Luteolin can ameliorate renal interstitial fibrosis-induced renal anaemia through the SIRT1/FOXO3 pathway.

Luteolin is a natural flavonoid exhibiting multiple pharmacological activities. Renal anaemia is an important complication of chronic kidney disease (CKD). Whether luteolin can ameliorate renal interstitial fibrosis-induced renal anaemia remains unclear. We examined the therapeutic effects of luteolin in in vitro and in vivo models of renal interstitial fibrosis-induced renal anaemia. After high-throughput sequencing analysis of animal samples, we screened differentially expressed genes (DEGs) associated with luteolin-mediated improvements, performed GO and KEGG functional and pathway enrichment analyses, and validated the mechanism in vitro and in vivo. In vivo, haemoglobin and haematocrit were increased significantly, blood urea nitrogen and creatinine were decreased significantly, and the degree of renal interstitial injury and fibrosis was significantly alleviated in luteolin-treated mice compared with model mice. Erythropoietin (EPO) and hypoxia inducible factor 2A (HIF2A) levels were significantly increased and alpha smooth muscle actin (α-SMA), collagen I (COLI) and fibronectin (FN) levels were significantly decreased. Transcriptomic analysis revealed significant increases in sirtuin 1 (SIRT1) and forkhead box O3 (FOXO3) after luteolin intervention; these effects were validated in vitro and in vivo. Combined treatment with luteolin and the SIRT1 activator resveratrol or the SIRT1 inhibitor sirtinol and SIRT1-siRNA transfection revealed that blocking SIRT1 reduced FOXO3 expression and significantly decreased the benefits of luteolin, while resveratrol had the opposite effects. Molecular docking analysis indicated a stable conformation between luteolin and SIRT1. In vitro and in vivo systematic and transcriptomic studies showed that luteolin attenuates renal anaemia caused by renal fibrosis through the SIRT1/FOXO3 pathway.

Immune Infiltration Landscape on Identified Molecular Subtypes of Chronic Kidney Disease.

Immune imbalance has become an important factor in the progression of chronic kidney disease (CKD). Molecular typing of CKD may be key to achieving precise treatment. xCell allows immune cell phenotyping in CKD. We integrated two independent microarray datasets and divided 87 CKD patients into two subgroups using unsupervised consensus clustering to study the correlation between CKD and patient sex, age, and CKD stage. We found different expression patterns and clinical characteristics between the two groups. CKD stage was more advanced in cluster I than in cluster II, and the weighted gene coexpression network analysis module characteristics showed enrichment of interferon and leukocyte-associated immune pathways in cluster I. Differentially expressed gene analysis revealed the 12 most significantly changed genes, of which sirtuin 1 (SIRT1) was significantly downregulated in cluster I. Gene set enrichment analysis identified multiple immune-related processes involved in CKD. xCell immune infiltration analysis revealed the significant upregulation of natural killer T (NKT) cells and the significant downregulation of most T and B cell types in cluster I. SIRT1 showed a significant negative correlation with NKT cell infiltration but a positive correlation with CD4+ T cell and natural killer cell infiltration. We systematically studied the molecular typing of the CKD transcriptome and estimated the degree of immune cell infiltration based on molecular subtypes. Our results indicate that different subgroups may have unique gene expression patterns and immune dysregulation patterns, thus providing a basis for precise treatment and immune research in CKD.

Nomogram prediction model for renal anaemia in IgA nephropathy patients.

In this study, we focused on the influencing factors of renal anaemia in patients with IgA nephropathy and constructed a nomogram model. We divided 462 patients with IgA nephropathy diagnosed by renal biopsy into anaemic and non-anaemic groups. Then, the influencing factors of renal anaemia in patients with IgA nephropathy were analysed by least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression, and a nomogram model for predicting renal anaemia was established. Eventually, nine variables were obtained, which are easy to apply clinically. The areas under the receiver operating characteristic (ROC) curve and precision-recall (PR) curve reached 0.835 and 0.676, respectively, and the C-index reached 0.848. The calibration plot showed that the model had good discrimination, accuracy, and diagnostic efficacy. In addition, the C-index of the model following internal validation reached 0.823. Decision curve analysis suggested that the model had a certain degree of clinical significance. This new nomogram model of renal anaemia combines the basic information, laboratory findings, and renal biopsy results of patients with IgA nephropathy, providing important guidance for predicting and clinically intervening in renal anaemia.

