Association of physical performance with cognitive impairment in middle-aged to older haemodialysis patients: a multicentre cross-sectional observational study.

OBJECTIVE: To determine the prevalence of cognitive impairment (CI) among middle-aged to older patients receiving maintenance haemodialysis (MHD) and to investigate the potential association between CI and physical performance. METHODS: This cross-sectional observational study enrolled participants aged 55-85 years who received MHD. Cognitive status was assessed using the Mini Mental State Examination (MMSE). Physical performance was measured by hand grip strength, the Timed Up and Go Test (TUGT) and the 4-m walking speed. Sociodemographic, clinical and laboratory parameters were recorded for each patient. RESULTS: The study included 592 patients (363 males); and of these, 126 (21.3%) were diagnosed with CI. Compared with patients with normal cognitive function, those with CI were significantly older and had significantly longer dialysis duration, lower educational level, higher Malnutrition Inflammation Score, higher depression and higher Charlson Comorbidity Index score. After adjustment for covariates, multiple regression analysis suggested that grip strength (odds ratio [OR] = 0.959, 95% confidence interval [CI] = 0.924, 0.996) and 4-m walking speed (OR = 0.161, 95% CI = 0.070, 0.368) were protective factors. TUGT (OR = 1.037, 95%CI = 1.003, 1.071) was a risk factor. CONCLUSION: Physical performance was correlated with CI and might be a significant indicator for the early identification of CI in middle-aged to older MHD patients.

Association between hearing loss and physical performance in patients on maintenance hemodialysis.

BACKGROUND: The correlation between hearing loss (HL) and physical performance in patients receiving maintenance hemodialysis (MHD) remains poorly investigated. This study explored the association between HL and physical performance in patients on MHD. METHODS: This multicenter cross-sectional study was conducted between July 2020 and April 2021 in seven hemodialysis centers in Shanghai and Suzhou, China. The hearing assessment was performed using pure-tone average (PTA). Physical performance was assessed using the Timed Up and Go Test (TUGT), handgrip strength, and gait speed. RESULTS: Finally, 838 adult patients (male, 516 [61.6%]; 61.2 ± 2.6 years) were enrolled. Among them, 423 (50.5%) had mild to profound HL (male, 48.6% and female, 53.4%). Patients with HL had poorer physical performance than patients without HL (p < 0.001). TUGT was positively correlated with PTA (r = 0.265, p < 0.001), while handgrip strength and gait speed were negatively correlated with PTA (r = -0.356, p < 0.001 and r = -0.342, p < 0.001, respectively). Physical performance in patients aged <60 years showed significant dose-response relationships with HL. After adjusting for confounders, the odds ratios (95% confidence intervals) for HL across the TUGT quartiles (lowest to highest) were 1.00 (reference), 1.15 (0.73-1.81), 1.69 (1.07-2.70), and 2.87 (1.69-4.88) (p for trend = 0.005). CONCLUSION: Lower prevalence of HL was associated with a faster TUGT and a stronger handgrip strength in patients on MHD.

Comprehensive cell surface protein profiling of human mesenchymal stromal cells from peritoneal dialysis effluent and comparison with those from human bone marrow and adipose tissue.

