mRNA expression profiles analyses revealed that 63 miRNAs were significantly upregulated and 1424 genes were significantly downregulated in HA-VSMCs after EXO treatment. Functional miRNA-gene regulatory network revealed that mTOR, MAPK, and Wnt signaling pathway were involved in vascular calcification. BMSC-derived exosomes alleviated high phosphorus-induced calcification in HA-VSMC through modifying miRNA profiles.

Resveratrol inhibits parathyroid hormone-induced apoptosis in human aortic smooth muscle cells by upregulating sirtuin 1.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease, so there is an urgent need to identify therapeutic targets to control the progression of cardiovascular disease. Apoptosis of aortic smooth muscle cells can promote cardiovascular disease, but the role of parathyroid hormone (PTH) and sirtuin 1 in the pathophysiology of apoptosis is still unclear. METHODS: Cultured human aortic smooth muscle cells (HASMCs) were stimulated with 10-6, 10-8, or 10-10 mol/L PTH for different days, apoptosis was measured by flow cytometry and sirtuin 1 and Bcl-2 protein levels in cell extracts were analyzed by western blotting. HASMCs were stimulated with PTH (10-8 mol/L) and 50 or 100 µmol/L RES for 3 d, apoptosis was measured by flow cytometry and sirtuin 1 and Bcl-2 protein levels in cell extracts were analyzed by western blotting. RESULTS: We found that PTH decreased the expression of sirtuin 1 and Bcl-2, inducing apoptosis (p<.05). Resveratrol (RES), a sirtuin 1 agonist, inhibited PTH-induced apoptosis and restored Bcl-2 expression (p<.05). CONCLUSIONS: PTH induces apoptosis in HASMCs. Resveratrol inhibits PTH-induced apoptosis in HASMCs.

Urine NGAL as an early biomarker for diabetic kidney disease: accumulated evidence from observational studies.

Objectives: Urine neutrophil gelatinase-associated lipocalin (NGAL) was found to increase in diabetic kidney disease (DKD). However, the clinical value of urine NGAL as diagnostic indicators in DKD remains to be clarified. Methods: Relevant studies were systematically retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. Stratified analyses and regression analyses were performed. Results: Fourteen studies with 1561 individuals were included in our analysis, including 1204 cross-sectional participants and 357 cohort participants. For the cross-sectional studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.82 (95% confidence interval (CI): 0.75-0.87) and 0.81 (95% CI: 0.68-0.90), respectively. The pooled diagnostic odds ratio was 19 (95% CI: 11-33), and the overall area under the curve was 0.88 (95% CI: 0.84-0.90). For the cohort studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.96 (95% CI: 0.91-0.98) and 0.89 (95% CI: 0.84-0.92), respectively. The overall area under the curve was 0.98, indicating good discriminative ability of NGAL as biomarkers for DKD. Conclusions: Urine NGAL, as the early diagnostic marker of DKD, might have the high diagnostic value, especially in cohort studies.

Circulating α-Klotho Levels in Hemodialysis Patients and Their Relationship to Atherosclerosis.

BACKGROUND/AIMS: Serum soluble Klotho (sKlotho) plays a role in cardiovascular disease in some populations. However, information regarding the effect of serum sKlotho on atherosclerosis in patients on maintenance hemodialysis (MHD) is limited. Therefore, we tested the level of serum sKlotho in MHD patients to investigate atherosclerosis disease and determine the relationship between sKlotho and atherosclerosis. METHODS: Using cross-sectional research, anthropometric and laboratory data were collected for 330 MHD patients. The levels of serum sKlotho before dialysis were tested by enzyme-linked immunosorbent assay. Carotid intima-middle thickness (cIMT) and the number of carotid artery atherosclerotic plaques were measured by color Doppler ultrasonography. The risk factors of atherosclerosis were explored by multivariate logistic regression analysis. RESULTS: Among 330 MHD patients, the average serum sKlotho was (379.93±143.66) pg/ml. The level of serum sKlotho was positively related to hemoglobin (P< 0.05). It was negatively correlated with systolic pressure, pulse pressure, ultrafiltration volume, serum phosphorus, corrected serum calcium×phosphorus, high-sensitivity C-reactive protein (Hs-CRP), cIMT and carotid atherosclerotic plaque quantity and atherosclerosis (P< 0.05). Multivariate logistic regression analysis showed that age (OR = 1.108, 95% CI = 1.067 ∼ 1.151, P = 0.000), dry weight (OR = 1.050, 95% CI = 1.014 ∼ 1.088, P = 0.007), Hs-CRP (OR = 1.126, 95% CI = 1.005 ∼ 1.261, P = 0.041), and serum sKlotho (OR = 0.997, 95% CI = 0.995 ∼ 1.000, P = 0.032) were risk factors for atherosclerosis in MHD patients. CONCLUSION: Serum sKlotho was related to systolic pressure, pulse pressure, ultrafiltration volume, hemoglobin, serum phosphorus, corrected serum calcium×phosphorus, Hs-CRP, increased cIMT, carotid atherosclerotic plaque quantity and atherosclerosis. Age, dry weight, Hs-CRP, and serum sKlotho were risk factors for atherosclerosis in MHD patients. Serum sKlotho may be a novel risk factor for atherosclerosis in MHD patients.

