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.

Objective: The objective of this study was to investigate the ability of phase angle and body composition to identify risk factors for mortality among patients receiving maintenance hemodialysis (MHD) treatment. Methods: In this retrospective study, we examined the causes of death in 43 MHD patients who were treated at our hemodialysis center between January 2016 and December 2021 and compared the patients to 71 patients who survived during the same period. Body composition was measured using direct segmental multi-frequency bioelectrical impedance to obtain phase angle, fat-free mass (FFM), extracellular water/total body water (ECW/TBW), and waist circumference (WC). Laboratory data were also collected. Phase angle cut-off value-associated variables were identified using ROC analysis. The ability of body composition variables to identify risk factors for death in MHD patients was evaluated. Results: We found that cardiovascular disease was the most common cause of death among MHD patients. ROC curve analysis revealed that the optimal cut-off value for phase angle as a predictor of death risk in MHD patients was 4.50°. Additionally, lower phase angle, increased age, longer dialysis vintage, lower KT/V, and hypoproteinemia were identified as significant risk factors for death in MHD patients. Conclusion: In conclusion, our findings suggest that cardiovascular disease is the leading cause of death among MHD patients and that lower phase angle, increased age, longer dialysis duration, and hypoproteinemia can be used to predict the risk of mortality in this patient population. The underlying mechanism by which lower phase angle can be used to predict the prognosis of MHD patients warrants further investigation.

A Chinese herbal formula, namely Jian-Pi-Yi-Shen (JPYS), has been clinically prescribed for patients with chronic kidney disease associated-anemia, and which can improve the patient’s immunological system. However, the mechanisms of JPYS involved in anemia and immune response have not been investigated. To study the role of JPYS in regulating hematopoietic and immunological functions, we investigated its activities on the expressions of erythropoietin and pro-inflammatory cytokines in cultured cells. The standardized herbal extracts of JPYS (0–30 μg/ml) were applied onto cultured cells for 24–48 h. Total RNA was collected from the treated cells and subjected to real-time quantitative PCR analysis. Cultured HEK293T cells, transfected with a construct composed of hypoxia response element tagged with a luciferase gene, i.e. pHRE-Luc, were treated with JPYS extracts (1–30 μg/ml) for 24 h. The cell lysates were subjected to luciferase assay. The treatment with JPYS extract onto cultured HEK293T cells induced erythropoietin expression in a dose-dependent manner, having the highest response by ~ 50% of increase. In parallel, application of JPYS extract for 24 h stimulated expressions of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in cultured RAW 264.7 macrophages. In contrast, the pretreatment with JPYS extract suppressed expressions of IL-1β, IL-6, and TNF-α in lipopolysaccharide-induced macrophages. These results confirmed the hematopoietic function of JPYS in regulating erythropoietin expression, as well as the bidirectional immune-modulatory roles of JPYS by regulating the expression of pro-inflammatory cytokines in cultures.

This study aimed to evaluate the effects of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) on iron metabolism and inflammation in dialysis-dependent chronic kidney disease (DD-CKD) patients. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov websites were searched for randomized controlled trials (RCTs) investigating HIF-PHIs versus ESAs for DD-CKD patients. Twenty studies with 14,737 participants were included in the meta-analysis, which demonstrated no significant difference in the effect of transferrin saturation and ferritin between HIF-PHIs and the ESAs group (MD, 0.65; 95%CI, −0.45 to 1.75; very low certainty; SMD, −0.03; 95% CI, −0.13 to 0.07; low certainty). However, HIF-PHIs significantly increased the iron (MD, 2.30; 95% CI, 1.40 to 3.20; low certainty), total iron-binding capacity (SMD, 0.82; 95% CI, 0.66 to 0.98; low certainty), and transferrin (SMD, 0.90; 95%CI, 0.74 to 1.05; moderate certainty) levels when compared with the ESAs group. In contrast, the hepcidin level and dosage of intravenous iron were significantly decreased in the HIF-PHIs group compared with the ESAs group (MD, −15.06, 95%CI, −21.96 to −8.16; low certainty; MD, −18.07; 95% CI, −30.05 to −6.09; low certainty). The maintenance dose requirements of roxadustat were independent of baseline CRP or hsCRP levels with respect to the effect on inflammation. HIF-PHIs promote iron utilization and reduce the use of intravenous iron therapy. Furthermore, HIF-PHIs, such as roxadustat, maintain the erythropoietic response independent of the inflammatory state. Thus, HIF-PHIs may be an alternative treatment strategy for anemia in DD-CKD patients, where ESA is hyporesponsive due to iron deficiency and inflammation.

This study aimed to explore the possible mechanisms of Ling Gui Zhu Gan decoction (LGZGD) in the treatment of nephrotic syndrome (NS) using network pharmacology combined with molecular docking and molecular dynamics simulation. The active ingredients of LGZGD and their targets were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Swiss Target Prediction database. The NS targets were retrieved from Genecards, OMIM and Drugbank databases. Next, the intersecting targets of drug and disease were imported into the String database for protein-protein interaction network analysis, and the core targets were identified through topological analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed in the Metascape platform. Finally, molecular docking and molecular dynamics simulation were performed for further validation. The network analysis showed that 109 active ingredients of LGZGD were associated with 105 targets in NS. The key active ingredients (quercetin, kaempferol, naringenin, licochalcone A, formononetin, beta-sitosterol) and the core targets (IL6, AKT1, TNF, VEGFA, TP53, JUN, IL1B, CASP3, EGFR, and STAT3) were further identified. Enrichment analysis indicated that multiple biological processes and pathways, including AGE-RAGE, PI3K-Akt, JAK-STAT, and HIF-1 signaling pathways, might be regulated by LGZGD in the treatment of NS. Molecular docking and molecular dynamics simulation results further indicated that the key active ingredients of LGZGD could stably bind to the core targets through hydrogen bonding and hydrophobic interaction. This study demonstrates that the active ingredients of LGZGD may regulate multiple targets, biological processes and signaling pathways in NS. Our findings may provide a theoretical basis for further studies on LGZGD in the treatment of NS.