Peritoneal mesenchymal stromal cells (pMSCs) are isolated from peritoneal dialysis (PD) effluent, and treatment with the pMSCs reduces peritoneal membrane injury in rat model of PD. This study was designed to verify the identity of the pMSCs. pMSCs were grown in plastic dishes for 4-7 passages, and their cell surface phenotype was examined by staining with a panel of 242 antibodies. The positive stain of each target protein was determined by an increase in fluorescence intensity as compared with isotype controls in flow cytometrical analysis. Here, we showed that pMSCs predominantly expressed CD9, CD26, CD29, CD42a, CD44, CD46, CD47, CD49b, CD49c, CD49e, CD54, CD55, CD57, CD59, CD63, CD71, CD73, CD81, CD90, CD98, CD147, CD151, CD200, CD201, ß2-micoglobulin, epithelial growth factor receptor, human leukocyte antigen (HLA) class 1, and, to a lesser extent, CD31, CD45RO, CD49a, CD49f, CD50, CD58, CD61, CD105, CD164, and CD166. These cells lacked expression of most hematopoietic markers such as CD11b, CD14, CD19, CD34, CD40, CD80, CD79, CD86, and HLA-DR. There was 38.55% difference in the expression of 83 surface proteins between bone marrow (BM)-derived MSCs and pMSCs, and 14.1% in the expression of 242 proteins between adipose tissue (AT)-derived MSCs and pMSCs. The BM-MSCs but not both AT-MSCs and pMSCs express cytokine receptors (IFNγR, TNFI/IIR, IL-1R, IL-4R, IL-6R, and IL-7R). In conclusion, pMSCs exhibited a typical cell surface phenotype of MSCs, which was not the same as on BM-MSCs or AT-MSCs, suggesting that the pMSCs may represent a different MSC lineage from peritoneal cavity.

Do medical alliances truly work? Perspectives on health service utilisation among outpatients with chronic diseases in Shanghai, China.

BACKGROUND: To achieve proper health utilisation among various health institutions and improve primary care capacity, China implemented medical alliance (MA) reform as part of healthcare reforms in 2009. With chronic disease management as the focus and priority of primary health institutions, this study aimed to analyse the specific distribution and trends of outpatient visits to various levels of health institutions (community health centres (CHCs) vs hospitals) in MAs. METHODS: All outpatient data were extracted from the Chuansha MA in Pudong New Area, Shanghai, between 2016 and 2020, and submitted to descriptive analysis, Chi-Square tests and correlation analysis. RESULTS: This article found that outpatients aged >60years visited CHCs more than hospitals for some chronic diseases. The adjusted average costs of outpatients presented upward trends both in hospitals and in CHCs. CONCLUSIONS: The Chuansha MA worked in guiding older outpatients to visit CHCs, but did not control the increasing medical costs. The Shanghai government should further improve medical capability of CHCs to attract all community-dwelling residents at all ages to implement hierarchical diagnosis and treatment systems, as well as make more efforts to control increasing medical costs.

Association of Sleep Duration with Physical Performance in Hemodialysis Patients: A Multicenter Cross-Sectional Study.

BACKGROUND: Hemodialysis (HD) patients have decreased physical function. Getting enough sleep is important for maintaining physical function. However, the relationship between sleep duration and physical performance in HD patients is unclear. METHODS: We conducted a multicenter cross-sectional study at seven HD centers in Shanghai and Suzhou, China. 880 HD patients were enrolled between July 2020 and April 2021. Clinical Characteristics, laboratory indicator, sleep assessment data were collected. Physical performance included balance function, muscle strength, and mobility, which were measured by timed up and go test (TUGT), handgrip, and 4-m walk test, respectively. We divided sleep duration into four groups <7 h, 7-8 h, >8-9 h, ≥9 h. RESULTS: A total of 840 patients had completed data (men 525, women 315, mean age 61.24 years). TUGT in group <7 h and ≥9 h was higher than mid-range sleep duration. Handgrip strength in group ≥9 h was lower than group <7 h and 7-8 h. Gait speed in group <7 h and ≥9 h was lower than group 7-8 h. Adjusting for the covariates, short and long sleep duration were associated with slower gait speed. CONCLUSION: HD patients with abnormal sleep duration had poorer physical performance. Short and long sleep duration were significantly associated with gait speed.

Development and validation of a diagnostic nomogram for sarcopenia in Chinese hemodialysis patients.