Influences of renal anemia on the pathology of IgA nephropathy: a study based on propensity score matching.

OBJECTIVE: This study aims to investigate the influences of renal anemia on the pathogenesis of IgA nephropathy using propensity score matching (PSM). METHODS: Renal biopsies from 462 patients with IgA nephropathy were enrolled in this study. PSM was used to balance intergroup covariates, and matching results were verified using a dot-plot of standardized mean differences and histograms of the propensity score distribution and distance distribution. The matched data were used to analyze the impact of renal anemia on the pathological indicators of IgA nephropathy by logistic regression. RESULTS: A total of 132 pairs of patients from the renal anemia group and the non-renal anemia group were matched by PSM; after matching, the standard deviations of 13 covariates were within 0.25. Multivariate logistic regression results suggested that the CKD4-5 stage of IgA nephropathy and tubular atrophy/interstitial fibrosis >50% were independent risk factors for renal anemia. CONCLUSIONS: Via PSM, we demonstrated that decreased eGFR and severe tubular atrophy/interstitial fibrosis are correlated with renal anemia in IgA nephropathy. In clinical practice, renal anemia in patients with IgA nephropathy of CKD3 stage or above should be closely monitored and managed.

Clinical and pathological factors of renal anaemia in patients with IgA nephropathy in Chinese adults: a cross-sectional study.

OBJECTIVE: Few studies with large sample populations concerning renal anaemia and IgA nephropathy have been reported worldwide. The purpose of this cross-sectional study was to examine the clinical and pathological characteristics and influencing factors associated with renal anaemia in patients with IgA nephropathy, which is the most common aetiology of chronic kidney disease. METHODS: A total of 462 hospitalised patients with IgA nephropathy confirmed by renal biopsy who met the inclusion criteria were consecutively recruited from January 2014 to January 2016. Their general information, routine blood test results, blood chemistries, estimated glomerular filtration rates (eGFRs) and renal pathologies were collected. The Oxford classification was used to characterise the renal pathologies. Univariable and multivariate logistic regression models were used to analyse the influencing factors of anaemia associated with IgA nephropathy. RESULTS: The incidence of renal anaemia was 28.5% (132/462 patients) in our study (21.3% in males and 38.9% in females). The anaemia type was primarily normocytic and normochromic. The rate of anaemia in patients with eGFR values of 30-59 mL/min/1.73 m2 was higher than that in patients with an eGFR >60 mL/min/1.73 m2 (42.9% vs 17.8%, p<0.001). Notably, in the group with eGFR values <15 mL/min/1.73 m2, the anaemia rate was 100%. Logistic regression analysis showed that factors affecting anaemia in patients with IgA nephropathy included being female (OR 3.02, 95% CI 1.76 to 5.17), low albumin levels (OR 0.87, 95% CI 0.82 to 0.93), reduced eGFR values (OR 0.98, 95% CI 0.97 to 0.99) and renal tubulointerstitial lesions >50% (OR 2.57, 95% CI 1.22 to 5.40). CONCLUSIONS: The female sex, hypoalbuminaemia, reduced eGFR levels and severe renal tubulointerstitial lesions were correlated with renal anaemia in patients with IgA nephropathy. These results provide new insight into our understanding of anaemia in IgA nephropathy and may improve the management and treatment of clinical renal anaemia.

Protective Effects and Mechanisms of Shenhua Tablet () on Toll-Like Receptors in Rat Model of Renal Ischemia-Reperfusion Injury.

OBJECTIVES: To investigate the protective effects and potential mechanisms of Shenhua Tablet (, SHT) on the toll-like receptors (TLRs)-mediated signaling pathways in a rat model of kidney ischemia-reperfusion injury (IRI). METHODS: Sixty 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. RESULTS: Compared 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). CONCLUSION: TLRs 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.

Valsartan Alleviates Insulin Resistance in Skeletal Muscle of Chronic Renal Failure Rats.

