CircME1 promotes aerobic glycolysis and sunitinib resistance of clear cell renal cell carcinoma through cis-regulation of ME1.

Circular RNAs (circRNAs) play critical roles in clear cell renal cell carcinoma (ccRCC). However, their involvement in sunitinib resistance remains largely unknown. Herein, we identified a novel circRNA, named circME1, which contributes to sunitinib resistance development in ccRCC. CircME1 also promoted proliferation, migration, and invasion of ccRCC cells. Further mechanism analysis showed that circME1 interacted with U1 snRNP at the promoter of its parental gene ME1, thereby upregulating the expression of ME1, enhancing aerobic glycolysis of ccRCC, and promoting its malignant phenotype. Furthermore, ME1 specific inhibitor could effectively repress the oncogenic functions of circME1. Taken together, our study demonstrates that the circME1/ME1 pathway is involved in ccRCC progression and sunitinib resistance development, which may be exploited for anticancer therapy.

Association of Ratio of Apolipoprotein B to Apolipoprotein A1 With Survival in Peritoneal Dialysis.

Background: Although the ratio of apolipoprotein B (apo B) to apolipoprotein A1 (apo A1) (apo B/apo A1) seems to be associated with mortality in hemodialysis (HD) patients, the association of apo B/apo A1 ratio with death remains not clear in peritoneal dialysis (PD) patients. Aims: The study targets to examine the relationship of apo B/apo A1 ratio with survival in patients receiving PD treatment. Methods: In this single-center prospective observational cohort study, we enrolled 1,616 patients receiving PD treatment with a median follow-up time of 47.6 months. We used a multivariable Cox proportional hazards model to examine the relationship between apo B/apo A1 ratio and cardiovascular (CV) and all-cause mortality. The association of apo B/apo A1 ratio with atherosclerotic and non-atherosclerotic CV mortality was further evaluated by competing risk regression models. Results: During the follow-up, 508 (31.4%) patients died, 249 (49.0%) died from CV events, of which 149 (59.8%) were atherosclerotic CV mortality. In multivariable models, for 1-SD increase in apo B/apo A1 ratio level, the adjusted hazard ratios for CV and all-cause mortality were 1.26 [95% confidence interval (CI), 1.07-1.47; P = 0.005] and 1.20 (95% CI, 1.07-1.35; P = 0.003), respectively. The adjusted subdistribution hazard ratios for atherosclerotic and non-atherosclerotic CV mortality were 1.43 (95% CI, 1.19-1.73; P < 0.001) and 0.85 (95% CI, 0.64-1.13; P = 0.256), respectively. For quartile analysis, patients in quartile 4 had higher CV, all-cause, and atherosclerotic CV mortality compared with those in quartile 1. Moreover, apo B/apo A1 ratio had a diabetes-related difference in CV, all-cause, and atherosclerotic CV mortality. Conclusion: Elevated apo B/apo A1 ratio level was significantly associated with CV, all-cause, and atherosclerotic CV mortality in patients undergoing PD. Moreover, the association was especially statistically significant in patients with diabetes.

Renal Function and All-Cause Mortality Risk Among Cancer Patients.

Renal dysfunction predicts all-cause mortality in general population. However, the prevalence of renal insufficiency and its relationship with mortality in cancer patients are unclear.We retrospectively studied 9465 patients with newly diagnosed cancer from January 2010 to December 2010. Renal insufficiency was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m using the Chronic Kidney Disease Epidemiology Collaboration equation. The hazard ratio (HR) of all-cause mortality associated with baseline eGFR was assessed by Cox regression.Three thousand sixty-nine patients (32.4%) exhibited eGFR <90 mL/min/1.73 m and 3% had abnormal serum creatinine levels at the time of diagnosis. Over a median follow-up of 40.5 months, 2705 patients (28.6%) died. Compared with the reference group (eGFR ≥ 60 mL/min/1.73 m), an elevated all-cause mortality was observed among patients with eGFR < 60 mL/min/1.73 m stratified by cancer stage in the entire cohort, the corresponding hazard ratios were 1.87 (95% CI, 1.41-2.47) and 1.28 (95% CI, 1.01-1.62) for stage I to III and stage IV, respectively. However, this relationship was not observed after multivariate adjustment. Subgroup analysis found that eGFR < 60 mL/min/1.73 m independently predicted death among patients with hematologic (adjusted HR 2.93, 95% CI [1.36-6.31]) and gynecological cancer (adjusted HR 2.82, 95% CI [1.19-6.70]), but not in those with other cancer. Five hundred fifty-seven patients (6%) had proteinuria. When controlled for potential confounding factors, proteinuria was a risk factor for all-cause mortality among patients in the entire cohort, regardless of cancer stage and eGFR values. When patients were categorized by specific cancer type, the risk of all-cause death was only significant in patients with digestive system cancer (adjusted HR, 1.85 [1.48-2.32]).The prevalence of renal dysfunction was common in patients with newly diagnosed cancer. Patients with eGFR < 60 mL/min/1.73 m or proteinuria were associated with increased risk for all-cause mortality, this relation depended on cancer site.