Microwave ablation: an effective treatment for mild-to-moderate secondary hyperparathyroidism in patients undergoing haemodialysis.

BACKGROUND: Microwave ablation (MWA) is an effective treatment for severe secondary hyperparathyroidism (SHPT), but it can also be used for mild-to-moderate secondary hyperparathyroidism (SHPT). In this randomised, controlled study, the efficacy of MWA in the treatment of mild-to-moderate hyperparathyroidism is investigated. MATERIALS AND METHODS: We assessed outcomes 12 months after the randomisation of 28 patients with mild-to-moderate SHPT. The subjects received either MWA plus calcitriol or calcitriol alone. The primary end-points were the rate of achieving target levels of intact parathyroid hormone (iPTH), changes in iPTH levels and the rate of patients developing severe SHPT. RESULTS: Primary end points: the overall rates of achieving target levels of iPTH were comparable between the MWA and calcitriol alone groups (24% vs. 22%, p = 0.85). However, the rate of iPTH <150 pg/mL (lower limit of the target range) in the MWA group was higher than that in the calcitriol alone group (23% vs. 8%, p = 0.02). The mean iPTH level in the MWA group after MWA was lower than that in the calcitriol alone group (373.09 ± 322.31 vs. 552.28 ± 361.87 pg/mL, p < 0.001). There was a significant difference in the change in iPTH levels over time within the MWA group (p < 0.001) but not in the calcitriol alone group. Only one patient developed severe SHPT in the MWA group, while six patients in the calcitriol alone group developed severe SHPT (p = 0.04). CONCLUSIONS: Compared with calcitriol alone, MWA plus calcitriol decreases iPTH levels and prevents the progression of mild-to-moderate SHPT.

Efficacy of microwave ablation for severe secondary hyperparathyroidism in subjects undergoing hemodialysis.

Severe secondary hyperparathyroidism (SHPT) is a serious problem in patients undergoing hemodialysis. The efficacy and safety of microwave ablation (MWA), a minimally invasive treatment, for severe SHPT are as yet unclear. To clarify the role of MWA, we administered it to patients with severe SHPT and assessed its efficacy and safety. This was a prospective, single-center, single-arm, clinical trial. We enrolled patients with severe SHPT attending our hemodialysis center who met the inclusion and exclusion criteria. We then assessed primary outcome measures (serum concentrations of intact parathyroid hormone) and secondary outcome measures (serum concentrations of calcium and phosphorus). Twenty-six patients were enrolled in this study, 10 of whom (38.46%) were responsive to MWA and 16 (61.54%) of whom were not. The main complication was hypocalcemia (10 cases, 38.46%), which had occurred in all cases by one week after administration of MWA. Responding patients with hypocalcemia all achieved normal serum calcium concentrations within seven months and non-responding patients within three months. There were no changes in serum phosphorus concentrations after MWA in either responders or non-responders. Microwave ablation is relatively ineffective in patients with severe SHPT undergoing maintaining hemodialysis and should not be the initial therapy in such cases.

Secreted Frizzled-Related Protein 5 Attenuates High Phosphate-Induced Calcification in Vascular Smooth Muscle Cells by Inhibiting the Wnt/ß-Catenin Pathway.

Vascular calcification (VC) is highly prevalent and represents a major cardiovascular risk factor in chronic kidney disease (CKD) patients. High phosphate (HP) levels are strongly associated with VC in this population. Secreted frizzled-related protein 5 (SFRP5), one of the inhibitors of the Wnt pathway, is a known anti-inflammatory adipokine with a positive effect on metabolic and cardiovascular diseases, in addition to its anticancer potency. However, the role of SFRP5 in the pathophysiology of VC is unclear. This work aimed to study the mechanism of action of SFRP5 on the progression of HP-induced VC, which resembles the CKD-related VC, through its direct effect on vascular smooth muscle cells (VSMCs) in vitro. Addition of SFRP5 significantly inhibited HP-induced calcification of VSMCs as determined by Alizarin red staining and calcium content. The inhibitory effect of SFRP5 on calcification of VSMCs was due to the suppression of HP-induced expression of calcification and osteoblastic markers. In addition, SFRP5 abrogated HP-induced activation of the Wnt/ß-catenin pathway, which plays a key role in the pathogenesis of VC. The specificity of SFRP5 for the inhibition of calcification of VSMCs was confirmed by using a neutralizing antibody to SFRP5. Our results suggest that SFRP5 inhibits HP-induced calcification of VSMCs by inhibiting the expression of calcification and osteoblastic markers, as well as the Wnt/ß-catenin pathway. Our study may indicate that SFRP5 is a potential therapeutic agent in calcification of VSMCs.