Lymphocyte-to-C reactive protein ratio as novel inflammatory marker for predicting outcomes in hemodialysis patients: A multicenter observational study.

Background: Patients undergoing hemodialysis experience inflammation, which is associated with a higher risk of mortality. The lymphocyte-to-C reactive protein ratio (LCR) is a novel marker of inflammation that has been shown to predict mortality in patients with malignant cancer. However, the utility of LCR has not been evaluated in patients undergoing hemodialysis. Methods: We performed a multi-center cohort study of 3,856 patients who underwent hemodialysis as part of the Beijing Hemodialysis Quality Control and Improvement Project between 1 January 2012 and December 2019. The relationship between LCR and all-cause mortality was assessed using a restricted cubic spline model and a multivariate Cox regression model. An outcome-oriented method was used to determine the most appropriate cut-off value of LCR. Subgroup analysis was also performed to evaluate the relationships of LCR with key parameters. Results: Of the 3,856 enrolled patients, 1,581 (41%) were female, and their median age was 62 (53, 73) years. Over a median follow-up period of 75.1 months, 1,129 deaths occurred. The mortality rate for the patients after 60 months was 38.1% (95% confidence interval (CI) 36%-40.1%), resulting in a rate of 93.41 events per 1,000 patient-years. LCR showed an L-shaped dose-response relationship with all-cause mortality. The optimal cut-off point for LCR as a predictor of mortality in hemodialysis patients was 1513.1. An LCR of ≥1513.1 could independently predict mortality (hazard ratio 0.75, 95% CI 0.66-0.85, P<0.001). Conclusions: Baseline LCR was found to be an independent prognostic biomarker in patients undergoing hemodialysis. Implying that it should be a useful means of improving patient prognosis and judging the timing of appropriate interventions in routine clinical practice.

Endoplasmic reticulum stress mediates parathyroid hormone-induced apoptosis in vascular smooth muscle cells.

Vascular calcification is one of the most common complications of chronic kidney disease (CKD), which is closely associated with increased mortality and morbidity rates of CKD patients. It has been reported that increased parathyroid hormone (PTH) aggravates vascular calcification in CKD patients. However, the direct role of PTH in vascular smooth muscle cells (VSMCs) is less elucidated. Here, we present evidence that PTH promotes apoptosis of VSMCs and endoplasmic reticulum (ER) stress participates in this process. Human aorta vascular smooth muscle cells (HASMCs) were treated with different concentrations of PTH for various time. HASMC apoptosis was detected by flow cytometry. Expression of phosphorylated (p)-PERK, CHOP, IRE1, p-JNK, and cleaved caspase 3 was determined by Western blotting. We found that PTH induced HASMC apoptosis and increased the expression of cleaved caspase 3. Furthermore, PTH activated PERK-CHOP and IRE1-JNK ER stress pathways. Either inhibition of JNK by SP600125 or CHOP by siRNA ameliorated PTH-induced apoptosis in HASMCs. We therefore suggest that ER stress participates in PTH-induced apoptosis of VSMCs, which may be a possible mechanism of PTH-promoted vascular calcification in CKD patients.

Bone marrow mesenchymal stem cell-derived exosomes improve renal fibrosis via regulating Smurf 2/Smad 7.

