Astragaloside IV attenuates indoxyl sulfate-induced injury of renal tubular epithelial cells by inhibiting the aryl hydrocarbon receptor pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus Fisch. ex Bunge has long been used to treat chronic kidney disease (CKD) in China. However, the mechanism of action requires further study. Indoxyl sulfate accumulation is the key cause of CKD progression. The aryl hydrocarbon receptor (AhR) plays an essential role in the renal tubular injury induced by indoxyl sulfate (IS). AIM: We explored the effects of Astragaloside IV (AS-IV), a minor component of the flowering perennial Astragalus membranaceus Fisch. ex Bunge, on AhR activity during IS-induced injury of renal tubular epithelial cells. METHODS: C57BL/6 mice fed a 0.2% adenine diet (adenine + IS) and intraperitoneally injected with IS were used to study the protective effects of AS-IV, and specifically the effect on the AhR. In addition, apoptosis (annexin/PI), oxidative stress and the AhR pathway were investigated in IS-stimulated HK-2 cells treated with AS-IV. The binding of AS-IV to the AhR was assessed in a molecular docking analysis. AhR knockdown using AhR siRNA allowed determination of the effects of AS-IV in IS-stimulated HK-2 cells. RESULTS: AS-IV inhibited tubulointerstitial injury in adenine + IS mice. While AS-IV did not reduce serum IS levels, it did inhibit AhR expression in the kidney. In IS-stimulated HK-2 cells, AS-IV also dramatically reduced apoptosis, decreased oxidative stress responses and inhibited the expression of the AhR pathway. The molecular docking analysis showed surface binding of AS-IV to the AhR. Following AhR knockdown in HK-2 cells, IS-induced apoptosis was reduced and could not be further reduced by AS-IV. CONCLUSION: By targeting the AhR, AS-IV may alleviate IS-induced renal tubular injury, thus offering a novel therapeutic approach to the treatment of chronic renal failure.

Rhubarb Enema Increasing Short-Chain Fatty Acids that Improves the Intestinal Barrier Disruption in CKD May Be Related to the Regulation of Gut Dysbiosis.

The incidence of CKD seriously endangers people's health. Researchers have proposed that improving the intestinal barrier damage in CKD may be an effective target for delaying the progression of CKD. Rhubarb can effectively improve the intestinal barrier and renal fibrosis, which may be related to the regulation of gut dysbiosis, but the mechanism needs to be further studied. Short-chain fatty acids (SCFAs) are important metabolites of the gut microbiota and play an important role in maintaining the intestinal barrier. The purpose of this study was to investigate whether rhubarb enema regulates the production of short-chain fatty acid-related gut microbiota and improves the intestinal barrier damage of CKD. 5/6 nephrectomy rats were used as the animal model, sevelamer was used as the positive control group, and the sham operation rats were used as the control group. After 4 weeks of enema treatment, the general clinical indicators, short-chain fatty acid levels, renal pathology, intestinal tissue pathology, intestinal tight junction protein, and changes in gut microbiota were detected. The results showed that rhubarb enema can increase the level of short-chain fatty acids in the 5/6 nephrectomy model rats, improve the intestinal barrier damage, inhibit the decrease of intestinal tight junction proteins, reduce inflammation levels, improve kidney pathology, reduce blood creatinine levels, and regulate the intestinal tract, the abundance, and composition of the flora. Further correlation analysis showed that rhubarb enema increased the level of short-chain fatty acids in 5/6 nephrectomy model rats, which may be related to the 7 strains that may regulate the production of short-chain fatty acids. This study indicated that rhubarb enema can improve the intestinal barrier damage of 5/6 nephrectomy model rats and improve CKD, which may be related to the regulation of short-chain fatty acid-producing gut microbiota.

Rhubarb Enema Decreases Circulating Trimethylamine N-Oxide Level and Improves Renal Fibrosis Accompanied With Gut Microbiota Change in Chronic Kidney Disease Rats.

Objectives: Trimethylamine N-oxide (TMAO), a metabolic product of gut flora, is increased in chronic kidney disease (CKD) subjects and is recognized as one type of uremic toxins which is associated with poor cardiovascular outcomes and kidney function loss. Previous studies have suggested that rhubarb enema could reduce circulating uremic toxins such as urea, creatinine, and indoxyl sulfate and also regulate the intestinal microbiota. However, whether rhubarb enema retards kidney dysfunction by reducing circulating TMAO and its underlying mechanism, are still unclear. The present study aims to investigate the impact of rhubarb enema on TMAO and its precursors, as well as on the intestinal microbiota in 5/6 nephrectomized (5/6Nx) CKD rats. Design: Rats in the treatment groups were given rhubarb enema after modeling. At the end of the study, blood, feces, and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses. Results: Rhubarb enema reduced serum TMAO and trimethylamine (TMA) levels, inhibited the expression of inflammatory markers (interleukin-6, tumor necrosis factor α and Interferon-γ) and alleviated tubular atrophy, monocyte infiltration and interstitial fibrosis in 5/6Nx CKD rats. Moreover, rhubarb enema significantly increased the abundance of some symbiotic bacteria and probiotics, while reduced the abundance of some potential pathogens at the genus level. In addition, Spearman's correlation analysis revealed that lachnospiraceae and romboutsia were positively correlated with TMAO. Conclusion: Rhubarb enema decreases circulating TMAO level and improves renal fibrosis in 5/6Nx CKD rats, which may be related to the regulation of intestinal microbial community.

