A Chinese patent medicine's long-term efficacy on non-dialysis patients with CKD stages 3-5: a retrospective cohort study.

Background: Chinese patent medicine is commonly used in China as an important treatment mechanism to thwart the progression of chronic kidney disease (CKD) stages 3-5, among which Niaoduqing granules are a representative Chinese patent medicine; however, its long-term efficacy on CKD prognosis remains unclear. Methods: Patients were grouped according to Niaoduqing granule prescription duration (non-Niaoduqing granule (non-NDQ) group vs Niaoduqing granule (NDQ) group). Serum creatinine (SCr) variation was compared using a generalized linear mixed model (GLMM). Multivariate Cox regression models were constructed, adjusting for confounding factors, to explore the risk of composite outcomes (receiving renal replacement therapy (RRT) or having an estimated glomerular filtration rate (eGFR)<5 mL/min/1.73 m2, ≥50% decline in the eGFR from the baseline, and doubling of SCr) in individuals consuming Niaoduqing granules. Results: A total of 1,271 patients were included, with a median follow-up duration of 29.71 (12.10, 56.07) months. The mean SCr Z-scores for the non-NDQ group and NDQ group were -0.175 and 0.153, respectively, at baseline (p = 0.015). The coefficients of the NDQ group from visit 1 to visit 5 were -0.207 (95% CI: -0.346, -0.068, p = 0.004), -0.214 (95% CI: 0.389, -0.039, p = 0.017), -0.324 (95% CI: 0.538, -0.109, p = 0.003), -0.502 (95% CI: 0.761, -0.243, p = 0.000), and -0.252 (95% CI: 0.569, 0.065, p = 0.119), respectively. The survival probability was significantly higher in the NDQ group (p = 0.0039). Taking Niaoduqing granules was a significant protective factor for thwarting disease progression (model 1: HR 0.654 (95% CI 0.489-0.875, p = 0.004); model 2: HR 0.646 (95% CI 0.476, 0.877, p = 0.005); and model 3: HR 0.602 (95% CI 0.442, 0.820, p = 0.001)). Conclusion: The long-term use of Niaoduqing granules improved SCr variation and lowered the risk of CKD progression by 39.8%.

Bupi Yishen formula may prevent kidney fibrosis by modulating fatty acid metabolism in renal tubules.

BACKGROUND: Bupi Yishen formula (BYF), a traditional Chinese herbal mixture, has demonstrated better effectiveness than Losartan in preserving renal function and preventing composite severe adverse outcomes in patients with advanced chronic kidney disease (CKD) in a recent randomized controlled trial. Prior studies have shown that BYF exerts anti-inflammatory and anti-fibrotic effects in the kidneys of CKD models, but the underlying mechanisms have not been fully elucidated. PURPOSE: The aim of this study was to investigate the protective effects of BYF administration on profibrotic phenotypic changes in the kidney and to elucidate its fundamental mechanisms of action. METHODS: Adenine and 5/6 nephrectomy rat models were administered with two doses of BYF extract (15 or 30 g/kg/d) by intragastric administration, and Losartan treatment was used as a positive control group. The relationship between BYF renoprotection and restoration of fatty acid dysregulation was examined using the two fibrosis models and TGFb1-induced human tubular HK2 cells. Transcriptomic profiles of the fibrotic kidneys obtained from adenine-induced CKD rats were used to identify the key mechanisms that are affected by BYF intervention. Human relevance and clinical implications were established by re-analysis of the microarray databases of CKD patients and immunostaining on human biopsy specimens. RESULTS: BYF effectively prevented kidney histological damage and ameliorated renal malfunction in the adenine rat model of CKD. BYF robustly attenuated the significant increase in profibrotic and proapoptotic markers in fibrotic kidneys of adenine-induced CKD rats. Transcriptomic analyses of the fibrotic kidneys of the adenine rats identified fatty acid metabolism as the key dysregulated pathway affected by BYF prevention. BYF significantly reversed defective fatty acid oxidation (FAO) and the intracellular lipids accumulation in the fibrotic kidneys induced by 5/6 nephrectomy. Furthermore, BYF prevented dysfunctional fatty acid metabolism, which were associated with the significant improvement of TGFb1-induced profibrotic changes in HK2 human proximal tubular cells. Furthermore, analyses of kidney microarray databases and biopsy specimens of CKD patients suggested that FAO defect is common in CKD in humans. CONCLUSION: Our exploratory study found that BYF may exert protective effects on renal fibrosis by regulating the fatty acid metabolism of renal tubular cells, which may be a key mechanism for preventing kidney fibrosis in CKD.