BACKGROUND: Sarcopenia is a clinical condition that is common in patients with chronic kidney disease (CKD), especially in those on dialysis. However, the relatively complicated diagnostic procedure limits its use in clinical situations. In this study we aimed to establish a simplified tool for the diagnosis of sarcopenia in patients on hemodialysis (HD). METHODS: Overall, 757 eligible patients from seven HD centers in Shanghai and Suzhou, China, were recruited from 2020 to 2021. The cross-sectional data were analyzed. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Among them, 511 consecutive patients (77 with and 434 without sarcopenia) from five centers were included in the training set for the establishment of a diagnostic nomogram. Ten investigative parameters including clinical characteristics, body measurements and physical performance were used to derive the diagnostic nomogram. A total of 246 consecutive patients (47 with and 199 without sarcopenia) were included for validation of the diagnostic model. RESULTS: The average age of the enrolled patients was 60.4 ± 12.1 years, 59.8% were males and 90.5% received dialysis using an arteriovenous fistula. Overall, the sarcopenia rate was 16.4%. The training and validation sets showed no significant differences in sarcopenia rate (15.1% and 19.1%, respectively; P = .160). The nomogram derived from the training set for sarcopenia, which was based on only four features-age, sex, body weight and grip strength-achieved high C-indexes of 0.929 [95% confidence interval (CI) 0.904-0.953] and 0.955 (95% CI 0.931-0.979) in the training and external sets, respectively, and had a well-fitted calibration curve. The cut-off value was 0.725, with a sensitivity of 0.909 and a specificity of 0.816. The nomogram accurately diagnosed sarcopenia with fewer variables and more simplified diagnostic procedures. CONCLUSIONS: The nomogram had a good diagnostic capability for sarcopenia in patients on HD and may be a convenient tool for clinical use.

Comparison of three nutritional screening tools for detecting sarcopenia in patients with maintenance hemodialysis.

Background: Malnutrition, dynapenia, and sarcopenia are prevalent conditions among patients with maintenance hemodialysis (MHD). They are related to numerous adverse health outcomes. The aim of this study was to compare the effect of three nutritional screening tools on predicting the risk of dynapenia and sarcopenia in patients with MHD. Methods: From July 2020 to April 2021, a total of 849 patients with MHD were enrolled at seven different healthcare facilities in Shanghai, China in this multi-center cross-sectional study. Geriatric nutritional risk index (GNRI), malnutrition inflammation score (MIS), and creatinine (Cr) index were used for nutritional assessment. The cutoff values of muscle mass and strength to define dynapenia, pre-sarcopenia, and sarcopenia were based on the consensus by the Asia Working Group of Sarcopenia in 2019. Results: Among 849, almost 60% were malnourished with the majority suffering from dynapenia (27.7%), followed by sarcopenia (22.7%), and pre-sarcopenia (6.2%).The area under the receiver-operating characteristic curve for GNRI was 0.722 [95% confidence interval (CI) = 0.684-0.760] and 0.723 (95% CI = 0.663-0.783) in predicting sarcopenia and pre-sarcopenia. The GNRI [odds ratio (OR) =6.28, 95% CI: 4.05-9.73], MIS (OR =1.91, 95% CI: 1.31-2.78), and the Cr index (OR =2.73, 95% CI: 1.71-4.34) were all significantly associated with the risk of sarcopenia. More importantly, the sarcopenia predictability of the GNRI appears greater than the MIS and Cr index, while MIS was similar to the Cr index. Similarly, the superiority of GNRI prediction was also found in pre-sarcopenia, but not in dynapenia. Conclusion: All the three nutritional screening tools were significantly associated with an increased risk of sarcopenia. The sarcopenia predictability of the GNRI was greater than the MIS and Cr index.

Comparative Analysis of Efficacy and Prognosis of Hemodialysis and Peritoneal Dialysis for End-Stage Renal Disease: A Meta-analysis.