Bupi Yishen formula attenuates kidney injury in 5/6 nephrectomized rats via the tryptophan-kynurenic acid-aryl hydrocarbon receptor pathway.

BACKGROUND: Bupi Yishen Formula (BYF), a patent traditional Chinese medicine (TCM) formulation, has been used in the clinical treatment of chronic kidney disease (CKD). However, the mechanism of action of BYF has not been fully elucidated. METHOD: To investigate the variation in the metabolic profile in response to BYF treatment in a rat model of 5/6 nephrectomy (Nx), rats in the treatment groups received low- or high-dose BYF. At the end of the study, serum and kidney samples were collected for biochemical, pathological, and western blotting analysis. Metabolic changes in serum were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: The results showed that BYF treatment could reduce kidney injury, inhibit inflammation and improve renal function in a dose-dependent manner. In total, 405 and 195 metabolites were identified in negative and positive ion modes, respectively. Metabolic pathway enrichment analysis of differential metabolites based on the Kyoto Encyclopedia of Genes and Genomes database identified 35 metabolic pathways, 3 of which were related to tryptophan metabolism. High-dose BYF reduced the level of kynurenic acid (KA) by more than 50%, while increasing melatonin 25-fold and indole-3-acetic acid twofold. Expression levels of aryl hydrocarbon receptor (AhR), Cyp1A1, and CyP1B1 were significantly reduced in the kidney tissue of rats with high-dose BYF, compared to 5/6 Nx rats. CONCLUSION: BYF has a reno-protective effect against 5/6 Nx-induced CKD, which may be mediated via inhibition of the tryptophan-KA-AhR pathway.

Microbiome-Metabolomics Analysis Reveals the Protection Mechanism of α-Ketoacid on Adenine-Induced Chronic Kidney Disease in Rats.

Objectives: As nitrogen-free precursors of corresponding essential amino, α-ketoacid have been widely prescribed to end-stage renal disease patients together with a low protein diet However, the impact of α-ketoacid on intestinal microbiota in chronic kidney disease (CKD) individuals is unknown. The study aims at investigating the variation in the intestinal microbiota and metabolic profile in response to α-ketoacid treatment in an adenine-induced CKD rat model. Design: Rats in the treatment groups were given solution of compound α-ketoacid tablets. At the end of the study, blood, feces, colon tissues and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses. Results: α-Ketoacid treatment reduced serum creatinine, blood urea nitrogen and 24 h urine protein, and alleviated tubular atrophy, glomerulosclerosis and interstitial fibrosis in adenine-induced CKD rats. Moreover, α-ketoacid significantly improved intestinal barrier and increased the abundance of Methanobrevibacter, Akkermansia, Blautia and Anaerositipes while reduced the abundance of Anaerovorax and Coprococcus_3 at the genus level. In addition, our results also demonstrated that α-ketoacid significantly reduced the concentrations of indoxyl sulfate, betaine, choline and cholesterol. Spearman's correlation analysis revealed that the abundance of Coprococcus_3 was positively correlated with serum level of betaine, trimethylamine N-oxide, indoxyl sulfate, cholic acid and deoxycholic acid. Conclusion: α-Ketoacid has a reno-protective effect against adenine-induced CKD, which may be mediated regulation of serum metabolic profiles via affecting intestinal microbial community.

Effectiveness and safety of pneumococcal vaccines used alone or combined with influenza vaccination in dialysis patients: A systematic review and meta-analysis.