Protective effects of the Bupi Yishen formula on renal fibrosis through PI3K/AKT signaling inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: The Bupi Yishen Formula (BYF) is a patented Chinese herbal compound that has been long used to treat chronic kidney disease (CKD) in the clinic. However, its main active ingredients and underlying mechanisms remain to be elucidated. AIM: Identify the major active ingredients of BYF and investigate its protective effects and specific molecular mechanisms in renal fibrosis. METHODS: First, we performed network pharmacology analysis combined with molecular docking to predict the main active compounds, potential therapeutic targets, and intervention pathways that might exert the anti-fibrotic effect of BYF in the kidney. Then, we validated the predictions in both adenine-induced CKD rats and TGFß1-induced HK-2 cells. RESULTS: A total of 233 common targets, 25 core targets, and 10 main active compounds from BYF were selected by network pharmacology analyses. Then, GO and KEGG functional enrichment analyses indicated that the renoprotection conferred by BYF against renal fibrosis was mainly associated with the PI3K/AKT signaling. Besides, the molecular docking showed that the 10 main active compounds of BYF were closely docked with three main PI3K/AKT pathway proteins. During the experimental validations, BYF improved renal impairment and alleviated fibrosis by inhibiting the PI3K/AKT signaling activity in the kidney of adenine-induced CKD model rats. Moreover, increased PI3K/AKT signaling activation was associated with fibrotic phenotype changes in adenine-induced CKD rats and TGFß1-induced HK-2 cells. On the other hand, BYF treatment reduced PI3K/AKT signaling activation and decreased renal fibrogenesis in a dose-dependent manner, thereby indicating that PI3K/AKT signaling was essential for BYF to exert its anti-fibrotic effects. Finally, the inhibitory effect of BYF on renal fibrogenesis was not enhanced while blocking the PI3K/AKT pathway with a broad spectrum PI3K inhibitor (LY294002). CONCLUSION: In the present study, we applied a comprehensive strategy based on systemic pharmacology to reveal the anti-fibrotic mechanisms of BYF, at least partially, through the inhibition of PI3K/AKT signaling activation. We also identified BYF as a potential therapeutic agent for renal fibrosis and CKD progression.

Uncovering Bupi Yishen Formula Pharmacological Mechanisms Against Chronic Kidney Disease by Network Pharmacology and Experimental Validation.

Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality, but the therapies remain limited. Bupi Yishen Formula (BYF) - a patent traditional Chinese medicine (TCM) formula - has been proved to be effective for CKD treatment in a high-quality clinical trial. However, BYF's underlying mechanism is unclear. Thus, we aimed to reveal BYF pharmacological mechanism against CKD by network pharmacology and experimental studies. Network pharmacology-based analysis of the drug-compound-target interaction was used to predict the potential pharmacological mechanism and biological basis of BYF. We performed a comprehensive study by detecting the expression levels of fibrotic and inflammatory markers and main molecules of candidate signal pathway in adenine-induced CKD rats and TGF-ß1-induced HK-2 cells with the treatment of BYF by western blotting and RT-qPCR analyses. Using small interfering RNA, we assessed the effect of BYF on the TLR4-mediated NF-κB mechanism for CKD renal fibrosis and inflammation. Network pharmacology analysis results identified 369 common targets from BYF and CKD. Based on these common targets, the BYF intervention pathway was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We found that Toll-like receptor (TLR) and NF-κB signaling pathways were enriched. Then, we demonstrated that BYF significantly improved the adenine-induced CKD rat model condition by kidney dysfunction improvement and reversing renal fibrosis and inflammation. Subsequently, we investigated BYF's effect on the TLR4/NF-κB signaling pathway. We found that TLR4 and phospho-NF-κB (p-p65 and p-IKßα) expression was significantly upregulated in adenine-induced CKD rats, then partially downregulated by BYF. Furthermore, BYF inhibited fibrotic and inflammatory responses, as well as TLR4, p-p65, and p-IKßα in TGF-ß1-induced HK-2 cells. Additionally, the BYF inhibitory effect on fibrosis and inflammation, and NF-κB pathway activation were significantly reduced in TGF-ß1-induced HK-2 cells transfected with TLR4 siRNA. Altogether, these findings demonstrated that the suppression of TLR4-mediated NF-κB signaling was an important anti-fibrotic and anti-inflammatory mechanism for BYF against CKD. It also provided a molecular basis for new CKD treatment drug candidates.

