N6-Methyladenosine Regulator-Mediated Methylation Modification Patterns with Distinct Prognosis, Oxidative Stress, and Tumor Microenvironment in Renal Cell Carcinoma.

OBJECTIVE: Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in renal cell carcinoma (RCC) progression. METHODS: Based on 23 m6A regulators, unsupervised clustering analyses were conducted to determine m6A modification subtypes across 893 RCC specimens in the Cancer Genome Atlas (TCGA) cohort. By performing principal component analysis (PCA) analysis, m6A scoring system was developed for evaluating m6A modification patterns of individual RCC patients. The activity of signaling pathways was assessed by gene-set variation analysis (GSVA) algorithm. The single-sample gene set enrichment analysis (ssGSEA) algorithm was applied for quantifying the infiltration levels of immune cells and the activity of cancer immunity cycle. Drug responses were estimated by genomics of drug sensitivity in cancer (GDSC), the Cancer Therapeutics Response Portal (CTRP) and Preservice Research Institute for Science and Mathematics (PRISM) database. RESULTS: Five m6A modification subtypes were characterized by different survival outcomes, oxidative stress, cancer stemness, infiltrations of immune cells, activity of cancer immunity cycle, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression and microsatellite instability (MSI) levels. According to m6A score, RCC patients were categorized into high and low m6A score groups. Patients with high m6A score displayed a prominent survival advantage, and the prognostic value of m6A score was confirmed in two anti-PD-1/PD-L1 immunotherapy cohorts. m6A score was significantly linked to oxidative stress-related genes, and high m6A score indicated the higher sensitivity to axitinib, pazopanib and sorafenib and the lower sensitivity to sunitinib. CONCLUSION: This study analyzed the extensive regulatory mechanisms of m6A modification on oxidative stress, the tumor microenvironment, and immunity. Quantifying m6A scores may enhance immunotherapeutic effects and assist in developing more effective agents.

Prevalence and associated factors of frailty in patients with chronic kidney disease: a cross-sectional analysis of PEAKING study.

AIM:  Frailty is common and is reported to be associated with adverse outcomes in patients with chronic diseases in Western countries. However, the prevalence of frailty remains unclear in individuals with chronic kidney disease (CKD) in China. We examined the prevalence of frailty and factors associated with frailty in patients with CKD. METHODS:  This was a cross-sectional analysis of 177 adult patients (mean age 54 ± 15 years, 52% men) with CKD from the open cohort entitled Physical Evaluation and Adverse outcomes for patients with chronic Kidney disease IN Guangdong (PEAKING). Frailty at baseline were assessed by FRAIL scale which included five items: fatigue, resistance, ambulation, illnesses, and loss of weight. Potential risk factors of frailty including age, sex, body mass index, and daily step counts recorded by ActiGraph GT3X + accelerometer were analyzed by multivariate logistic regression analysis. RESULTS: The prevalence of prefrailty and frailty was 50.0% and 11.9% in patients with stages 4-5 CKD, 29.6% and 9.3% in stage 3, and 32.1% and 0 in stages 1-2. In the multivariate logistic regression analysis, an increase of 100 steps per day (OR = 0.95, 95% CI 0.91-0.99, P = 0.01) and an increase of 5 units eGFR (OR = 0.82, 95% CI 0.68-0.99, P = 0.045) were inversely associated with being frail; higher BMI was associated with a higher likelihood of being frail (OR = 1.52, 95% CI 1.11-2.06, P = 0.008) and prefrail (OR = 1.25, 95% CI 1.10-1.42, P = 0.001). CONCLUSION:  Frailty and prefrailty were common in patients with advanced CKD. A lower number of steps per day, lower eGFR, and a higher BMI were associated with frailty in this population.

Nomogram for the prediction of crescent formation in IgA nephropathy patients: a retrospective study.

BACKGROUND: The 2017 Oxford classification of immunoglobulin A nephropathy (IgAN) recently reported that crescents could predict a worse renal outcome. Early prediction of crescent formation can help physicians determine the appropriate intervention, and thus, improve the outcomes. Therefore, we aimed to establish a nomogram model for the prediction of crescent formation in IgA nephropathy patients. METHODS: We retrospectively analyzed 200 cases of biopsy-proven IgAN patients. Least absolute shrinkage and selection operator(LASSO) regression and multivariate logistic regression was applied to screen for influencing factors of crescent formation in IgAN patients. The performance of the proposed nomogram was evaluated based on Harrell's concordance index (C-index), calibration plot, and decision curve analysis. RESULTS: Multivariate logistic analysis showed that urinary protein ≥ 1 g (OR = 3.129, 95%CI = 1.454-6.732), urinary red blood cell (URBC) counts ≥ 30/ul (OR = 3.190, 95%CI = 1.590-6.402), mALBU ≥ 1500 mg/L(OR = 2.330, 95%CI = 1.008-5.386), eGFR < 60ml/min/1.73m2(OR = 2.295, 95%CI = 1.016-5.187), Serum IgA/C3 ratio ≥ 2.59 (OR = 2.505, 95%CI = 1.241-5.057), were independent risk factors for crescent formation. Incorporating these factors, our model achieved well-fitted calibration curves and a good C-index of 0.776 (95%CI [0.711-0.840]) in predicting crescent formation. CONCLUSIONS: Our nomogram showed good calibration and was effective in predicting crescent formation risk in IgAN patients.

