Efficacy of liraglutide in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of liraglutide to treat type 2 diabetic nephropathy (T2DN) remains controversial. Thus, we conducted this meta-analysis to systematically evaluate the clinical effect of liraglutide on T2DN patients. METHODS: Eight databases (PubMed, Web of Science, the Cochrane Library, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, China Science and Technology Journal Database, and China Biology Medicine Database (CBM)) were searched for published articles to evaluate the clinical efficacy of liraglutide in subjects with T2DN. The Revman 5.3 and Stata 13 software were used for analyses and plotting. RESULTS: A total of 18 randomized controlled trials (RCTs) with 1580 diabetic nephropathy patients were screened. We found that the levels of UACR, Scr, Cysc were lower in the experimental group of T2DN patients treated with liraglutide than in the control group intervened without liraglutide. Liraglutide also reduced the levels of blood glucose (including FBG, PBG, and HbA1c), body mass index (BMI), and anti-inflammatory indicators (TNF-α, IL-6). However, there was no significant difference in BUN and eGFR between the experimental group and the control group. CONCLUSIONS: Liraglutide reduced the levels of Blood Glucose, BMI, renal outcome indicators, and serum inflammatory factors of patients with T2DN, suggesting the beneficial effects of liraglutide on renal function.

Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy.

Our intent is to examine the predictive role of Charlson comorbidity index (CCI) on mortality of patients with type 2 diabetic nephropathy (DN). Based on the CCI score, the severity of comorbidity was categorized into three grades: mild, with CCI scores of 1-2; moderate, with CCI scores of 3-4; and severe, with CCI scores ≥5. Factors influencing mortality and differences between groups stratified by CCI were determined by logistical regression analysis and one-way analysis of variance (ANOVA). The impact of CCI on mortality was assessed by the Kaplan-Meier analysis. A total of 533 patients with type 2 DN were enrolled in this study, all of them had comorbidity (CCI score >1), and 44.7% (238/533) died. The mortality increased with CCI scores: 21.0% (50/238) patients with CCI scores of 1-2, 56.7% (135/238) patients with CCI scores of 3-4, and 22.3% (53/238) patients with CCI scores ≥5. Logistical regression analysis showed that CCI scores, hemoglobin, and serum albumin were the potential predictors of mortality (P<0.05). One-way ANOVA analysis showed that DN patients with higher CCI scores had lower levels of hemoglobulin, higher levels of serum creatinine, and higher mortality rates than those with lower CCI scores. The Kaplan-Meier curves showed that survival time decreased when the CCI scores and mortality rates went up. In conclusion, CCI provides a simple, readily applicable, and valid method for classifying comorbidities and predicting the mortality of type 2 DN. An increased awareness of the potential comorbidities in type 2 DN patients may provide insights into this complicated disease and improve the outcomes by identifying and treating patients earlier and more effectively.

Spontaneous retroperitoneal hemorrhage after hemodialysis involving anticoagulant agents.

In this paper, we described the symptoms and treatment of a patient with diabetic nephropathy accompanied by spontaneous retroperitoneal hemorrhage after hemodialysis. An elderly female patient with diabetic nephropathy presented with severe pain, numbness, and an increasing swelling in the left hip and left thigh after six sessions of hemodialysis involving the use of an antiplatelet drug and an anticoagulant agent. Her hemoglobin decreased to 46 g/L. An abdominal ultrasound showed a hematoma in the left retroperitoneal space, and computed tomography (CT) findings revealed a 6 cm × 8 cm × 10 cm hematoma in the left psoas muscle. After aggressive supportive therapy [the administration of packed red blood cell transfusion, carbazochrome sodium sulfonate injection, and continuous venovenous hemofiltration (CVVH)], the patient's vital signs stabilized and her hemoglobin increased to 86 g/L. Repeat CT showed that the hematoma had been partially absorbed after two weeks. Eventually, the patient was discharged with stable vital signs. Physicians should be aware of the possibility of spontaneous retroperitoneal hemorrhage, particularly in patients with diabetic nephropathy undergoing hemodialysis involving the use of anticoagulant agents.

