Zhanzheng Zhao

Clinical and prognostic implications of serum uric acid levels on IgA nephropathy: a cohort study of 348 cases with a mean 5-year follow-up.

AIM To assess the prognostic implications of serum uric acid levels on patients with IgA nephropathy in a longitudinal 8-year follow-up study and to identify an association between serum uric acid levels and the clinical and pathological phenotypes of IgA nephropathy. SUBJECTS AND METHODS We reviewed the files of all consecutive patients with IgA nephropathy treated at our hospital between 2001 and 2009. Analyses were performed to investigate the association between the level of serum uric acid and both clinical and pathological phenotypes of IgA nephropathy. Prognosis was assessed based on follow-up data. RESULTS At the same glomerular filtration rate (GFR), there was no significant difference in the levels of 24 hours proteinuria, blood urea nitrogen (BUN), and serum creatinine between the two groups with different levels of serum uric acid (p > 0.05). The prevalence of glomerular sclerosis as well as the scores of tubulointerstitial and vascular injury was greater in patients with high serum uric acid levels compared to patients with normal levels of serum uric acid (p < 0.05). At the end of the follow-up period, patients with high serum uric acid levels had a higher prevalence of reduced GFR and end stage renal disease (ESRD) than those with normal serum uric acid levels (40.82 vs. 15.70% and 64.71 vs. 35.00%, respectively; p < 0.05). CONCLUSIONS The serum uric acid level in patients with IgA nephropathy affects the pathophysiology and prognosis of the disease. We also identified a correlation between hyperuricemia and a higher risk of renal end points.

Comparison between adults and children with Henoch–Schönlein purpura nephritis

BackgroundHenoch–Schönlein purpura (HSP) mainly affects children, but age is also thought to be an important prognostic factor. Kidney involvement is a major cause of mortality in HSP patients. The purpose of this study was to analyze the clinicopathological correlations between adults and children.MethodsA total of 208 children and 75 adult patients with HSP nephritis (HSPN) were evaluated. All patients underwent a renal biopsy.ResultsExtra-renal symptoms (arthritis and abdominal pain) were more common in the pediatric patient group than in the adult group (P < 0.05), but renal symptoms (edema and hypertension) were relatively rare (P < 0.05). A significant positive correlation was noted between pathological type and clinical type (P < 0.01). Pathological activity was positively related to renal failure, abdominal pain, microscopic hematuria, hypertension, and proteinuria (P < 0.05). Pathological chronicity was positively associated with age, duration of follow-up since the onset of palpable purpura, renal failure, lower extremity edema, hypertension, and proteinuria (P < 0.05).ConclusionsVarious clinicopathological differences exist between children and adults with HSPN. Massive proteinuria, renal failure, and abdominal pain usually correlated with severe pathology. Renal biopsy should be performed in both pediatric and adult HSPN patients with repeated hematuria and/or consistent minimal proteinuria.

MiRNA-29c regulates the expression of inflammatory cytokines in diabetic nephropathy by targeting tristetraprolin

Diabetic nephropathy is one of the most prevalent chronic complications of Diabetes mellitus, but its pathogenesis remains elusive. This study was designed to determine the role of tristetraprolin (TTP), inflammatory cytokines and microRNAs (miRNAs) in DN. The blood and urine samples were obtained from 32 patients with DN, 33 patients with type 2 DM, and 35 normal healthy subjects as controls. Renal tissue samples were also obtained from 10 DN patients and 10 normal controls. The miRNA microarray analyses were performed in pooled plasma and urine sediment samples of eight DN patients and eight age- and sex-matched health control subjects and three paired renal tissues from patients with DN and normal controls. Conditionally immortalized mouse podocytes (MPC5) were used a cell model. The expressions of TTP and cytokines in patient samples and cultured cells were determined by qRT-PCR and Western blotting or ELISA. Our results indicated that miRNA-29c directly targeted TTP and promoted inflammatory response under hyperglycemic conditions. Overexpression of miRNA-29c in podocytes resulted in an increase in inflammatory cytokines and inhibition of miRNA-29c by using its inhibitor reduced the inflammatory cytokines in podocytes. Finally, miRNA-29c promoted the progression of DN by targeting TTP, providing a target for a therapeutic intervention of DN.

NOD2 promotes endothelial-to-mesenchymal transition of glomerular endothelial cells via MEK/ERK signaling pathway in diabetic nephropathy.

Endothelial-to-mesenchymal transition (EndMT) of glomerular vascular endothelial cells (GEnCs) is now considered to play a critical role in diabetic nephropathy (DN). NOD2 is newly discovered to be closely related to DN renal injury. However, the relationship between NOD2 and EndMT of GEnCs has never been reported. In the present study, we found that NOD2 over-expression was positively correlated with the severity of DN injury in human renal biopsy samples. Immunohistochemical staining of DN renal slices showed gradual absence of endothelial character and gain of mesenchymal character, both of which were associated with NOD2 over-expression. In high glucose stimulated GEnCs, NOD2 was increased. Whats more, over-expression and activation of NOD2 could both promote EndMT of GEnCs. On the other hand, silencing of NOD2 markedly attenuated EndMT induced by high glucose. Mechanically, we further found that MEK/ERK signaling pathway was involved in NOD2-regulated EndMT. Collectively, our results indicate that NOD2 has a regulatory role in EndMT via activation of MEK/ERK in high glucose-treated GEnCs. Targeting this pathway is a promising strategy for intervention of DN endothelial dysfunction.

Urinary Heme Oxygenase‐1 as a potential biomarker for early diabetic nephropathy

Our previous study showed that increases of urinary heme oxygenase‐1 (uHO‐1) could be a potential biomarker indicating evaluating intrarenal oxidative damage in obstructive nephropathy. Activation of oxidative stress is an important mediator of diabetic nephropathy (DN). The aim of this study was to investigate the clinical implications of uHO‐1 levels in patients with type 2 diabetes.