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.

Telehealth for the management of blood pressure in patients with chronic kidney disease: A systematic review.

BACKGROUND: Most patients with chronic kidney disease (CKD) fail to achieve blood pressure (BP) management as recommended. Meanwhile, the effects of promising intervention and telehealth on BP control in CKD patients remain unclear. We aimed to evaluate the efficacy of telehealth for BP in CKD non-dialysis patients. METHODS: Databases including MEDLINE, EMBASE, CENTRAL, CNKI, Wanfang, VIP and CBM were systematically searched for randomised controlled trials or quasi-randomised controlled trials on telehealth for BP control of CKD3-5 non-dialysis patients. We analysed systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), serum creatinine, and estimated glomerular filtration rate (eGFR) with a fixed-effects model. RESULTS: Three studies, with total 680 subjects, were included in our systematic review and two were included for meta-analysis. Pooled estimates showed decreased SBP (pooled mean difference (MD), -5.10; 95% confidence interval (CI), -11.34, 1.14; p > 0.05, p = 0.11), increased DBP (pooled MD, 0.45; 95% CI, -4.24, 5.13; p > 0.05, p = 0.85), decreased serum creatinine (pooled MD, -0.38; 95% CI, -0.83, 0.07; p > 0.05, p = 0.10) and maintained eGFR (pooled MD, 4.72; 95% CI, -1.85, 11.29; p > 0.05, p = 0.16) in the telehealth group. There was no significant difference from the control group. MAP (MD, 0.6; 95% CI, -6.61, 7.81; p > 0.05, p = 0.87) and BP control rate ( p > 0.05, p = 0.8), respectively, shown in two studies also demonstrated no statistical significance in the telehealth group. CONCLUSIONS: There was no statistically significant evidence to support the superiority of telehealth for BP management in CKD patients. This suggests further studies with improved study design and optimised intervention are needed in the future.

Effects of Tongmai oral liquid in femoral ateriovenous fistula.

BACKGROUND: This study was conducted to investigate the protective effect of Tongmai oral liquid on arteriovenous fistula function and to provide an effective method to promote fistula maturation. METHODS: Fifteen female and fifteen male SPF New Zealand rabbits were randomly allocated into 3 groups including control, Aspirin and Tongmai oral liquid groups. A side-to-side femoral arteriovenous fistula was established in each rabbit and then animals were treated with Aspirin or Tongmai oral liquid for 2 weeks. The concentrations of circulating ET-1 and NO were determined before and after operation (on preoperative day, operative day, post-D1, post-D3, post-D7 and post-D15), respectively. Blood flow of the fistula stoma and contralateral artery and vein was determined on the 15th postoperative day. Last, the fistula stoma was dissected to observe patency, thrombosis and adhesion with surrounding tissues. RESULTS: 28 rabbits survived during the surgical process and the following 15-day observational period. Tissue adhesion of arteriovenous fistula with surrounding tissues was improved and fistula thrombosis was reduced by treatment with Tongmai oral liquid. NO concentration decreased to a different extent after vascular surgery. Tongmai oral liquid failed to regulate the equilibrium between NO and ET-1, but it improved blood flow of fistula stoma, as compared to control and Aspirin groups. Blood flow of fistula stoma in the three groups was lower than that of the contralateral femoral artery. CONCLUSIONS: Tongmai oral liquid improved the function of femoral ateriovenous fistula in the rabbit model by increasing blood flow and reducing thrombosis, probably not by regulating the dynamic equilibrium between NO and ET-1.