[Influence of mannose binding lectin to expression of TGF-beta1 and NF-kappaB in high concentration of glucose cultured human renal glomerular endothelial cells].

OBJECTIVE: To investigate the effect of mannose binding lectin (MBL) complement pathway on expression of transforming growth factor-beta1 (TGF-beta1) and NF-kappaB in cultured human renal glomerular endothelial cells (HRGECs) stimulated by high concentration of glucose. METHODS: Human glomerular endothelial cells in culture were randomly divided into 5 groups according to different managements: normal concentration of glucose as controlled group, MBL + normal concentration of glucose group, high concentration of glucose, MBL + high glucose and MBL + high glucose + MBL blocker respectively. Flow cytometry was used to detect the depositions of MBL and C3 on the surfaces of HRGECs. Real-time PCR method was used to detect the mRNA levels of TGF-beta1. Human TGF-beta1 ELISA kit was used to detect the concentration of TGF-beta1 in supernatant fluid. ESMA was used to detect the activity of NF-kappaB in HRGECs. RESULTS: Compared with the normal glucose group and high glucose group, the depositions of MBL, C3 were apparently increased in MBL + high glucose group (P < 0.05). Expression of TGF-beta1 were significantly higher (P < 0.05) in MBL + high concentration of glucose groups than the normal glucose group and the high concentration of glucose group. Compared with the high glucose group, the activity of NF-kappaB in HRGECs was apparently increased in MBL + high glucose group, which could be significantly downregulated by MBL blocking antibody. CONCLUSION: High concentration of glucose can increase the expression of TGF-beta1 of cultured human glomerular endothelial cells. At the same time, high glucose together with MBL can up regulate the expression of TGF-beta1 and the activity of NF-kappaB in HRGECs.

[Influence of high glucose and mannose binding lectin complement pathway activation to IL-6 and TNF-alpha's expression by human renal glomerular endothelial cells].

OBJECTIVE: To investigate the effect of high glucose and mannose binding lectin (MBL) complement pathway activation's effect on expression of Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-alpha) from human renal glomerular endothelial cells (HRGEC), to explore unknown pathogenesy of diabetic nephropathy. METHODS: Normal HRGEC was divided randomly into normal glucose group(5 mmol/L D-glucose), manicol group (5 mmol/L D-glucose+25 mmol/L manicol) and high glucose group (30 mmol/L D-glucose). Real-time PCR was used to detect IL-6 and TNF-alpha mRNA expression in each group, Euzymelinked Immunosorbent Assay (ELISA) was performed to examine the protein expression of IL-6 and TNF-alpha in supernatant after 24 hours' culture. HRGEC was then randomly divided into two groups: single high glucose group and high glucose + MBL group. After 24 hours' culture with 30 mmol/L D-glucose, 30% MBL deficiency human serum was added into two groups, 1 microg/mL MBL was only added into high glucose + MBL group, continued the culturation for another 4 hours. Flow cytometry and immunofluorescence technique were applied to evaluate MBL, C3 and membrane attacks complex (MAC) deposition on cell surface respectively. Real-time PCR and ELISA were performed to examine mRNA and protein expression of both IL-6 and TNF-alpha in each group. RESULTS: Compared with normal glucose group and manicol group, the mRNA and protein expression of IL-6 and TNF-alpha in high glucose group were increased (P < 0.05). Flow cytometry confirmed obvious MBL and C3 co-deposition and Immunofluorescence confirmed obvious MAC deposition on cell surface in high glucose+ MBL group. Compared with single high glucose group, the mRNA and protein expression of IL-6 and TNF-alpha in high glucose+ MBL group were significantly higher (P < 0.05). CONCLUSION: High glucose can bring inflammatory factors' overexpression from cultured HRGEC; high glucose together with MBL can bring MBL complement pathway activation and inflammatory factors' overexpression, this indicates that the activation of MBL complement pathway may be a potential unknown pathogenesy of diabetic nephropathy and its proinflammatory status.

Effect of anaphylatoxin C3a, C5a on the tubular epithelial-myofibroblast transdifferentiation in vitro.