IL-6 promotes epithelial-to-mesenchymal transition of human peritoneal mesothelial cells possibly through the JAK2/STAT3 signaling pathway

Long-term peritoneal dialysis (PD) therapy results in functional and structural alteration of the peritoneal membrane, including epithelial-to-mesenchymal transition (EMT). Interleukin 6 (IL-6) is a local pleiotropic cytokine, hypothesized to play an important role in EMT. This study was designed to investigate the role of IL-6 in EMT and peritoneal membrane dysfunction in long-term PD patients by assessing the level of IL-6 in dialysate and exploring the relationship between IL-6, the related signaling pathway JAK2/STAT3, and EMT, using in vitro cellular and molecular techniques. Plasma and dialysate levels of IL-6 were significantly higher in PD ultrafiltration failure patients compared with patients without ultrafiltration failure and were negatively correlated with measures of PD adequacy. In vitro IL-6 treatment changed human peritoneal mesothelial cell phenotype from a typical cobblestone-like to a fibroblast-like appearance and increased cell viability. IL-6 treatment increased α-smooth muscle actin and vascular endothelial growth factor expression but decreased E-cadherin expression. IL-6 treatment activated the JAK/STAT signaling pathway. However, the JAK2/STAT3 inhibitor WP1066 prevented IL-6-induced activation of the JAK2/STAT3 pathway and EMT. We conclude that IL-6 promotes the EMT process, possibly by activating the JAK2/STAT3 signaling pathway. IL-6 may serve as a novel therapeutic target for preventing EMT, and preservation of the peritoneal membrane may arise from these studies.

VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway

Background: Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice. Methods: The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol. Results: With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3β of and β-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3β and β-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway. Conclusion: VDR activation could reduce proteinuria of DN mice and alleviate high-glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway.

Endothelin-receptor antagonist can reduce blood pressure in patients with hypertension: a meta-analysis

Abstract The aim of this meta-analysis was to assess the effectiveness and safety of endothelin-receptor antagonist (ERA) in the patients with hypertension. Searches of the PubMed, EMBASE, and CENTRAL databases were conducted to include all the randomized control trials (RCTs). Eighteen trials including 4898 patients were used in the meta-analysis, of which nine were classified as low risk of bias and the other nine as unclear risk of bias. There was no statistically significant difference in all-cause mortality between ERA and placebo groups [6 trials, fixed effects model, RR 1.53 (0.89–2.62); random effects model, RR 1.45 (0.84–2.52)]. ERA significantly reduced 24-h ambulatory blood pressure and sitting blood pressure in patients with hypertension [5 trials, 24-h SBP: WMD −7.65 (−8.95 to −6.36), 24-h DBP: WMD −5.92 (−7.50 to −4.33); 18 trials, SBP: WMD −6.12 (−7.87 to −4.36), DBP: WMD −3.81 (−4.82 to −2.80)]. However, ERA had more adverse events [within 24 h: 3 trials, RR 1.16 (0.82–1.65); after 24 h, 13 trials, RR 1.21 (1.08–1.36)] and severe adverse events than placebo controls [SAE: 9 trials, RR 1.34 (1.13–1.60)]. In addition, there is a potential need for further RCTs that focus on the use of ERA in patients with hypertension.

Development and external validation of risk scores for cardiovascular hospitalisation and rehospitalisation in diabetes patients

Context Cardiovascular disease (CVD) is a common and costly reason for hospitalization and rehospitalization among patients with type 2 diabetes. Objective This study aimed to develop and externally validate two risk-prediction models for cardiovascular hospitalization and cardiovascular rehospitalization. Design Two independent prospective cohorts. Setting The derivation cohort includes 4704 patients with type 2 diabetes from 18 general practices in Cambridgeshire. The validation cohort comprises 1121 patients with type 2 diabetes from post-trial follow-up data. Main Outcome Measure Cardiovascular hospitalization over 2 years and cardiovascular rehospitalization after 90 days of the prior CVD hospitalization. Results The absolute rate of cardiovascular hospitalization and rehospitalization was 12.5% and 6.7% in the derivation cohort and 16.3% and 7.0% in the validation cohort. Discrimination of the models was similar in both cohorts, with C statistics above 0.70 and excellent calibration of observed and predicted risks. Conclusion Two prediction models that quantify risks of cardiovascular hospitalization and rehospitalization have been developed and externally validated. They are based on a small number of clinical measurements that are available for patients with type 2 diabetes in many developed countries in primary care settings and could serve as the tools to screen the population at high risk of cardiovascular hospitalization and rehospitalization.

Potential health impact and cost-effectiveness of drug therapy for prehypertension

BACKGROUND Studies have reported that pharmacologic interventions with candesartan or ramipril could reduce the risk of hypertension among prehypertensive subjects free of clinical cardiovascular disease (CVD), however, the cost-effectiveness and long-term cardiovascular risk of drug treatment among these population is unclear. METHOD A Markov state-transition model was developed to simulate a hypothetical cohort of Chinese adults with high-range prehypertension (130-139/85-89mmHg) but without CVD. Data on the incidence of CVD and hypertension was obtained from corresponding risk equations. Utility and disease-related costs were obtained from published literatures. Robustness and uncertainty was evaluated using deterministic and probabilistic sensitivity analyses. RESULTS Compared with placebo, drug treatment resulted in delaying the development of hypertension by nearly 12years and reducing the absolute incidence of hypertension by 32.01% over lifetime. The cumulative incidence of coronary heart disease, stroke and heart failure were reduced and survival was improved from 28.46 to 28.80years. The average incremental cost effectiveness ratio for drug treatment was