BACKGROUND: Exosomes can be secreted from bone marrow mesenchymal stem cells (BMSCs) to extracellular space and exert anti-fibrotic effects, but the underlying mechanisms remain to be elucidated. METHODS: 5/6 subtotal nephrotomy (SNx) rat models and TGF-ß1-induced human renal proximal tubular epithelial cells (HRPTEpiCs) were established to simulate renal fibrosis. Renal function and fibrosis were assessed by Hematoxylin and Eeosin (HE) staining, Masson staining, immunohistochemistry, and western blot. The expression of Smad 7/Smurf 2 was detected in rats and HRPTEpiCs by western blot, and a further potential mechanism was explored using si-Smurf 2. RESULTS: BMSC-Exo improved renal function, reduced the fibrotic region, down-regulated the expression of fibronectin, Collagen-I, α-SMA, and up-regulated E-cadherin in SNx models. In vitro study demonstrated that knocking down the expression of Smurf 2 significantly increased the expression of Smad 7, which could be enhanced by BMSC-Exo. BMSC-Exo could alleviate the fibrosis induced by TGF-ß1 in tubular epithelial cells and enhanced the protective effect of si-Smurf 2 on renal fibrosis. CONCLUSIONS: BMSC-Exo inhibited renal fibrosis both in vivo and in vitro, partially, by regulating the Smurf 2/Smad 7 axis. BMSC-Exo enhanced the protective effect of si-Smurf 2 on fibrosis induced by transforming growth factor-ß1 (TGF-ß1).

Association between the risk of death and serum calcium, phosphate, and intact parathyroid hormone levels in older patients undergoing maintenance hemodialysis: a cohort study in Beijing.

BACKGROUND: The number of patients ⩾65 years who require maintenance hemodialysis (MHD) is increasing. Although reduced bone turnover in older patients receiving hemodialysis, as reflected by lower serum intact parathyroid hormone (iPTH) and phosphate (P) levels, has been reported, focus on the association between abnormal bone metabolism and the risk of death in older patients receiving MHD has been limited. METHODS: We retrospectively examined data from the Beijing Hemodialysis Quality Control and Improvement Center for 1410 older patients who underwent hemodialysis from 1 January 2012 to 31 December 2016. Baseline, time-dependent (TD) Cox proportional hazards models and Kaplan-Meier analyses were used to evaluate the association between the markers of mineral and bone disorder (MBD) [calcium (Ca), P, and iPTH] and survival. The Kidney Disease: Improving Global Outcomes (KDIGO) target ranges were included as reference values. RESULTS: Serum P levels >2.49 mmol/l increased the risk of all-cause death [hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.04-2.07; p = 0.030] and cardiovascular death (HR: 2.01; 95%CI: 1.21-3.34; p = 0.007); iPTH levels >600 pg/ml increased the risk of cardiovascular death (HR: 1.95; 95%CI: 1.20-3.15; p = 0.007). Baseline results and TD Cox analyses were similar. All three MBD parameters were within the respective target ranges at least once during the follow-up period in 399 (28.3%) patients, and these patients had better survival rates than those who achieved two of the three target ranges (715/1410 patients; 50.7%); those who achieved one or no target range (296/1410; 21.0%) had the lowest survival rate (all-cause death: log-rank chi square = 83.96, p < 0.001; cardiovascular death: log-rank chi square = 47.06, p < 0.001). CONCLUSION: Older patients undergoing MHD who achieved the KDIGO target levels for any two or three MBD parameters had lower risks of all-cause and cardiovascular death.

Long-Term Effect of Microwave Ablation on Patients Undergoing Hemodialysis for Moderate Secondary Hyperparathyroidism: A Retrospective Cohort Study.

OBJECTIVES: A previous 12-month study confirmed that microwave ablation (MWA) was effective for moderate secondary hyperparathyroidism (SHPT). A further analysis was performed in this study to evaluate the efficacy of MWA for moderate SHPT over an observational follow-up period of up to 60 months. METHODS: This was a retrospective cohort study of patients involved in a previous randomized controlled trial. Patients were divided into an MWA group (those who underwent MWA followed by drug therapy according to the patient's clinical situation) and a control group (those who received drug therapy only). The primary outcome was the composite endpoint. During the efficacy assessment phase, the two groups were compared in terms of the proportion of patients with intact parathyroid hormone (iPTH) levels <300 pg/ml and the differences in iPTH levels. RESULTS: Twenty-seven patients were included in this study: 13 in the MWA group and 14 in the control group. The median (interquartile range) follow-up periods of the MWA and control groups were 58 (54-60) and 58 (49-60) months, respectively. The proportion of patients with iPTH levels <300 pg/ml in the MWA group was slightly higher than that in the control group (6/13 [46.2%] versus 2/14 [14.3%], respectively; p = .08). Furthermore, iPTH levels in the MWA group were lower than in the control group during the efficacy assessment phase (411 ± 299 pg/ml versus 516 ± 369 pg/ml, respectively; p <.01). CONCLUSIONS: MWA helped to contain the necessary iPTH levels in patients undergoing hemodialysis for moderate SHPT in a 60-month timeframe.