Proteomic analysis in peritoneal dialysis patients with different peritoneal transport characteristics.

Peritoneal membranes can be categorized as high, high average, low average, and low transporters, based on the removal or transport rate of solutes. In this study, we used proteomic analysis to determine the differences in proteins removed by different types of peritoneal membranes. Peritoneal transport characteristics in patients who received peritoneal dialysis therapy were assessed by a peritoneal equilibration test. Two-dimensional differential gel electrophoresis technology followed by quantitative analysis was performed to study the variation in protein expression from peritoneal dialysis effluents (PDE) among different groups. Proteins were identified by MALDI-TOF-MS/MS analyses. Further validation in PDE or serum was performed utilizing ELISA analysis. Proteomics analysis revealed ten protein spots with significant differences in intensity levels among different groups, including vitamin D-binding protein, complement C3, apolipoprotein-A1, complement factor C4A, haptoglobin, alpha-1 antitrypsin, immunoglobulin kappa light chain, alpha-2-microglobulin, retinol-binding protein 4 and transthyretin. The levels of vitamin D-binding protein, complement C3, and apolipoprotein-A1 in PDE derived from different groups were greatly varied (P<0.05). However, no significant difference was found in the serum levels of these proteins among different groups (P>0.05 for all groups). This study provides a novel overview of the differences in PDE proteomes of four types of peritoneal membranes. Vitamin D-binding protein, complement C3, and apolipoprotein-A1 showed enhanced expression in PDE of patients with high transporter.

Developing a reproducible method for the high-resolution separation of peritoneal dialysate proteins on 2-D gels.

PURPOSE: Despite recent progress in the proteomic analysis of peritoneal dialysate effluent (PDE), there remains unresolved problems in the development of an optimal sample preparation method. EXPERIMENTAL DESIGN: We examined five protocols for concentrating PDE proteins and the effects of immobilized pH gradient (IPG) strips with different pH ranges and sample loading techniques. In addition, we examined three kits for depleting high abundance proteins by SDS-PAGE and two-dimensional gel electrophoresis (2-DE). RESULTS: PDE proteins precipitated with 75% acetonitrile (ACN) showed the greatest number of protein spots by 2-DE, with over 800 distinct spots. Higher-resolution images were obtained using IPG strips with a pH range of 4-7. The ProteoPrep immunoaffinity albumin and IgG depletion kit removed high abundance proteins with higher efficiency and more compatibility with isoelectric focusing (IEF). Removing high abundance proteins also increased the resolution and improved the intensity of low abundance proteins. CONCLUSION AND CLINICAL RELEVANCE: High-resolution 2-DE images of PDE proteins were obtained by concentrating samples with 75% ACN, using pH 4-7 IPG strips, and depleting high abundance proteins. This optimized method will enable future studies to discover predictive biomarkers of disease in patients on dialysis.

Malnutrition-inflammation score predicts long-term mortality in Chinese PD patients.

BACKGROUND: Malnutrition-Inflammation Score (MIS) has proved to predict the prospective mortality in maintenance hemodialysis (MHD) patients. However, its value of long-term mortality predictability in peritoneal dialysis (PD) patients has not been adequately studied. METHODS: A total of 155 chronic stable PD patients from November 2005 to December 2006 were enrolled. At baseline, the MIS, Subjective Global Assessment (SGA), as well as clinical, laboratory, and anthropometric parameters were recorded. All patients were followed until October 2009 to evaluate mortality as a primary outcome. RESULTS: The MIS correlated very well with SGA and other nutrition and inflammation markers. Patients with a higher MIS had a worse survival rate compared to those with lower MIS. After adjusting for potential confounding factors, one unit increase of MIS was associated with a 1.27-fold greater death risk (hazard ratio: 1.27, 95% confidence interval: 1.19 - 1.36; p < 0.001). MIS had a superior mortality predictability compared with SGA. Moreover, univariate and multivariate analyses denoted MIS, age, dialysis vintage, and comorbidities as independent predictors of total mortality. CONCLUSION: MIS is a promising marker for malnutrition inflammation assessment and an independent predictor of long-term mortality in Chinese PD patients.

