Rong Gou

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.

In this paper, we investigate the effect and the possible mechanism of high glucose levels on the calcification of human aortic smooth muscle cells (HASMCs). HASMCs were divided into four groups: normal glucose group (NG), osmolality control group (OC), high glucose group (HG, HASMCs culture medium containing 30 mmol/L glucose), and high glucose plus recombinant human Noggin protein (bone morphogenetic protein-2 (BMP-2) antagonist) group (HN). The mRNA levels and the protein expressions of BMP-2 and core binding factor alpha-1 (Cbfα-1) were measured by real-time quantitative polymerase chain reaction (PCR) and Western blot. After induced by 10 mmol/L β-glycerol phosphoric acid, cells were harvested for assessments of alkaline phosphatase (ALP) activities at Days 1, 2, and 3, and intracellular calcium contents at Days 7 and 14, respectively. High glucose levels increased the mRNA levels and the protein expressions of BMP-2 and Cbfα-1 (P<0.05). The expression of Cbfα-1 was partially blocked by Noggin protein (P<0.05), while BMP-2 was not (P>0.05). After being induced by β-glycerol phosphoric acid, high glucose levels increased the ALP activity [(48.63±1.03) vs. (41.42±2.28) U/mg protein, Day 3; P<0.05] and the intracellular calcium content [(2.76±0.09) vs. (1.75±0.07) μmol/mg protein, Day 14; P<0.05] in a time-dependent manner when compared with the NG group, while the ALP activity could not be blocked by Noggin protein [(48.63±1.03) vs. (47.37±0.97) U/mg protein, Day 3; P>0.05]. These results show that high glucose levels can evoke the calcification of HASMCs by inducing osteoblastic trans-differentiation and intracellular calcium deposition via the BMP-2/Cbfα-1 pathway, which can be partially blocked by Noggin protein.

-terminal kinase (JNK) in ER stress. Tubular epithelial cells (TEC) are the main injury target and source of AKI inflammatory mediators. TEC injury may lead to glomerulosclerosis, however, the underlying mechanism remains unclear. Here, hypoxia/reoxygenation (H/R) HK-2 cells were used as an AKI model. To determine the partial effects of TEC injury on the glomerulus, HK-2 cells after H/R were co-cultured with human renal mesangial cells (HRMC). H/R up-regulated ER stress, IRE1/JNK pathway, IL-6 and MCP-1 in HK-2 cells. Stimulation of HRMC with IL-6 enhanced their proliferation and the expression of glomerulosclerosis-associated fibronectin and collagen IV via signal transducer and activator of transcription 3 (STAT3) activation. Similar responses were observed in HRMC co-cultured with HK-2 cells after H/R. IRE1/JNK inhibition reversed these injury responses in HRMC. IRE1/JNK stable knock-down in HK-2 cells and shRNA-mediated STAT3 depletion in HRMC confirmed their role in inflammation/glomerulosclerosis. These findings suggest that IRE1/JNK pathway mediates inflammation in TEC, affecting mesangial cells. The inhibition of this pathway could be a feasible approach to prevent AKI-CKD transition.

BACKGROUND: Intravenous soybean oil (SO) is a commonly used lipid emulsion for children with intestinal failure (IF); however, it is associated with IF-associated liver disease (IFALD). Studies have demonstrated that intravenous fish oil (FO) is an effective treatment for IFALD. However, there is a lack of long-term data on children who stop FO and resume SO. This study's objective was to investigate our institution's outcomes for children with IFALD treated with 6 months of FO and who then restarted SO. METHODS: Inclusion criteria for FO included children with IFALD. Parenteral nutrition (PN)-dependent children resumed SO after FO and were prospectively followed for 4.5 years or until death, transplant, or PN discontinuation. The primary outcome was the cumulative incidence rate (CIR) for cholestasis after FO. RESULTS: Forty-eight subjects received FO, and conjugated bilirubin decreased over time (-0.22 mg/dL/week; 95% confidence interval [CI]: -0.25, -0.19; P < .001). The CIR for cholestasis resolution after 6 months of FO was 71% (95% CI: 54%, 82%). Twenty-seven subjects resumed SO and were followed for a median of 16 months (range 3-51 months). While the CIR for enteral autonomy after 3 years of follow-up was 40% (95% CI: 17%, 26%), the CIR for cholestasis and transplant was 26% (95% CI: 8%, 47%) and 6% (95% CI: 0.3%, 25%), respectively. CONCLUSION: In this study, FO effectively treated cholestasis, and SO resumption was associated with cholestasis redevelopment in nearly one-fourth of subjects. Long-term FO may be warranted to prevent end-stage liver disease.

Peritoneal dialysis (PD)-associated peritoneal fibrosis is a chronic progress which induces ultrafiltration failure. It remains a challenge to prevent the progression of PD-associated fibrosis in clinic practice. Wnt/β-catenin pathway plays important role in many severe fibrotic diseases, here we investigated its contribution to the development of peritoneal damage. We isolated mesothelial cells (MC) from the effluent of PD patients and found that the expressions of Wnt1, Wnt5a, β-catenin, and LEF1 were increased in patients with more than 1-year PD compared with patients who just started with PD (<1 month). The elevated expressions of Wnts and β-catenin were accompanied with changes in the expressions of E-cadherin, α-SMA, COL-I, and FN mRNA and proteins, which are known related to mesothelial-mesenchymal transition (MMT). In addition, treatment with high glucose significantly increased the expression of Wnt1, Wnt5a, β-catenin, and LEF1 as well as the expression of α-SMA, COL-I, and FN in human peritoneal mesothelial cells (HPMC), whereas the expression of E-cadherin was reduced. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/β-catenin signaling. Overexpression of DKK1 transgene significantly decreased the expression of β-catenin and attenuated the process of MMT as indicated by the decreased expression of α-SMA, COL-I, and FN and the increased expression of E-cadherin. Furthermore, TGF-β1 treatment significantly activated the Wnt/β-catenin pathway in HPMCs, while DKK1 blocked the TGF-β1-induced Wnt signaling activation and significantly inhibited the process of MMT. These data suggest that the canonical Wnt/β-catenin pathway plays an important role in the MMT and fibrosis induced by PD.