Objective: This meta-analysis is aimed at systematically assessing the efficacy and prognosis of hemodialysis (HD) and peritoneal dialysis (PD) in the treatment of end-stage renal disease (ESRD). Methods: China National Knowledge Infrastructure, VIP, SinoMed, Cochrane Library, PubMed, and Embase databases were searched for relevant studies to evaluate the two different dialysis methods for ESRD. The search time was set from 2010 to 2021. Meta-analysis was performed using Stata16.0. The treatment group received PD, while the control group was given HD. Results: Out of 317 articles initially retrieved, 14 studies were finally included in our meta-analysis. The analysis results showed that there was no marked difference in the 1-year survival rate between the two groups (RR = 1.05; 95% CI: 1.00, 1.10; P > 0.05), but the incidence rate of adverse reactions in the treatment group was significantly lower than that in the control group (RR = 0.51; 95% CI: 0.37, 0.70; P < 0.05). In addition, PD and HD treatments caused significant decreases in serum creatinine levels (PD, SMD = -2.91; 95% CI: -3.79, -2.04; P < 0.05; HD, SMD = -3.09; 95% CI: -4.01, -2.16; P < 0.05) and blood urea nitrogen levels (PD, SMD = -2.54, 95% CI: -3.37, -1.72, P < 0.05; HD, SMD = -2.62, 95% CI: -3.47, -1.77, P < 0.05); however, there was no significant statistical difference in posttreatment levels of serum creatinine and blood urea nitrogen between the two groups. Compared with the control group, the hemoglobin (SMD = 0.56, 95% CI: 0.07, 1.06; P < 0.05) and serum albumin (SMD = 1.11, 95% CI: 0.46, 1.76, P < 0.05) levels were significantly increased in the treatment group after treatment. Conclusion: In summary, both PD and HD can improve renal function in uremic patients, but PD is superior to HD in reducing the incidence of adverse reactions, improving the nutritional status, and therefore improving the quality of life of patients.

Depression of caregivers is significantly associated with depression and hospitalization of hemodialysis patients.

INTRODUCTION: The current study aims to elucidate the relationships of depression of caregivers with depression of hemodialysis patients and determine predictors of hospitalization of hemodialysis patients. METHODS: The single-center, cross-sectional study consisted of 200 pairs of eligible hemodialysis patients and caregivers from January 2019 to January 2020. Depression was evaluated using Hospital Anxiety and Depression Scale (HADS) questionnaire. FINDINGS: There were 89 hemodialysis patients with depression (44.5%) and 74 caregivers with depression (37.0%). In multi-variable logistic regression analysis, the hemodialysis patients with depressed caregivers were at increased risk of depression after adjusting for potential confounders (OR = 2.36, p = 0.04). Depression of hemodialysis patients (ß = 0.51, p = 0.00) and depression of caregivers (ß = 0.36, p = 0.04) were predictors of hospitalization of hemodialysis patients. DISCUSSION: Depression was prevalent among hemodialysis patients and their caregivers. Depression of caregivers was a risk factor for depression and hospitalization of hemodialysis patients. Implementation of appropriate screening programs and specific interventions for depression of hemodialysis patients and their caregivers is required.

Comparison of mesenchymal stromal cells from peritoneal dialysis effluent with those from umbilical cords: characteristics and therapeutic effects on chronic peritoneal dialysis in uremic rats.

BACKGROUND: A long-term of peritoneal dialysis (PD) using a hypertonic PD solution (PDS) leads to patient's peritoneal membrane (PM) injury, resulting in ultrafiltration failure (UFF) and PD drop-out. Our previous study shows that PD effluent-derived mesenchymal stromal cells (pMSCs) prevent the PM injury in normal rats after repeated exposure of the peritoneal cavity to a PDS. This study was designed to compare the cytoprotection between pMSCs and umbilical cord-derived MSCs (UC-MSCs) in the treatment of both PM and kidney injury in uremic rats with chronic PD. METHODS: 5/6 nephrectomized (5/6Nx) Sprague Dawley rats were intraperitoneally (IP) injected Dianeal (4.25% dextrose, 10 mL/rat/day) and were treated with pMSCs or umbilical cord (UC)-MSCs (approximately 2 × 106/rat/week, IP). Ultrafiltration was determined by IP injection of 30 mL of Dianeal (4.25% dextrose) with 1.5-h dewell time, and kidney failure by serum creatinine (SCr) and blood urea nitrogen (BUN). The structure of the PM and kidneys was assessed using histology. Gene expression was examined using quantitative reverse transcription PCR, and protein levels using flow cytometric and Western blot analyses. RESULTS: We showed a slight difference in the morphology between pMSCs and UC-MSCs in plastic dishes, and significantly higher expression levels of stemness-related genes (NANOG, OCT4, SOX2, CCNA2, RAD21, and EXO1) and MSCs surface markers (CD29, CD44, CD90 and CD105) in UC-MSCs than those in pMSCs, but no difference in the differentiation to chondrocytes, osteocytes or adipocytes. pMSC treatment was more effective than UC-MSCs in the protection of the MP and remnant kidneys in 5/6Nx rats from PDS-induced injury, which was associated with higher resistance of pMSCs than UC-MSCs to uremic toxins in culture, and more reduction of peritoneal mesothelial cell death by the secretome from pMSCs than from UC-MSCs in response to PDS exposure. The secretome from both pMSCs and UC-MSCs similarly inactivated NOS2 in activated THP1 cells. CONCLUSIONS: As compared to UC-MSCs, pMSCs may more potently prevent PDS-induced PM and remnant kidney injury in this uremic rat model of chronic PD, suggesting that autotransplantation of ex vivo-expanded pMSCs may become a promising therapy for UFF and deterioration of remnant kidney function in PD patients.

