Meng-jie Huang

Blood coagulation system in patients with chronic kidney disease: a prospective observational study

Objectives Thromboembolic events are the major factor affecting the prognosis of patients with chronic kidney disease (CKD). Haemostatic alterations are possible causes of these complications, but their roles remain poorly characterised. In the prospective observational study, we investigated the entire coagulation process in patients with CKD to elucidate the mechanisms of their high thromboembolic risk. Methods A total of 95 patients with CKD and 20 healthy controls who met the inclusion criteria were consecutively recruited from September 2015 to March 2016. The platelet count, platelet aggregation, von Willebrand factor antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), fibrinogen, factor V (FV), FVII, FVIII, antithrombin III, protein C, protein S, D-dimer, standard coagulation tests and thromboelastography were measured in patients with CKD and controls. Associations between the estimated glomerular filtration rate (eGFR) and haemostatic biomarkers were tested using multivariable linear regression. Results The adjusted and unadjusted levels of vWF:Ag, vWF:RCo, fibrinogen, FVII, FVIII and D-dimer were significantly higher in patients with CKD than that in the healthy controls, and were elevated with CKD progression. However, after adjustment for baseline differences, platelet aggregation and thromboelastography parameters showed no significant differences between patients with CKD and healthy controls. In the correlation analysis, vWF:Ag, vWF:RCo and FVIII were inversely associated with eGFR (r=−0.359, p<0.001; r=−0.391, p<0.001; r=−0.327, p<0.001, respectively). During the 1-year of follow-up, one cardiovascular event occurred in patients with CKD 5 stage, whereas no thromboembolic event occurred in the CKD 3 and 4 and control groups. Conclusions Patients with CKD are characterised by endothelial dysfunction and increased coagulation, especially FVIII activity. The abnormal haemostatic profiles may contribute to the elevated risk of thrombotic events but further longer-term study with large samples is still required to more precisely determine the relationship between the elevation of procoagulant factors and clinical outcomes.

Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism

Background Contrast-induced nephropathy (CIN) refers to acute renal damage that occurs after the use of contrast agents. This study investigated the renal protective effect of probucol in a rat model of contrast-induced nephropathy and the mechanism of its effect. Material/Methods Twenty-eight Wistar rats were randomly divided into the control group, model group, N-acetylcysteine(NAC) group, and probucol group. We used a rat model of iopromide-induced CIN. One day prior to modeling, the rats received gavage. At 24 h after the modeling, blood biochemistry and urine protein were assessed. Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in renal tissue. Kidney sections were created for histopathological examination. Results The model group of rats showed significantly elevated levels of blood creatinine, urea nitrogen, 24-h urine protein, histopathological scores, and parameters of oxidative stress (P<0.05). Both the NAC and probucol groups demonstrated significantly lower Scr, BUN, and urine protein levels compared to the model group (P<0.05), with no significant difference between these 2 groups. The NAC group and the probucol group had significantly lower MDA and higher SOD than the model group at 24 h after modeling (P<0.05). The 8-OHdG-positive tubule of the probucol group and NAC group were significantly lower than those of the model group (p=0.046, P=0.0008), with significant difference between these 2 groups (P=0.024). Conclusions Probucol can effectively reduce kidney damage caused by contrast agent. The underlying mechanism may be that probucol accelerates the recovery of renal function and renal pathology by reducing local renal oxidative stress.

Decreased Serum C3 Levels in Immunoglobulin A (IgA) Nephropathy with Chronic Kidney Disease: A Propensity Score Matching Study

Background The effects of low serum C3 levels and the activation of the complement system on the development and the prognosis of IgAN are unclear. The present study aimed to determine whether decreased levels of complement C3 influence the prognosis of IgAN patients with chronic kidney disease. Material/Methods We enrolled a total of 1564 patients with primary IgAN diagnosed by renal biopsy at the Chinese PLA General Hospital from January 2011 to March 2015. The endpoint was end-stage renal disease (ESRD) or a doubling of the baseline serum creatinine (D-SCr) level. All patients were using 1: 1 propensity score matching (PSM), and the baseline values were not significantly different between these 2 groups (P>0.05). Results During a follow-up period, 14 patients in the group with decreased C3 levels reached the endpoint, with 12 patients with normal C3 levels. There was no significant difference between the 2 groups in achieving D-SCr or ESRD (P=0.676). In multivariate Cox analysis, adjusted for demographic and laboratory examination, the risk of reaching the endpoint was comparable in the 2 groups (HR, 0.70; 95% CI, 0.27–1.78; P=0.449;). Furthermore, the risk of reaching ESRD (HR, 0.83; 95% CI, 0.25–2.75; P=0.757) and D-SCr (HR, 1.45; 95% CI, 0.20–10.60; P=0.718) did not differ between the 2 groups. Conclusions Decreased serum C3 levels in IgA nephropathy with chronic kidney disease did not play a decisive role in renal progression.