BACKGROUND Studies on insulin resistance (IR) in chronic kidney disease (CKD) patients are rare, and its exact mechanism remains unclear. In this study, we explored the molecular mechanism of IR with chronic renal failure (CRF) and interventions to alleviate IR in patients with CRF. MATERIAL AND METHODS In vivo and in vitro models of CRF were established by 5/6 nephrectomy and urea stimulation C2C12 cells, respectively. Based on the CRF model, angiotensin II (Ang II) and valsartan groups were established to observe the effect of drug intervention on IR. Western blot assays were performed to detect the expression and phosphorylation of IRS-1 and Akt, which are 2 critical proteins in the insulin signaling pathway. RESULTS Both urea stimulation and 5/6 nephrectomy induced glucose uptake disorder in skeletal muscle cells (P<0.01). Skeletal muscle IR was aggravated in the Ang II group (P<0.05) but alleviated in the valsartan group (P<0.01). Regardless of the experimental method (in vivo or in vitro), tyrosine phosphorylation of IRS-1 and Akt were significantly lower (P<0.01) and serine phosphorylation was significantly higher (P<0.01) in the model group than in the sham/control group. Compared to the model group, additional Ang II aggravated abnormal phosphorylation (P<0.05); conversely, additional valsartan alleviated abnormal phosphorylation to some extent (P<0.05). CONCLUSIONS There is skeletal muscle insulin resistance in the presence of CRF. This phenomenon can be aggravated by Ang II and partially relieved by valsartan. One of the mechanisms of IR in CRF patients may be associated with the critical proteins in the IRS-PI3k-Akt pathway by changing their phosphorylation levels.

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.

Efficacy and Safety of Niaoduqing Particles for Delaying Moderate-to-severe Renal Dysfunction: A Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Study.

BACKGROUND: Chronic kidney disease (CKD) with moderate-to-severe renal dysfunction usually exhibits an irreversible course, and available treatments for delaying the progression to end-stage renal disease are limited. This study aimed to assess the efficacy and safety of the traditional Chinese medicine, Niaoduqing particles, for delaying renal dysfunction in patients with stage 3b-4 CKD. METHODS: The present study was a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. From May 2013 to December 2013, 300 CKD patients with an estimated glomerular filtration rate (eGFR) between 20 and 45 ml·min-1·1.73 m-2, aged 18-70 years were recruited from 22 hospitals in 11 Chinese provinces. Patients were randomized in a 1:1 ratio to either a test group, which was administered Niaoduqing particles 5 g thrice daily and 10 g before bedtime for 24 weeks, or a control group, which was administered a placebo using the same methods. The primary endpoints were changes in baseline serum creatinine (Scr) and eGFR after completion of treatment. The primary endpoints were analyzed using Student's t-test or Wilcoxon's rank-sum test. The present study reported results based on an intention-to-treat (ITT) analysis. RESULTS: A total of 292 participants underwent the ITT analysis. At 24 weeks, the median (interquartile range) change in Scr was 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) µmol/L for the test and control groups, respectively (Z = 2.642, P = 0.008), and the median change in eGFR was -0.2 (-4.3-2.7) and -2.2 (-5.7-0.8) ml·min-1·1.73 m-2, respectively (Z = -2.408, P = 0.016). There were no significant differences in adverse events between the groups. CONCLUSIONS: Niaoduqing particles safely and effectively delayed CKD progression in patients with stage 3b-4 CKD. This traditional Chinese medicine may be a promising alternative medication for patients with moderate-to-severe renal dysfunction. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR-TRC-12002448; http://www.chictr.org.cn/showproj.aspx?proj=7102.

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 AND 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.

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.

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

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.

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 AND 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.

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

A 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 ±â€Š1.4 g/L, P = 0.036; MA: 74.6 ±â€Š5.0 vs 70.5 ±â€Š5.3 mm, P = 0.020; G: 15.7 ±â€Š5.3 vs 12.5 ±â€Š3.3, 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.

Clinical predictors differentiating non-diabetic renal diseases from diabetic nephropathy in a large population of type 2 diabetes patients.

