Background: Hemodialysis (HD) is the most important renal replacement therapy for patients with end-stage kidney disease (ESKD). Systemic inflammation is a risk factor of mortality in HD patients. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are new inflammatory markers. However, previous studies have inconsistent conclusions about the predictive value of NLR, MLR and PLR on mortality of HD patients. The aim of this study was to establish an inflammation scoring system by including NLR, MLR and PLR, and evaluate the association between the inflammation score and all-cause and cardiovascular mortality in HD patients. Methods: In this single center retrospective cohort study, 213 incident HD patients from January 1, 2015 to December 31, 2020 were included. Baseline demographic and clinical data and laboratory measurements were collected. According to the optimal cut-off values, NLR, MLR and PLR were assigned 0 or 1 point, respectively. Then, the inflammation score was obtained by adding the NLR, MLR and PLR scores. All patients were followed until July 31, 2021. The associations of the inflammation score with all-cause and cardiovascular mortality were assessed by multivariable-adjusted Cox models. Results: Of 213 patients, the mean (± SD) age was 56.8 ± 14.4 years, 66.2% were men, and 32.9% with diabetes. The primary cause of ESKD was mainly chronic glomerulonephritis (46.5%) and diabetic nephropathy (28.6%). The median inflammation score was 2 (interquartile range = 1–3). During a median 30 months (interquartile range = 17–50 months) follow-up period, 53 patients had died, of which 33 deaths were caused by cardiovascular disease. After adjusting for demographics, primary diseases and other confounders in multivariable model, the inflammation score = 3 was associated with a hazard ratio for all-cause mortality of 4.562 (95% confidence interval, 1.342–15.504, P = 0.015) and a hazard ratio for cardiovascular mortality of 4.027 (95% confidence interval, 0.882–18.384, P = 0.072). Conclusion: In conclusion, an inflammation scoring system was established by including NLR, MLR and PLR, and the higher inflammation score was independently associated with all-cause mortality in HD patients.

Huangqi–Danshen decoction (HDD) is a commonly used drug pair for clinical treatment of chronic kidney disease (CKD) in traditional Chinese medicine with good efficacy. However, the potential mechanisms of this action have not been well elucidated. The aim of this study was to explore the metabolic profiling variations in response to HDD treatment in a CKD rat model. CKD rat model was induced by adding 0.75% adenine to the diet for 4 weeks. The rats in the treatment group received HDD extract orally at the dose of 4.7 g/kg/day during the experiment. At the end of the experiment, serum and kidney samples were collected for biochemical and pathological examination. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was used to analyze metabolic profiling variations in the kidney. The results showed that treatment with HDD markedly attenuated kidney injury and improved renal function. A total of 28 metabolites contributing to CKD phenotype were found and identified in the kidney samples. The primary metabolic pathways disordered in the kidney of CKD rats were glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, and citrate cycle. Partial least squares discriminant analysis (PLS-DA) score plot showed that the three groups of renal samples were obviously divided into three categories, and the metabolic trajectory of the HDD treatment group moved to the control group. (E)-Piperolein A, phosphatidylcholines (PC) (18:1/22:6), phosphatidylinositols (PI) (13:0/18:1), PI (15:0/20:3), phosphatidylserines (PS) (O-20:0/12:0), and triglyceride (TG) (22:4/24:0/O-18:0) represented potential biomarkers of the renoprotective effects of HDD against CKD. In conclusion, HDD has renoprotective effect against adenine-induced CKD, which may be mediated via partially restoration of perturbed metabolism in the kidney.