Treatment with irbesatan may improve slit diaphragm alterations in rats with adriamycin-induced nephropathy

Objective: The study aimed to evaluate the effects of oral administration of irbesartan in adriamycin-induced nephropathy considering laboratory changes, kidney histology, and expression of proteins related to slit diaphragm and cytoskeleton of the podocyte. Methods: The animals were divided into control, model, methylprednisolone (MP), and irbesartan groups. The 24-hour urinary protein and biochemical indicators were determined, and renal pathological changes were observed. The mRNA and protein expression of nephrin, podocin, CD2-associated protein (CD2AP), and desmin in the kidney tissue were analyzed. Results: The urinary protein excretion levels in the MP and irbesartan groups were lower than those in the model group (p<0.01). Electron microscopy showed that fusion of the glomerular foot processes of the rats in the irbesartan group was significantly reduced. The mRNA and protein expression levels of nephrin and podocin in the renal tissue in the MP and irbesartan groups were up-regulated compared with the model group (p<0.05), whereas the mRNA and protein expression levels of CD2AP and desmin were significantly down-regulated (p<0.01). Conclusions: For rats with adriamycin-induced nephropathy, irbesartan could significantly reduce proteinuria. As a possible mechanism, irbesartan may improve the slit diaphragm protein of the glomerular podocyte and stabilize the cytoskeleton of the podocyte.

Mechanisms of hypercoagulability in nephrotic syndrome associated with membranous nephropathy as assessed by thromboelastography

INTRODUCTION Thromboelastography (TEG) was performed to assess potential hypercoagulability in Nephrotic syndrome (NS) patients with membranous nephropathy (MN) and to explore correlated factors contributing to hypercoagulable status MATERIALS AND METHODS 101 MN patients, 61 minimal change disease (MCD) patients and 20 healthy controls met the inclusion criteria. The MN and MCD patients were stratified into two layers according to serum albumin (SALB) levels (<20g/l or 20-30g/l). Primary outcome measures included reaction time (R), α-angle, maximum amplitude (MA) and coagulation index (CI). TEG parameters of four patient subgroups were analyzed in factorial designed ANOVA with factors disease and SALB. RESULTS By linear regression analysis, TEG parameters in MN patients correlated with SALB (P<0.01) and the ANOVA for factorial designed data confirmed that the main effects of factors SALB and disease were both statistically significant. Besides, comparison between control group and patient subgroups showed that R value in normal controls was significantly higher than that in MN subgroups, but was not statistically different from that in MCD subgroups. NS patients (MCD, MN) had significantly higherα-angle, MA and CI values than healthy controls (p<0.05). CONCLUSIONS MN patients tend to be more hypercoagulable than normal and MCD patients. Hypercoagulability in MN patients involves the whole thrombotic processes acceleration (activated intrinsic pathway, fibrinogen, platelet function and fibrin-platelet interaction), whereas hypercoagulable state in MCD patients may be that the coagulation factors are not fully activated. Greater efforts should be made to prevent hypercoagulability especially for MN patients with severe hypoalbuminemia.

Albuminuria and Endothelial Dysfunction in Patients with Non-Diabetic Chronic Kidney Disease.