Division of developmental phases of freshwater leech Whitmania pigra and key genes related to neurogenesis revealed by whole genome and transcriptome analysis.

The freshwater leech Whitmania pigra (W. pigra) Whitman (Annelida phylum) is a model organism for neurodevelopmental studies. However, molecular biology research on its embryonic development is still scarce. Here, we described a series of developmental stages of the W. pigra embryos and defined five broad stages of embryogenesis: cleavage stages, blastocyst stage, gastrula stage, organogenesis and refinement, juvenile. We obtained a total of 239.64 Gb transcriptome data of eight representative developmental phases of embryos (from blastocyst stage to maturity), which was then assembled into 21,482 unigenes according to our reference genome sequenced by single-molecule real-time (SMRT) long-read sequencing. We found 3114 genes differentially expressed during the eight phases with phase-specific expression pattern. Using a comprehensive transcriptome dataset, we demonstrated that 57, 49 and 77 DEGs were respectively related to morphogenesis, signal pathways and neurogenesis. 49 DEGs related to signal pathways included 30 wnt genes, 14 notch genes, and 5 hedgehog genes. In particular, we found a cluster consisting of 7 genes related to signal pathways as well as synapses, which were essential for regulating embryonic development. Eight genes cooperatively participated in regulating neurogenesis. Our results reveal the whole picture of W. pigra development mechanism from the perspective of transcriptome and provide new clues for organogenesis and neurodevelopmental studies of Annelida species.

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.

Effects of Tiaopi Xiezhuo decoction on constipation and gut dysbiosis in patients with peritoneal dialysis.

CONTEXT: A Chinese herbal formula, Tiaopi Xiezhuo decoction (TXD), is developed from a classical Chinese prescription Sanhuang Xiexin decoction. OBJECTIVE: To investigate the regulatory effect of TXD on gut dysbiosis, as a treatment of constipation in patients with peritoneal dialysis (PD). MATERIALS AND METHODS: The chemical content of TXD was assessed by high-performance liquid chromatography. A total of 29 PD patients were enrolled and treated with TXD orally (3 g crude drug/each/twice/day) for 3 months. Blood and faecal samples were collected at the beginning and end, to determine the changes in biochemical characteristics and gut microbial composition. The stool conditions were asked to be scored. Additional 30 healthy individuals were recruited as a control for the analysis of gut microbiota. RESULTS: Although having no significant effects on serum biochemical characteristics, 3-month TXD intervention improved constipation in PD patients: decreased 80% abdominal distention (p < 0.01), increased 2.6-fold sloppy stools (p < 0.05) and eliminated hard stool completely (p < 0.01). The analysis of gut microbiota showed that, compared to the healthy group, the microbial richness was reduced in PD patients. After a 3-month TXD treatment, this reduced richness was raised, and Paraprevotella clara, Lachnospiraceae bacterium 2-146FA, Phascolarctobaterium succinatutens, Lachnospiraceae bacterium 2-1-58FAA, Fusobacterium mortiferum, and Prevotella copri were accumulated in the intestinal flora. Furthermore, the bacterial species enriched by TXD correlated with the improvement of constipation. DISCUSSION AND CONCLUSIONS: TXD treatment may improve constipation by modulating gut dysbiosis in PD patients. These findings provide data to support the further application of TXD in the adjuvant treatment of PD.

Piperacillin/tazobactam and risk of acute kidney injury in adults hospitalized with infection without vancomycin: a multi-centre real-world data analysis.

BACKGROUND: There is uncertainty about whether piperacillin/tazobactam (PT) increases the risk of acute kidney injury (AKI) in patients without concomitant use of vancomycin. This study compared the risk of hospital-acquired AKI (HA-AKI) among adults treated with PT or antipseudomonal ß-lactams (meropenem, ceftazidime) without concomitant use of vancomycin. METHODS: This real-world study analysed the data from China Renal Data System and assessed the risk of HA-AKI in adults hospitalized with infection after exposure to PT, meropenem or ceftazidime in the absence of concomitant vancomycin. The primary outcome was any stage of HA-AKI according to the Kidney Disease Improving Global Outcomes guidelines. A multi-variable Cox regression model and different propensity score (PS) matching models were used. RESULTS: Among the 29,441 adults [mean (standard deviation) age 62.44 (16.84) years; 17,980 females (61.1%)] included in this study, 14,721 (50%) used PT, 9081 (31%) used meropenem and 5639 (19%) used ceftazidime. During a median follow-up period of 8 days, 2601 (8.8%) develped HA-AKI. The use of PT was not associated with significantly higher risk of HA-AKI compared with meropenem [adjusted hazard ratio (aHR) 1.07, 95% confidence interval (CI) 0.97-1.19], ceftazidime (aHR 1.09, 95% CI 0.92-1.30) or both agents (aHR 1.07, 95% CI 0.97-1.17) after adjusting for confounders. Results were consistent in stratified analyses, PS matching using logistic regression or random forest methods to generate a PS, and in an analysis restricting outcomes to AKI stage 2-3. CONCLUSIONS: Without concomitant use of vancomycin, the risk of AKI following PT therapy is comparable with that of meropenem or ceftazidime among adults hospitalized with infection.