Proteomic profiling identifies haptoglobin as a potential serum biomarker for steroid-resistant nephrotic syndrome.

BACKGROUND: Long-term outcomes for patients with adult idiopathic nephrotic syndrome correlate closely with steroid responsiveness. The aim of this prospective study was to evaluate the difference in serum proteomes between steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) patients and identify potential biomarkers for the prediction of SRNS. METHODS: We performed a gel-based proteomic study of serum obtained from SRNS and SSNS patients and healthy controls at the time of presentation (n = 6 for each group). Proteins from the serum samples were separated using 2-D electrophoresis, digested in-gel and subjected to MALDI-TOF-MS/MS analysis. Further validation was performed utilizing Western blot and ELISA. The sensitivities and specificities of the candidate proteins for predicting SRNS were determined using receiver operating characteristic curves. RESULTS: Thirteen differentially expressed proteins were identified as haptoglobin (Hp) with different isoelectric points and molecular weights. Western blot and ELISA analysis of samples from 146 subjects (healthy controls = 52, SSNS = 54, SRNS = 40) showed a markedly increased level of Hp in the serum, but not urine, of SRNS compared to SSNS patients. The optimal serum cutoff level of Hp was set at ≥1,279 µg/ml using the receiver operating characteristic curve. The sensitivity and specificity for predicting SRNS were 85.0 and 96.3%, respectively. CONCLUSIONS: This study provides a novel overview of the difference in serum proteomes of SSNS and SRNS patients. Serum Hp may be a useful predictive biomarker for steroid therapy efficacy in the treatment of idiopathic nephrotic syndrome.

Elevated neutrophil to lymphocyte ratio predicts overall and cardiovascular mortality in maintenance peritoneal dialysis patients.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) is widely used as a marker of inflammation and an indicator of cardiovascular outcomes in patients with coronary artery disease. However, its prognostic value in peritoneal dialysis (PD) patients is still unknown. METHODS: We studied 138 newly started PD patients and 60 healthy controls at the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Baseline NLR as well as demographic, clinical, and biochemical parameters were recorded. All patients were followed up until March 2011 to evaluate mortality as the primary outcome. Overall and cardiovascular disease-free survival rates were compared according to NLR level. Multivariate analysis was performed to assess the prognostic value of NLR. RESULTS: Baseline NLR levels (mean 3.5 ± 1.6) were significantly increased in PD patients compared to healthy controls (mean 1.5 ± 0.5; P < 0.001). Patients with higher NLR had a higher mortality rate compared with patients with lower NLR (51.5% vs 22.9%; P = 0.006). The 1-year and 3-year overall survival rates were 86.6% and 65.9% for patients with higher NLR compared with 97% and 85.1% for patients with lower NLR (P = 0.006). Patients with higher NLR also showed a higher cardiovascular mortality rate, compared with patients with lower NLR (38% vs 7.6%; P = 0.003). The 1-year and 3-year cardiovascular event-free survival rates were 90.7% and 81.9% for patients with higher NLR, compared with 98.6% and 95.1% for patients with lower NLR. Multivariate analysis showed high NLR value was an independent risk factor for all-cause and cardiovascular mortality. CONCLUSION: Neutrophil to lymphocyte ratio is a strong predictor for overall and cardiovascular mortality in PD patients.

Successfully managing a rapidly growing peritoneal dialysis program in Southern China.

BACKGROUND: The maximal use of the limited resource to improve peritoneal dialysis (PD) penetration and clinical outcomes is a challenge for all PD centers. In this study, we reported the experience and outcomes in successfully managing a rapidly growing PD center in Southern China. METHODS: A standard PD program with a team consisted of 6 nephrologists (3 doctors were in charge of catheter insertion and in-patients care, the other 3 doctors focused on PD patients' follow-up and education) and 11 nurses in a PD center at Sun Yat-sen University was established for PD patients follow-up in 2005. A prospective and observational study was conducted in all patients undergoing continuous ambulatory PD (CAPD) at our center from January 1, 2006 to December 31, 2009. RESULTS: The yearly number of prevalent CAPD patients was 297, 409, 547 and 695 in 2006, 2007, 2008 and 2009, respectively. The PD catheter insertion was performed by the nephrologists with open surgical procedure and 94% of catheters were patent at one year. In 841 incident CAPD patients, the survival rates at the end of 1, 2, 3 and 4 years were 94%, 87%, 83% and 76%, respectively, while cumulative technique survival rates (death-censored) were 98%, 95%, 91% and 90%, respectively. Peritonitis rate was 1/68.5 patient months. CONCLUSIONS: Better patient and technical survival rates as well as lower peritonitis episode have been achieved in our rapidly growing PD center. A standardized PD program, well-trained team members of PD doctors and nurses, and continuous quality improvement of PD are important elements in managing a successful PD program.