Background Albuminuria has been associated with cardiovascular events, but whether such an association can be explained by endothelial dysfunction is not fully understood. In this study, we examined the relationship between the urine albumin-to-creatinine ratio (UACR) and biomarkers of endothelial function in patients with chronic kidney disease (CKD). Material/Methods The cross-sectional associations of renal dysfunction and UACR with procoagulant and inflammatory factors were evaluated for 151 consecutive CKD (stage 3–5) patients. Subjects were grouped by UACR (≤300 mg/g or >300 mg/g) and estimated glomerular filtration rate (eGFR) (30≤ eGFR <60, 15≤ eGFR <30, or eGFR <15 ml/min per 1.73 m2). Results A higher UACR level was associated with an increase in von Willebrand factor antigen (vWF: Ag) levels, vWF activity, factor VIII, interleukin-2, and log (interleukin-6), even after adjustment for risk factors. Linear regression analysis indicated that for every 88.5 mg/g increase in UACR, the vWF activity and factor VIII were elevated by 8.3% and 6.3%, respectively. The factorial design ANOVA data showed no statistically significant interaction between UACR and CKD stage with procoagulant and inflammatory factors. Conclusions Our study shows an eGFR-independent association of higher UACR with elevations in markers of endothelial dysfunction and inflammatory factors in CKD patients.

Impact of acute kidney injury on coagulation in adult minimal change nephropathy.

AbstractA hypercoagulable state exists in patients with nephrotic syndrome (NS), which more easily leads to venous thromboembolism (VTE). However, whether acute kidney injury (AKI), a common complication of NS, affects the hypercoagulable state and VTE has rarely been elucidated. In this study, we aimed to explore coagulation changes and analyze relevant influencing factors in NS-AKI patients.A total of 269 consecutive NS patients with minimal change disease (MCD) between 2011 and 2016 were included in this observational study. Ninety-one cases were in the AKI group and 178 cases in the non-AKI group. The 1:1 propensity score matching (PSM) method was applied to match the baseline information. The coagulation biomarkers were compared, and the thrombosis events were recorded. Linear correlation was performed to detect any relation between D-dimer and clinical data.The PSM method gave matched pairs of 88 MCD patients with AKI and non-AKI patients, resulting in no differences in baseline information. The D-dimer, fibrinogen, and thromboelastography parameters maximum amplitude (MA), G values of the MCD-AKI patients were significantly higher than the levels of the MCD patients without AKI (D-dimer: 1.8 [1.0, 3.3] vs 1.1 [0.6, 1.7] mg/L, P < 0.001; fibrinogen: 7.0±2.0 vs 6.5 ± 1.4 g/L, P = 0.036; MA: 74.6 ± 5.0 vs 70.5 ± 5.3 mm, P = 0.020; G: 15.7 ± 5.3 vs 12.5 ± 3.3, P = 0.034). For the MCD patients, the serum creatinine, white blood cell count, and interleukin-6 levels in the patients with D-dimers >1 mg/L were significantly higher than those of patients with D-dimers ⩽1 mg/L. The correlation analysis showed that the D-dimer level was correlated with serum creatinine, white blood cell count, and interleukin-6 (r = 0.410, P =  < 0.001; r = 0.248, P =  < 0.001; r = 0.306, P =  < 0.001, respectively). Five deep vein thrombosis events occurred in the AKI group and 1 pulmonary embolism event occurred in the non-AKI group after adjusting the propensity score value. AKI appeared to have an association with higher incidence of VTE, but the difference was not statistically significant (RR: 4.9, 95% CI: 0.6–42.7, P = 0.154).The MCD-NS patients complicated with AKI had a more severe hypercoagulable state, which might be associated with the active inflammation of AKI that mediated activation of the coagulation system.

The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission

The accumulation of uremic toxins in chronic kidney disease (CKD) induces inflammation, oxidative stress and endothelial dysfunction, which is a key step in atherosclerosis. Accumulating evidence indicates increased mitochondrial fission is a contributing mechanism for impaired endothelial function. Hippurate, a uremic toxin, has been reported to be involved in cardiovascular diseases. Here, we assessed the endothelial toxicity of hippurate and the contribution of altered mitochondrial dynamics to hippurate-induced endothelial dysfunction. Treatment of human aortic endothelial cells with hippurate reduced the expression of endothelial nitric oxide synthase (eNOS) and increased the expression of intercellular cell adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF). The mechanisms of hippurate-induced endothelial dysfunction in vitro depended on the activation of Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and overproduction of mitochondrial reactive oxygen species (mitoROS). In a rat model in which CKD was induced by 5/6 nephrectomy (CKD rat), we observed increased oxidative stress, impaired endothelium-dependent vasodilation, and elevated soluble biomarkers of endothelial dysfunction (ICAM-1 and vWF). Similarly, endothelial dysfunction was identified in healthy rats treated with disease-relevant concentrations of hippurate. In aortas of CKD rats and hippurate-treated rats, we observed an increase in Drp1 protein levels and mitochondrial fission. Inhibition of Drp1 improved endothelial function in both rat models. These results indicate that hippurate, by itself, can cause endothelial dysfunction. Increased mitochondrial fission plays an active role in hippurate-induced endothelial dysfunction via an increase in mitoROS.