Rationale and design of the Helping Ease Renal failure with Bupi Yishen compared with the Angiotensin II Antagonist Losartan (HERBAAL) trial: a randomized controlled trial in non-diabetes stage 4 chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem. Currently, as for advanced CKD populations, medication options limited in angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), which were partially effective. A Chinese herbal compound, Bupi Yishen formula, has showed renal protective potential in experiments and retrospective studies. This study will evaluate the efficacy and safety of Bupi Yishen formula (BYF) in patients with CKD stage 4. DESIGN: In this double blind, double dummy, randomized controlled trial (RCT), there will be 554 non-diabetes stage 4 CKD patients from 16 hospitals included and randomized into two groups: Chinese medicine (CM) group or losartan group. All patients will receive basic conventional therapy. Patients in CM group will be treated with BYF daily while patients in control group will receive losartan 100 mg daily for one year. The primary outcome is the change in estimated glomerular filtration rate (eGFR) over 12 months. Secondary outcomes include the incidence of endpoint events, liver and kidney function, urinary protein creatinine ratio, cardiovascular function and quality of life. DISCUSSION: This study will be the first multi-center, double blind RCT to assess whether BYF, compared with losartan, will have beneficial effects on eGFR for non-diabetes stage 4 CKD patients. The results will help to provide evidence-based recommendations for clinicians. TRIAL REGISTRATION: Chinese Clinical Trial Registry Number: ChiCTR-TRC-10001518 .

Ginkgo biloba Extract for Patients with Early Diabetic Nephropathy: A Systematic Review.

Objectives. To evaluate the effectiveness and safety of a Ginkgo biloba extract for patients with early diabetic nephropathy. Methods. Randomised controlled trials (RCTs) conducted on adults with early diabetic nephropathy which used Gingko biloba extract were included. The major databases were searched, and manufacturers of Gingko biloba products were contacted for information on any published or unpublished studies. Two authors independently extracted the data from the included studies. Data analysis was conducted using Review Manager 5.0 software. Results. Sixteen RCTs were included. Ginkgo biloba extract decreased the urinary albumin excretion rate (UAER), fasting blood glucose (FBG), serum creatinine (SCR), and blood urea nitrogen (BUN). The extract also improved hemorheology. The methodological quality in the included studies was low. The explicit generation of the allocation sequence was described in only 6 trials. None of the included trials were confirmed to use blinding. Three studies had observed adverse events. One study using angiotensin-converting enzyme inhibitor (ACEi) reported mild cough in both groups. No serious adverse effects were reported. Conclusions. Gingko biloba extract is a valuable drug which has prospect in treating early diabetic nephropathy, especially with high UAER baseline level. The safety for early diabetic nephropathy is uncertain. Long-term, double-blinded RCTs with large sample sizes are still needed to provide stronger evidence.

Colon may provide new therapeutic targets for treatment of chronic kidney disease with Chinese medicine.

Chronic kidney disease (CKD) has become a worldwide health and social problem. Retarding its progression to end-stage renal disease is beneficial both to the patients and the healthcare system. Plenty of clinical trials have indicated that enema with Chinese medicine could effectively prevent chronic renal failure, and was widely used in the clinical practice. However, studies on mechanism were still nearly blank, which may prevent further improvement of therapeutic efficacy. Recent studies had discovered that colon was an important organ where uremic toxins were generated. The uremic toxins involved could not only promote CKD progression, but also was closely correlated with CKD mortality. Reducing production and promoting excretion of toxins were confirmed to reduce renal tubule interstitial fibrosis and delay renal progression. On the basis of the theory of gut-kidney axis above, we had conducted pilot clinical researches to evaluate the effect of enema with Chinese medicine on the intestinal flora, gut barrier, enterogenous uremic toxins and renal protection. The preliminary results revealed that rheum enema through colon could accelerate intestinal dynamics, improve intestinal barrier function, regulate intestinal flora and reduce production and absorption of intestine-derived uremic toxins such as indoxyl sulfate, which may reduce renal fibrosis and delay renal progression. Further studies could provide more evidence for colon as a new therapeutic target for the treatment of CKD with Chinese medicine.