BACKGROUND: Tubulointerstitial renal fibrosis is the common end point of progressive kidney diseases, and tubular epithelial-myofibroblast transdifferentiation (TEMT) plays a key role in the progress of tubulointerstitial renal fibrosis. Anaphylatoxin C3a and C5a are identified as novel profibrotic factors in renal disease and as potential new therapeutic targets. The aim of this study was to investigate whether C3a, C5a can regulate TEMT by transforming growth factor-ß1 (TGF-ß)/connective tissue growth factor (CTGF) signaling pathway and the effects of C3a and C5a receptor antagonists (C3aRA and C5aRA) on C3a- and C5a-induced TEMT. METHODS: HK-2 cells were divided into C3a and C5a groups which were subdivided into four subgroups: control group, 10 ng/ml TGF-ß1 group, 50 nmol/L C3a group, 50 nmol/L C3a plus 1 µmol/L C3aRA group; control group, 10 ng/ml TGF-ß1 group, 50 nmol/L C5a group, 50 nmol/L C5a plus 2.5 µmol/L C5aRA group. TGF-ß1 receptor antagonist (TGF-ß1RA) 10 µg/ml was used to investigate the mechanism of C3a- and C5a-induced TEMT. Electron microscopy was used to observe the morphological changes. Immunocytochemistry staining, real-time PCR and Western blotting were used to detect the expressions of a smooth muscle actin (α-SMA), E-cadherin, Col-I, C3a receptor (C3aR), C5aR, CTGF and TGF-ß1. RESULTS: HK-2 cells cultured with C3a and C5a for 72 hours exhibited strong staining of α-SMA, lost the positive staining of E-cadherin, and showed a slightly spindle-like shape and loss of microvilli on the cell surface. The expressions of α-SMA, E-cadherin, Col-I, C3aR, C5aR, TGF-ß1 and CTGF in C3a- and C5a-treated groups were higher than normal control group (P < 0.05). C3aRA and C5aRA inhibited the expressions of α-SMA, Col-I, C3aR, C5aR, and up-regulated the expression of E-cadherin (P < 0.05). TGF-ß1 and CTGF mRNA expressions induced by C3a and C5a were partly blocked by TGF-ß1RA (P < 0.05). CONCLUSION: C3a and C5a can induce TEMT via the up-regulations of C3aR and C5aR mRNA and the activation of TGF-ß1/CTGF signaling pathway in vitro.

[Effects of high glucose on expression of core binding factor alpha1 and osteocalcin in vascular smooth muscle cells].

OBJECTIVE: To investigate the effects of high glucose on expression of core binding factor alpha1 (cbfalpha-1) and osteocalcin (OC) in vascular smooth muscle cells (VSMCs), and discuss the mechanism of small vessels calcification induced by high glucose (GS) in vitro. METHODS: The primary cultured VSMCs from rats' aortic segments were divided into three groups, including normal control group (5 mmol/L D-glucose), high glucose group (25 mmol/L D-glucose) and mannitol group (5 mmol/L D-glucose plus 25 mmol/L mannitol). We measured quantitatively the calcium deposition in VSMCs and investigated the calcium extent of VSMCs by alizarin red stain in each group. The mRNA levels of cbfalpha-1 and OC were measured by real-time PCR, and the protein expression levels of cbfalpha-1 and OC were examined by Western blot. The activity of alkaline phosphatase was measured by alkaline phosphatase activity testing kit, and the protein level of alpha-smooth muscle actin (a-SMA) was detected by immunohistochemistry. RESULTS: When compared with the normal group and mannitol group, the high glucose group showed that the calcium deposition and calcium extent of VSMCs increased obviously, the mRNA and protein levels of cbfalpha-1 and OC also increased significantly (P < 0.05), while the protein level of alpha-SMA decreased (P < 0.05), which were in a dose-dependent manner. The level of alkaline phosphatase activity of VSMCs was approximately doubled in high glucose group. CONCLUSION: The mechanism of high glucose induced calcification in VSMCs may be due to the increased expression of cbfalpha-1 and OC. High glucose decrease the expression of alpha-SMA in VSMCs, which could induce the transdifferentiation from RVSMCs to osteoblast-like cells.