Protective effects and mechanisms of Shenhua Tablet () on toll-like receptors in rat model of renal ischemia-reperfusion injury.

ObjectivesTo investigate the protective effects and potential mechanisms of Shenhua Tablet (肾华片, SHT) on the toll-like receptors (TLRs)-mediated signaling pathways in a rat model of kidney ischemia-reperfusion injury (IRI).MethodsSixty male Wistar rats were randomly divided into 5 groups: sham surgery, model control, astragaloside (150 mg•kg-1•d-1), low- and high-dose SHT (1.5 and 3.0 g•kg-1•d-1, repectively) groups. One week after drug treatment, rats underwent surgery to establish the IRI models. At 24 h and 72 h after the modeling, serum creatinine (Scr) and blood urea nitrogen (BUN) were analyzed; pathological damage were scored after periodic acid-Schiffstaining. TLR2, TLR4 and myeloid differentiation factor 88 (MyD88) protein and mRNA expressions were detected by inmmunohistochemistry, Western blot and qPCR. Tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) protein expressions were detected by enzyme linked immunosorbent assay.ResultsCompared with the sham group, the model group exhibited severe change in renal function (Scr: 189.42±21.50, P<0.05), pathological damage (damage score: 4.50±0.55, P<0.05), and the expression levels of TLR2, TLR4, MyD88, TNF-α, IL-6 were significantly higher than other groups. Meanwhile, the levels of TLRs in model group showed upward tendency from 24 to 72 h, unparalleled with pathological and functional changes. The aforementioned parameters were alleviated to a certain extent, and, in addition to TLRs, presented the obvious downward trending from the 24 to 72 h after the intervention in the SHT and astragaloside groups relative to the model (P<0.05); in particular, the most significant mitigation of these changes was observed in the SHT-H group (P<0.05).ConclusionTLRs may be an important spot to treat and research in acute kidney injury. SHT could effectively mitigate renal injuries and promote recovery of IRI injuries through suppression of degeneration induced by up-regulation of TLR2 and TLR4 expression levels in the MyD88-dependent signaling pathway and exhibit some dose dependence.

Protective effect of glucagon-like peptide-1 agents on reperfusion injury for acute myocardial infarction: a meta-analysis of randomized controlled trials

Abstract Background: The cardioprotective properties of glucagon-like peptide-1 (GLP-1) receptor agonists in acute myocardial infarction (AMI) patients against reperfusion injury remain unclear. We performed a meta-analysis to assess their role in the acute phase of AMI. Methods and results: Randomized controlled trials (RCTs) comparing GLP-1 agents with placebo in AMI patients undergoing percutaneous coronary intervention were identified by searching PubMed, Embase and Cochrane libraries. Six RCTs with 800 patients were included in the meta-analysis. Compared with placebo, GLP-1 agents improved left ventricular ejection fraction (LVEF) by 2.46 [95% confidence interval (CI): 0.23–4.70%] and reduced the infarct size in grams as well as in percentage of the area at risk [weighted mean difference (WMD) − 5.29, 95% CI: −10.39 to −0.19; WMD −0.08, 95% CI: −0.12 to −0.04, respectively]. The incidence of cardiovascular events appeared to be lower with GLP-1 therapy, but the statistical significance was not reached [relative risk (RR): 0.78; 95% CI: 0.58–1.06]. In terms of safety evaluation, GLP-1 treatment increased the risk of gastrointestinal adverse events (RR: 5.50, 95% CI: 2.85–10.60). Conclusions: Our analysis shows that in patients with AMI undergoing PCI, GLP-1 treatment is associated with improved LVEF and reduced infarct size.