Correlation of Serum Adropin Levels with Risk Factors of Cardiovascular Disease in Hemodialysis Patients.

Background: Many preclinical studies have shown that adropin has physiological effects such as regulating glucose, lipid, and energy metabolism, protecting endothelial cells and antiatherosclerosis. Our aim is to explore whether adropin is correlated with risk factors of cardiovascular disease (CVD) in hemodialysis (HD) patients. Methods: We recruited 170 HD patients and 120 healthy controls. The serum adropin concentration and clinical characteristics were measured. Results: The serum adropin concentration in HD patients was significantly lower than that in healthy controls and which in HD patients with CVD or diabetes mellitus (DM) was significantly lower than that in patients without CVD or DM. The correlation analysis showed that serum adropin levels were correlated negatively with Age, CVD history, DM history, C-reactive protein, type B natriuretic peptide, phosphorus, intact parathyroid hormone, carotid artery plaque amount and carotid intima-media thickness (CIMT), left ventricular septal thickness (LVSTd), and left ventricular posterior wall thickness, whereas it was correlated positively with albumin, hemoglobin, serum creatinine and Kt/V, and ejection fraction value. Partial correlation analysis verified that serum adropin levels were correlated negatively with CIMT, and multiple linear regression analysis revealed that low serum adropin levels may be one independent predictors of CIMT. However, the partial correlation analysis and multiple linear regression analysis did not identify the significant correlation between serum adropin levels and LVSTd. Conclusions: Our study revealed that serum adropin level is significantly correlated with risk factors of CVD and low serum adropin levels may be a potential predictor of CVD in HD patients.

Comparison of Surface-Enhanced Raman Scattering Properties of Serum and Urine for the Detection of Chronic Kidney Disease in Patients.

Chronic kidney disease (CKD) affects more than 10% of the global population and is associated with significant morbidity and mortality. In most cases, this disease is developed silently, and it can progress to the end-stage renal failure. Therefore, early detection becomes critical for initiating effective interventions. Routine diagnosis of CKD requires both blood test and urinalyses in a clinical laboratory, which are time-consuming and have low sensitivity and specificity. Surface-enhanced Raman scattering (SERS) is an emerging method for rapidly assessing kidney function or injury. This study was designed to compare the differences between the SERS properties of the serum and urine for easy and simple detection of CKD. Enrolled for this study were 126 CKD patients (Stages 2-5) and 97 healthy individuals. SERS spectra of both the serum and urine samples were acquired using a Raman spectrometer (785 nm excitation). The correlation of chemical parameters of kidney function with the spectra was examined using prinicpal component analysis (PCA) combined with linear discriminant analysis (LDA) and partial least squares (PLS) analysis. Here, we showed that CKD was discriminated from non-CKD controls using PCA-LDA with a sensitivity of 74.6% and a specificity of 93.8% for the serum spectra, and 78.0% and 86.0 % for the urine spectra. The integration area under the receiver operating characteristic curve was 0.937 ± 0.015 (p < 0.0001) for the serum and 0.886 ± 0.025 (p < 0.0001) for the urine. The different stages of CKD were separated with the accuracy of 78.0% and 75.4% by the serum and urine spectra, respectively. PLS prediction (R2) of the serum spectra was 0.8540 for the serum urea (p < 0.001), 0.8536 for the serum creatinine (p < 0.001), 0.7500 for the estimated glomerular filtration rate (eGFR) (p < 0.001), whereas the prediction (R2) of urine spectra was 0.7335 for the urine urea (p < 0.001), 0.7901 for the urine creatinine (p < 0.001), 0.4644 for the eGFR (p < 0.001) and 0.6579 for the urine microalbumin (p < 0.001). In conclusion, the accuracy of associations between SERS findings of the serum and urine samples with clinical conclusions of CKD diagnosis in this limited number of patients is similar, suggesting that SERS may be used as a rapid and easy-to-use method for early screening of CKD, which however needs further evaluation in a large cohort study.