Angiotensin­converting enzyme­2 improves diabetic nephropathy by targeting Smad7 for ubiquitin degradation.

Angiotensin­converting enzyme 2 (ACE2), an important component of the renin­angiotensin system, protects against renal tubulointerstitial fibrosis, but its level of involvement in the mechanism of diabetic nephropathy (DN) currently remains unclear. Herein, the effects of ACE2 in DN and the associated mechanisms were investigated using serum and renal biopsy specimens from patients with DN and control participants, and human renal proximal tubular epithelial cells (HRPTEpiCs). The present study determined that the circulating concentration of ACE2 was high, but renal ACE2 expression was markedly lower, and there was abundant expression of Arkadia, an E3 ubiquitin ligase, in patients with DN. In vitro, ACE2 attenuated high­glucose­induced tubular epithelial to mesenchymal cell transition (EMT), which was demonstrated by increased expression of α­SMA and loss of E­cadherin expression, as demonstrated by western blot analysis and reverse transcription­quantitative PCR. Adenovirus­mediated ACE2 overexpression was also revealed to significantly inhibit Arkadia expression and alleviated high­glucose­induced EMT, while ACE2 inhibition had the opposite effects. Furthermore, western blot analysis demonstrated that ACE2­alleviated EMT was associated with downregulated Arkadia and increased SMAD family member 7 (Smad7) protein, followed by TGF­ß/Smad pathway inhibition in HRPTEpiCs. In conclusion, ACE2 is protective in DN, which may be due to the inhibition of Arkadia­mediated Smad7 degradation, whereby TGF­ß/Smad­mediated EMT is ameliorated in high­glucose­stimulated HRPTEpiCs.

C1q/tumor necrosis factor-related protein-3 improves renal fibrosis via inhibiting notch signaling pathways.

C1q/tumor necrosis factor-related protein-3 (CTRP3) has been extensively reported as an important role involved in antifibrosis, antiapoptosis, and anti-inflammation. However, the role of CTRP3 involved in renal fibrosis remains unclear. Our current study explored the role of CTRP3 in renal fibrosis and its underlying mechanisms by using serums and renal biopsy specimens from renal fibrosis patients and control subjects, rats models with the surgery of unilateral ureteral obstruction (UUO) and human renal proximal tubular epithelial cells (HRPTEpiCs). We found that circulating levels of CTRP3 had no significant difference between renal fibrosis patients and healthy subjects; however, renal CTRP3 expression was markedly downregulated in the fibrotic region with an abundant expression of collagen-I. In UUO rat models, circulating levels of CTRP3 have not changed with the prolonged obstruction of the kidney; renal CTRP3 expression was decreased with the severity of renal fibrosis; adenovirus-mediated CTRP3 treatment inhibited renal interstitial fibrosis. In vitro experiments revealed that CTRP3 attenuates TGF-ß1 induced tubular epithelial cells fibrotic changes; CTRP3 knockdown facilitates the expression of fibrotic markers in TGF-ß1-induced HRPTEpiCs; recombinant CTRP3 or adenovirus-mediated CTRP3 overexpression significantly inhibited the Notch signaling pathway-associated factors, and knockdown of CTRP3 increased TGF-ß1-mediated activation of the Notch signaling pathways. Collectively, our current study found that CTRP3 could improve renal fibrosis, to some extent, through inhibiting the Notch pathway.