BACKGROUND: A lower conversion vaccination rate and a more rapid decline in antibody titers over time in dialysis patients raise concerns about the effectiveness of pneumococcal vaccination (PV) in this population, which has not been systematically reviewed. METHODS: We searched PubMed, Cochrane Library, Embase and three Chinese databases from inception until February 29th, 2020 for interventional, cohort and case-control studies evaluating PV alone or combined with influenza vaccination (IV) on outcomes (all-cause mortality, pneumonia, cardiovascular events, antibody response and safety). Independent reviewers completed citation screening, data extraction, risk assessment, meta-analysis, and GRADE rating of the quality of evidence. RESULTS: Five cohort studies and one quasirandomized control trial enrolling 394,299 dialysis patients with high to moderate quality were included. Compared with unvaccinated individuals, those receiving PV had lower risk of all-cause mortality [Adjusted relative risk (RR) 0.73, 95% CI 0.67-0.79, I2 = 31.1%, GRADE low certainty] and cardiovascular events (adjusted RR 0.80, 95% CI 0.69-0.93, I2 = 47.2%, GRADE low certainty) without serious adverse effect reported. Compared with no vaccination, lower all-cause mortality was observed in those receiving PV combined with IV (Adjusted RR 0.71, 95%CI 0.67-0.75, I2 = 63.3%), PV alone (Adjusted RR 0.86, 95% CI 0.78-0.94,I2 = 0%], and IV alone (Adjusted RR 0.76, 95% CI 0.73-0.79, I2 = 0%]. There was no difference between pneumococcal vaccinated patients vs non-vaccinated patients with respect to pneumonia. Immune response to pneumococcal conjugate vaccine-13 was weaker in polysaccharide pneumococcal vaccine-23-pre-vaccinated compared with vaccine-naive patients. CONCLUSIONS: The use of pneumococcal vaccine especially combined with influenza vaccination is associated with lower risks of all-cause mortality but may be affected by residual confounding/healthy vaccinee bias.

Effects of dialysis modality choice on the survival of end-stage renal disease patients in southern China: a retrospective cohort study.

BACKGROUND: The optimal choice of treatment, with hemodialysis (HD) or peritoneal dialysis (PD), for end-stage renal disease (ESRD) patients, is still controversial. Only a few studies comparing HD and PD have been conducted in China, which has the largest number of dialysis patients in the world. METHODS: A retrospective cohort study was conducted on ESRD patients who began renal replacement treatment from January 1, 2012 to December 31, 2017 in Guangdong Provincial Hospital of Chinese Medicine. Propensity scoring match was applied to balance the baseline conditions and multivariate Cox regression analysis to compare the mortality between HD and PD patients, and evaluated the correlation between mortality and various baseline characteristics. RESULTS: A total of 436 HD patients and 501 PD patients were included in this study, and PD patients had better survival than HD patients, but the difference was not statistically significant. For younger ESRD patients (≤60-year-old), the overall survival of PD was better than that of HD, but HD was associated with a lower risk of death in older patients (> 70-year-old). This difference was still significant after adjustment for a variety of confounding factors. Female gender, age at dialysis initiation, cardiovascular disease, cholesterol, and HD were risk factors of all-cause mortality in the younger subgroup, while PD was risk factor in the older subgroup. CONCLUSION: PD may be a better choice for younger ESRD patients, and HD for the older patients.

The Aryl Hydrocarbon Receptor in Chronic Kidney Disease: Friend or Foe?

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that promotes cell responses to small molecules derived from the diet, microorganisms, metabolism and pollutants. The AhR signal regulates many basic cellular processes, including cell cycle progression, adhesion, migration, apoptosis and cell proliferation. Many studies have shown that AhR is associated with chronic kidney disease (CKD) and its complications. This article reviews the current knowledge about the role of AhR in CKD, showing that AhR mediates CKD complications, including cardiovascular disease, anemia, bone disorders, cognitive dysfunction and malnutrition, and that it influences drug metabolism in individuals with CKD. AhR enhances the intestinal barrier function to reduce the harmful effects of uremic toxins. Therefore, understanding the complex roles of AhR during CKD is important to be able to target this transcription factor safely and effectively for CKD prevention and treatment.

Shenfu injection for intradialytic hypotension: a systematic review and meta-analysis.

Objective. To evaluate the effectiveness and safety of Shenfu injection (SFI) for intradialytic hypotension (IDH). Methods. A systematic review of data sources published as of April 2014 was conducted. These included the Cochrane Central Register of Controlled Trials (2014 issue 4), Pubmed, Embase, CBM, CNKI, VIP, and Wangfang Data. Randomized controlled trials (RCTs) involving SFI for treatment and prevention of IDH were identified. Two researchers independently selected articles, extracted data, assessed quality, and cross checked the results. Revman 5.2 was used to analyze the results. Results. Eight RCTs were included. The meta-analysis indicated that compared with conventional therapies alone, SFI could elevate systolic blood pressure (SBP), increase the clinical effective rate, decrease the incidence of hypotension, increase serum albumin (ALB) levels, and reduce C-reactive protein (CRP) levels without serious adverse effects. GRADE Quality of Evidence. the quality of SBP, the effective rate, ALB, and CRP were low, and hypotension incidence and DBP were very low. Conclusions. SFI is more effective than conventional therapies for prevention and treatment of IDH. However, a clinical recommendation is not warranted due to the small number of studies included and low methodology quality. Multi-center and high-quality RCTs with large sample sizes are needed to provide stronger evidence.