Background: Host cell autophagy is implicated in the control of intracellular pathogen. Escherichia coli (E.coli) is the most common organism caused single-germ enterobacterial peritonitis during peritoneal dialysis. In this study, we investigated autophagy of peritoneal mesothelial cells and its role in defense against E.coli. Results: Autophagy in human peritoneal mesothelial cell line (HMrSV5) was induced by lipopolysaccharide (LPS) in a dose-dependent and time-dependent way, which was demonstrated by increased expression of Beclin-1 and light chain 3 (LC3)-II, the accumulation of punctate green fluorescent protein-LC3, and a higher number of monodansylcadaverine-labeled autophagic vacuoles. After incubation of HMrSV5 cells with E.coli following LPS stimulation, both the intracellular bactericidal activity and the co-localization of E.coli (K12-strain) with autophagosomes were enhanced. Conversely, blockade of autophagy with 3-methyladenine, wortmannin or Beclin-1 small-interfering RNA (siRNA) led to a significant reduction in autophagy-associated protein expression, attenuation of intracellular bactericidal activity, and reduced co-localization of E.coli with monodansylcadaverine-labeled autophagosomes. In addition, treatment of HMrSV5 cells with LPS caused a dose-dependent and time-dependent increase in Toll-like receptor 4 (TLR4) expression. Both knockdown of TLR4 with siRNA and pharmacological inhibition of TLR4 with Polymyxin B significantly decreased LPS-induced autophagy. Furthermore, TLR4 siRNA attenuated remarkably LPS-induced intracellular bactericidal activity. Conclusions: Our findings demonstrated for the first time that LPS-induced autophagy in peritoneal mesothelial cells could enhance the intracellular bactericidal activity and the co-localization of E.coli with autophagosomes. The activation of TLR4 signaling was involved in this process. These results indicate that LPS-induced autophagy may be a cell-autonomous defense mechanism triggered in peritoneal mesothelial cells in response to E.coli infection.

Chronic kidney disease (CKD) is a global public health problem with high morbidity and mortality. Decreased nicotinamide adenine dinucleotide (NAD⁺) levels were found to be associated with aging, cancer, and neurodegenerative and metabolic disorders. However, the alteration of renal NAD⁺ levels and biosynthesis pathways in CKD is less known. In the present study, we aimed to evaluate renal NAD⁺ levels and tested the expression of key enzymes in three NAD⁺ biosynthesis pathways in two different types of CKD rat model. CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathology was evaluated by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The expression of key enzymes in three NAD⁺ biosynthesis pathways was determined and quantified by Western blot analysis. The results showed CKD rat models were successfully established as evidenced by increased Scr and BUN levels, upregulation of neutrophil gelatinase-associated lipocalin (NGAL), glomerular hypertrophy, and renal fibrosis. Renal NAD⁺ and NADH content were both declined in two CKD rat models, and NAD⁺ levels were negatively correlated with Scr and BUN levels in CKD rats. Three key enzymes involved in NAD⁺ biosynthesis were significantly downregulated in the kidney of both of the two CKD models. They were quinolinate phosphoribosyltransferase (QPRT) in the de novo pathway, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and NMNAT3 in the salvage pathway. Moreover, the expression of NAD⁺-consuming enzymes sirtuin 3 (SIRT3) and CD38 decreased significantly in CKD rats. In conclusion, NAD⁺ biosynthesis was significantly impaired in CKD, which may attribute to downregulation of QPRT and NMNAT 1/3.

Jian-Pi-Yi-Shen Formula (JPYSF), a Chinese herbal decoction with the efficacies of ‘fortify the spleen and tonify the kidney’ and ‘activate blood and resolve stasis’, is effective for the treatment of chronic kidney disease in clinic. However, the underlying mechanism remains unclear. The aim of this study was to investigate the therapeutic effects and possible mechanisms of JPYSF on retarding chronic kidney disease progression in 5/6 nephrectomized (5/6 Nx) rats. Perindopril (4 mg/kg/d) and JPYSF (2.72 g/kg/d) were administrated by gavage to 5/6 Nx rats daily for 6 weeks. The therapeutic effects of JPYSF were evaluated by renal function, pathological injury, and fibrosis. The protein levels associated with mitochondrial quality control network were measured by Western blot and immunofluorescence analysis. 5/6 Nx rats showed obvious decline in renal function as evidenced by increased serum creatinine, blood urea nitrogen, and urinary protein excretion, and significant injury in kidney structure as evidenced by glomerular hypertrophy, tubular atrophy, and interstitial fibrosis. Administration of JPYSF for 6 weeks could improve renal function and ameliorate kidney structure injury in 5/6 Nx rats. Furthermore, the remnant kidneys of 5/6 Nx rats showed unbalanced mitochondrial quality control network manifested as decreased mitochondrial biogenesis, fusion, and mitophagy, and increased mitochondrial fission. Treatment of JPYSF could restore aforesaid aspects of mitochondrial quality control network. These results indicate that JPYSF can notably ameliorate 5/6 Nx-induced chronic kidney disease, which may be related with modulation of mitochondrial quality control network.