Protection of the Peritoneal Membrane by Peritoneal Dialysis Effluent-Derived Mesenchymal Stromal Cells in a Rat Model of Chronic Peritoneal Dialysis.

Peritoneal dialysis (PD) is a renal replacement option for patients with end-stage renal disease. However, a long-term exposure to hypertonic PD solutions leads to peritoneal membrane (PM) injury, resulting in ultrafiltration (UF) failure. This study was designed to primarily evaluate efficacy of PD effluent-derived mesenchymal stromal cells (pMSCs) in the prevention of PM injury in rats. The pMSCs were isolated from PD effluent. Male Wistar rats received daily intraperitoneal (IP) injection of 10 mL of Dianeal (4.25% dextrose) and were treated with pMSCs (1.2-1.5 × 106/rat/wk, IP). UF was determined by IP injection of 30 mL of Dianeal (4.25% dextrose) with dwell time of 1.5 h, and PM injury was examined by histology. Apoptosis was quantitated by using flow cytometric analysis, and gene expression by using the PCR array and Western blot. Here, we showed that as compared to naive control, daily IP injection of the Dianeal PD solution for 6 weeks without pMSC treatment significantly reduced UF, which was associated with an increase in both PM thickness and blood vessel, while pMSC treatment prevented the UF loss and reduced PM injury and blood vessels. In vitro incubation with pMSC-conditioned medium prevented cell death in cultured human peritoneal mesothelial cells (HPMCs) and downregulated proinflammatory (i.e., CXCL6, NOS2, IL1RN, CCL5, and NR3C1) while upregulated anti-inflammatory (i.e., CCR1, CCR4, IL9, and IL-10) gene expression in activated THP1 cells. In conclusion, pMSCs prevent bioincompatible PD solution-induced PM injury and UF decline, suggesting that infusing back ex vivo-expanded pMSCs intraperitoneally may have therapeutic potential for reduction of UF failure in PD patients.

Targeting Src attenuates peritoneal fibrosis and inhibits the epithelial to mesenchymal transition.

Src has been reported to mediate tissue fibrosis in several organs, but its role in peritoneal fibrosis remains unknown. In this study, we evaluated the therapeutic effect of KX2-391, a highly selective inhibitor of Src, on the development of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, as indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts. This was accompanied by time-dependent phosphorylation of Src at tyrosine 416. Administration of KX2-391 attenuated peritoneal fibrosis and abrogated increased phosphorylation of Src and multiple signaling molecules associated with tissue fibrosis, including epidermal growth factor receptor, Akt, Signal transducer and activator of transcription 3 and nuclear factor-κB in the injured peritoneum. KX2-391 also inhibited the production of proinflammatory cytokines and the infiltration of macrophages into the injured peritoneum. In cultured human peritoneal mesothelial cells, inhibition of Src by KX2-391 or siRNA resulted in decreased expression of α-smooth muscle actin (α-SMA), fibronectin and collagen I, the hallmarks of epithelial to mesenchymal transition. These results suggest that Src is a critical mediator of peritoneal fibrosis and the epithelial to mesenchymal transition. Thus, Src could be a potential therapeutic target in the treatment of peritoneal fibrosis.

Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease.

Nintedanib (BIBF1120) is a triple kinase inhibitor of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptor (VEGFR), and Src family kinase, which has recently been approved by FDA to treat idiopathic pulmonary fibrosis. Whether it affects renal fibrosis remains unknown. Here, we demonstrated that administration of nintedanib immediately or 3 days after unilateral ureteral obstruction (UUO) injury and with folic acid (FA) injection attenuated renal fibrosis and inhibited activation of renal interstitial fibroblasts. Delayed administration of nintedanib also partially reversed established renal fibrosis. Treatment with nintedanib blocked UUO-induced phosphorylation of PDGFRß, FGFR1, FGFR2, VEGFR2, and several Src family kinases including Src, Lck, Lyn as well as activation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB (NF-κB), and Smad-3 in the kidney. Furthermore, nintedanib inhibited UUO-elicited renal proinflammatory cytokine expression and macrophage infiltration. These data indicate that nintedanib is a potent anti-fibrotic agent in the kidney and may hold therapeutic potential as a treatment of chronic fibrotic kidney disease.

Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment.

Novel compound, organic cation transporter 3 detection agent and organic cation transporter 3 activity inhibitor, WO2015002150 A1: a patent evaluation.

Increasing pharmacological studies have demonstrated that organic cation transporter 3 (OCT3) plays an important role in controlling the extracellular concentrations of released monoamine neurotransmitter, suggesting that OCT3 might be a promising target in the treatment of depression. As a consequence, compounds showing inhibitory effects on the function of OCT3 have the potential for depression treatment. The current patent WO2015002150 A1 described the synthesis of 59 novel guanidine derivatives. All investigated compounds exhibited significant inhibitory effects (41.9-88.2%) on human OCT3 activity at 30 µM, using human OCT3-transfected human embryonic kidney 293 cell. Concentration-response curves (IC50 values) were determined for seven compounds with higher inhibition potency from the initial screening. IC50 values ranged from 1.9 to 24 µM. In addition, the concentration of these compound in aqueous solution with artificial membranes containing human OCT3 protein was measured. The concentration of compound 6 (SR-2045) was significantly reduced in the presence of human OCT3. Therefore, these compounds have the potential to be further developed as novel antidepressant and human OCT3 detection agent. Future investigations are needed to study the pharmacokinetic and pharmacological properties of these compounds and potential interaction with other transporters.

Association of peroxisome proliferator-activated receptorγ gene Pro12Ala and C161T polymorphisms with cardiovascular risk factors in maintenance hemodialysis patients.

The Pro12Ala and C161T polymorphisms in peroxisome proliferator-activated receptor γ (PPARγ) have been shown to be associated with carotid artery atherosclerosis. It remains unclear whether these two polymorphisms are associated with risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Therefore, the PPARγ genotypes in 99 HD patients and 149 controls were determined, and clinical characteristics among the different genotypes were compared. We found that the frequency of the Pro12Ala and C161T polymorphisms in HD patients was similar to that in healthy controls, but C161T polymorphism and T allele frequencies in HD patients with CVD were lower than that in HD patients without CVD. Carotid artery plaque (CAP) and carotid intima-media thickness (CIMT) in HD patients with CT + TT or Pro12Ala genotypes were also less than that in patients with CCor Pro12Pro genotypes, respectively. HD patients with CT + TT genotype had lower serum C reactive protein (CRP) levels, as well as higher triceps skin fold (TSF) thickness, mid arm circumference (MAC) and mean mid arm circumference (MMAC) than HD patients with CC genotype (P < 0.05). Moreover, CIMT of the Pro12Ala-CT161 subgroup was less than the Pro12Pro-CC161 and Pro12Pro-CT161 subgroup, and, CAP amounts of the Pro12Ala-CT161 subgroup was less than the Pro12Pro-CC161 subgroup. Our results indicate that the Pro12Ala and C161T polymorphisms were associated with some important risk factors for CVD in HD patients in the Han Chinese population.