Association between depression and malnutrition-inflammation complex syndrome in patients with continuous ambulatory peritoneal dialysis.

OBJECTIVE: Depression, the most common psychological disorder among patients with end-stage renal disease (ESRD), is associated with poor survival. The prevalence of depression and its relation with the malnutrition-inflammation complex syndrome (MICS) have not yet been clearly defined in Chinese continuous ambulatory peritoneal dialysis (CAPD) patients. PATIENTS AND METHODS: A total of 142 patients on CAPD were enrolled in the First Affiliated Hospital of Sun Yat-Sen University. The Hamilton Depression Scale (HAMD) and the malnutrition-inflammation score (MIS) were used for depression and MICS evaluation, respectively. Clinical, socioeconomic, and malnutrition-inflammation factors were compared among patients with and without depression. Binary regression analysis was performed to investigate the independent association between depression and MICS. RESULTS: The mean HAMD and MIS scores were 7.12 ± 5.28 and 4.45 ± 3.56, respectively. According to HAMD, 37 patients (26.1%) had depression and 70 patients (49.3%) had potential depression. Older age, longer dialysis vintage, worse residual renal function, lower employment and reimbursement status, and higher comorbidity index were positively correlated with depression. Compared to non-depressed patients, the depressed ones also showed lower levels of serum albumin and higher levels of C-reactive protein (CRP). Correlation results showed that the HAMD scores were significantly and positively correlated with MIS (r = 0.46, P < 0.01). Moreover, the incidence of peritonitis was significantly higher in depressed compared to non-depressed patients. Binary regression analysis showed that MIS was the only independent risk factor for depression. CONCLUSION: Depression is commonly encountered in Chinese CAPD patients. A close relationship exists between depression and MICS.

[Expression of tumor necrosis factor-alpha signaling adapter proteins in peripheral blood mononuclear cells from patients with systemic lupus erythematosus].

OBJECTIVE: To investigate the mRNA expression of the tumor necrosis factor (TNF)-adapter proteins, TNF receptor-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), receptor-interacting protein 1 (RIP-1), and TNF receptor-associated factor-2 (TRAF-2) in peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE), and to explore the relationship between the expression of these adaptors and the SLE disease activity. METHODS: PBMC were isolated from venous blood of 51 SLE patients and 17 healthy subjects. The mRNA expression of TRADD, FADD, RIP-1, TRAF-2, Caspase 3, and interleukin (IL)-1beta were analyzed by quantitative real time RT-PCR. Disease activity was measured using the SLE Disease Activity Index (SLEDAI). RESULTS: All healthy subjects showed mRNA expressions of TRADD, FADD, RIP-1, and TRAF-2. The mRNA expression levels of TRADD, FADD, RIP-1, and TRAF- in the PBMC from the patients were 0.38, 0.69, 0.59, and 0.55 tomes that from the control subjects (all P < 0.05). The expression levels of these 4 adapters of the SLE patients with the SLEDAI >/= 10 were significantly lower than those of the SLE patients with the SLEDAI < 10 (all P < 0.05). The Caspase3 mRNA expression of the SLE patients was significantly higher than that of the healthy controls (P < 0.01); however, the IL-1beta mRNA expression was not significantly different between the SLE and control subjects. The mRNA expression levels of TRADD, FADD, RIP-1 and TRAF-2 in the PBMC from the SLE patients were all negatively correlated with the SLE activity index with the coefficient correlation of -0.285, -0.280, -0.307, and -0.298 respectively (all P < 0.05). CONCLUSION: The mRNA expression levels of the TNF adapter molecules, such as TRADD, FADD, RIP-1, and TRAF-2, decrease significantly in the PBMC from the SLE patients, and are negatively correlated with the SLE activity index. These abnormalities may participate in the immunopathogenic injury mediated by the aberration TNFalpha signaling pathway in SLE.