AIMS: Non-diabetic renal diseases (NDRDs) are associated with better renal outcomes than diabetic nephropathy (DN). This study was conducted to determine the common clinical markers predicting NDRDs in type 2 diabetes patients. METHODS: Patients with type 2 diabetes mellitus who underwent a renal biopsy were screened. Eligible patients were categorized into two groups: DN group and NDRD group. Patient's clinical characteristics and laboratory data were collected. Logistic regression analysis was performed to identify risk factors for NDRD development, and the diagnostic performance of these variables was evaluated. RESULTS: The study included 248 patients, 96 (38.71%) in the DN group and 152 (61.29%) in the NDRD group. Patients in the NDRD group had a shorter duration of DM and higher hemoglobin, estimated glomerular filtration rate, and urine osmotic pressure values as well as a higher incidence of glomerular hematuria than patients in the DN group. In the NDRD patients, the most common pathological type was membranous nephropathy (55, 36.18%). Absence of retinopathy (OR, 44.696, 95% CI, 15.91-125.566), glomerular hematuria (OR, 9.587, 95% CI, 2.027-45.333), and DM history ⩽5years (OR, 4.636, 95% CI, 1.721-12.486) were significant and independent risk factors for the development of NDRD (P<0.01). Absence of retinopathy achieved the overall highest diagnostic efficiency with a sensitivity of 92.11% and specificity of 82.29%. Glomerular hematuria had the highest specificity (93.75%). CONCLUSION: Shorter duration of diabetes (⩽5years), absence of retinopathy, and presence of glomerular hematuria were independent indicators associated with NDRDs, indicating the need for renal biopsy.

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.

Protective effects of astragaloside in rats with adriamycin nephropathy and underlying mechanism.

The present study was designed to determine the mechanism underlying the treatment of nephrotic syndrome using astragaloside by observing the effects of astragaloside on the expression of nephrin and podocin proteins and genes in kidneys of rats with adriamycin nephropathy. The rats were injected with adriamycin and, after successful model establishment, randomly divided into a model group, a Methylprednisolone (MP) group, and an astragaloside group. The 24-h complete urine samples were collected. Biochemical indicators were monitored, and kidney tissues were collected for pathological analysis using light microscopy and electron microscopy. The mRNA expression of nephrin and podocin was measured in the kidney tissues using the real-time qPCR, and the protein expression levels of nephrin and podocin were detected using Western blot analysis. At the end of 12 weeks of drug intervention, the urinary protein level was lower in the MP and astragaloside groups than that in the model group (P = 0.008 and P = 0.01, respectively). Serum albumin was higher in the MP and astragaloside groups than in the model group (P < 0.001 and P = 0.012, respectively). Podocytes in the MP group were nearly normal, and fusion of podocytes in the astragaloside group was significantly less than that in the control group. The nephrin and podocin mRNA and protein expression levels in the intervention groups were higher (P < 0.05) than that in the model group. Due to the increased expression of podocyte-related nephrin and podocin proteins, astragaloside maintained slit diaphragm integrity and decreased the level of proteinuria in rats with adriamycin nephropathy.

Shenhua Tablet inhibits mesangial cell proliferation in rats with chronic anti-Thy-1 nephritis.

BACKGROUND: In China, mesangial proliferative glomerulonephritis (MsPGN) is one of the most common kidney diseases. In this study, we treated a rat model of chronic anti-Thy-1 MsPGN with Shenhua Tablet and evaluated whether the tablet was able to protect the kidney function. Thirty-six Wistar rats were randomly divided into six groups: (1) Sham surgery (Sham); (2) anti-Thy-1 nephritis model (Thy-1); (3) anti-Thy-1 nephritis model + irbesartan-treated (Irb); (4) anti-Thy-1 nephritis model + low-dose of Shenhua Tablet (SHL); (5) anti-Thy-1 nephritis model + medium-dose of Shenhua Tablet (SHM); (6) anti-Thy-1 nephritis model + high-dose of Shenhua Tablet (SHH). RESULTS: Thirteen weeks after drug treatment, urinary proteins were quantified and renal pathological changes were thoroughly examined at the time point of 24 h. Meanwhile, the expression levels of p-Erk1/2, cyclin D1 and p21 at the renal cortex were also tested. The levels of urinary proteins and total cholesterol in the blood were significantly reduced in rats treated with any drug tested in this study. The level of triglyceride was significantly reduced in all three Shenhua Tablet-treated groups. Renal pathomorphological scores were significantly improved in groups of Irb, SHM and SHH. Mesangial cell proliferation was significantly inhibited in any drug-treated group. p-Erk1/2 and cyclin D1 were downregulated whereas p21 was upregulated in the renal cortex. CONCLUSIONS: Our study indicated that Shenhua Tablet is able to inhibit the abnormal proliferation of mesangial cells and to prevent kidney damage, which is likely associated with downregulation of p-Erk1/2 and reduced activity of its downstream target-cyclin D1.

Therapeutic effect of double-filtration plasmapheresis combined with methylprednisolone to treat diffuse proliferative lupus nephritis.

OBJECTIVE: The efficacy of double-filtration plasmapheresis (DFPP), combined with methylprednisolone, to treat diffuse proliferative lupus nephritis (LN) was studied. METHODS: Twenty-four patients who were admitted to the hospital and diagnosed with diffuse proliferative LN (LN Class IV-G(A)) through renal biopsy from 2011 to 2013 were recruited as the study subjects. The patients' clinical manifestations were nephritic syndrome and/or renal insufficiency. The pathological features were glomerular diffuse proliferative lesions. The patients were divided into two groups: the treatment group and the control group, with 12 patients in each group. The patients in the treatment group were first treated with DFPP combined with methylprednisolone (0.8-1.0 mg/kg/day); subsequently, they were put on methylprednisolone therapy only. The patients in the control group were first put on methylprednisolone pulse therapy (500-1,000 mg) for 3 days; subsequently, they were treated with methylprednisolone (0.8-1.0 mg/kg/day) combined with mycophenolate mofetil (1.5 g/day). The patients were observed for 24 months. Levels of hemoglobin, platelet, albumin, serum creatinine, 24-h urinary protein, serum C3 , antinuclear antibody (ANA), anti-dsDNA, and anti-Smith were measured at 0, 3, 6, 12, and 24 months. Complete remission and recurrence standards were established. The total dosages of methylprednisolone were calculated. Repeated renal biopsy was performed on several patients. RESULTS: There was no statistical significance in the baseline conditions of the treatment and the control groups. For the treatment group, no plasmapheresis-related complications occurred. The two groups showed no significant difference in complete remission. The patients' edema and serous effusion resolved, urine volume, serum creatinine, and albumin levels returned to normal, urine protein decreased in treatment group more rapidly than the patients in the control group. The mean dose of methylprednisolone received in the treatment group was lower than in the control group. The complement C3 levels in the treatment group were significantly higher than in the control group. The recurrence rate in the treatment group was lower than in the control group. Repeated renal biopsies on several patients in the treatment group indicated that their pathology improved significantly, changing from LN (IV) to LN(II-III). CONCLUSIONS: Appropriate application of DFPP combined with glucocorticoid therapy could accelerate the remission of diffuse proliferative LN, reduce overall glucocorticoid dosage, prevent recurrence, and maintain C3 level in a higher level. J. Clin. Apheresis 31:375-380, 2016. © 2015 Wiley Periodicals, Inc.

Hypercoagulable state evaluated by thromboelastography in patients with idiopathic membranous nephropathy.

The aims of this study were to evaluate the characteristics of hypercoagulable states in patients with membranous nephropathy (MN) via thromboelastography (TEG) and to identify risk factors. 235 MN patients who had undergone TEG examinations from 2011 to 2014 were included. An abnormality in at least two TEG parameters is considered a hypercoagulable state. Patient data was compared between the hypercoagulable and non-hypercoagulable groups. Potential risk factors for hypercoagulability were analyzed by logistic regression models. Subgroup analysis was performed in hypercoagulable patients. Compared to the non-hypercoagulable MN patients, the hypercoagulable patients showed a significantly higher proportion of female patients, urinary protein, platelet count, triglyceride and fibrinogen level, along with more severe hypoproteinemia and a reduction of serum antithrombin III. Correlation analysis showed that hypoproteinemia was the primary risk factor for hypercoagulability in MN patients. Among the hypercoagulable MN patients, a subgroup TEG parameter analysis showed that glucocorticoids-used subgroup and smoker subgroup had shortened time to initial fibrin formation (R value) and increased coagulation index respectively (P < 0.05), indicating a more serious hypercoagulable state. Meanwhile, the time to initial fibrin formation (R value) and time to clot formation (K value) of the statin-used patients were remarkably higher than those of the non-statin patients. TEG examinations facilitated the detection of hypercoagulable states in MN patients, and hypoproteinemia was the most important risk factor for hypercoagulability in these patients. The use of glucocorticoids and smoking may help to aggravate hypercoagulable states, while statin drugs may alleviate hypercoagulability.