Metagenomics-based systematic analysis reveals that gut microbiota Gd-IgA1-associated enzymes may play a key role in IgA nephropathy.

Background: IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia. Its pathogenesis involves higher expression of galactose-deficient IgA1 (Gd-IgA1) and dysregulated intestinal mucosal immunity. The objective of this study was to explore whether specific gut microbiota and associated enzymes affect Gd-IgA1 in IgAN. Methods: This study carried out shotgun metagenomic sequencing with Illumina on fecal samples collected from 20 IgAN patients (IgAN group) and 20 healthy controls (HCs group) who were recruited from January 2016 to December 2018 at the Second Clinical College of Guangzhou University of Chinese Medicine. Differences analysis in gut microbiota was performed to determine the overall microbiota composition, the representative enterotypes, and the microbiota abundance. Correlations between gut microbiota and clinical indicators were assessed by Spearman's analysis. Moreover, the functional prediction of microbial communities and the quantitative calculation of enzymes encoded by microbiome were performed using the MetaCyc pathway and the bioBakery three platform, respectively. Results: Bacteroides plebeius and Bacteroides vulgatus levels were higher, while Prevotella copri and Alistipes putredinis levels were lower in the IgAN group compared to HCs group. Enterotype I characterized by Bacteroides was closely related to the IgAN patients. Moreover, Bacteroides fragilis, Flavonifractor plautii and Ruminococcus gnavus were characteristic bacteria enriched in IgAN patients. Spearman's correlation analysis found that Eggerthella lenta and Ruminococcus bromii were positively correlated with urine protein-creatinine ratio, while Ruminococcus gnavus showed a direct association with red blood cells in urine, and Bacteroides vulgatus and Ruminococcus gnavus were positively correlated with eGFR. These results indicated that intestinal dysbacteriosis occurred in IgAN patients and was associated with clinical and biochemical features. In addition, MetaCyc pathway analysis predicted microbiota-related metabolic pathways, including the biosynthesis of amino acids and glycans, were associated with the IgAN group. Microbial enzymes analysis highlighted that Gd-IgA1-associated α-galactosidase and α-N-acetyl-galactosaminidase secreted by Flavonifractor plautii were enriched in IgAN patients. Conclusion: These findings suggested that α-galactosidase and α-N-acetyl-galactosaminidase secreted by Flavonifractor plautii might be related to the production of Gd-IgA1, indicating that enzymes originated from abnormal intestinal microbiota may contribute to the production of Gd-IgA1 and play an important role in the pathogenesis of IgAN.

Protective effect of quercetin on kidney diseases: From chemistry to herbal medicines.

Kidney injuries may trigger renal fibrosis and lead to chronic kidney disease (CKD), but effective therapeutic strategies are still limited. Quercetin is a natural flavonoid widely distributed in herbal medicines. A large number of studies have demonstrated that quercetin may protect kidneys by alleviating renal toxicity, apoptosis, fibrosis and inflammation in a variety of kidney diseases. Therefore, quercetin could be one of the promising drugs in the treatment of renal disorders. In the present study, we review the latest progress and highlight the beneficial role of quercetin in kidney diseases and its underlying mechanisms. The pharmacokinetics and bioavailability of quercetin and its proportion in herbal medicine will also be discussed.

Comparison between outcomes of IgA nephropathy with nephrotic-range proteinuria and nephrotic syndrome: do podocytes play a role?

BACKGROUND: Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. METHODS: We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. RESULTS: Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan-Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835-76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078-0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047-0.689; p = 0.012) was further reduced. CONCLUSIONS: NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.

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.

Salvia miltiorrhiza Bunge (Danshen) and Bioactive Compound Tanshinone IIA Alleviates Cisplatin-Induced Acute Kidney Injury Through Regulating PXR/NF-κB Signaling.

Objective: The present study aims to provide evidence on the potential protective role of Salvia miltiorrhiza Bunge (Danshen) and its bioactive compound Tanshinone IIA (TanIIA) in AKI and to reveal the specific regulatory function of PXR/NF-κB signaling in AKI-induced renal inflammation. Methods: A network pharmacological analysis was used to study target genes and regulatory networks in the treatment of Salvia miltiorrhiza on AKI. Further experiments with in vivo AKI mouse model and in vitro studies were applied to investigate the renal protective effect of TanIIA in AKI. The mechanisms of TanIIA regulating PXR/NF-κB signaling in renal inflammation were also studied. Results: Network pharmacology had suggested the nuclear receptor family as new therapeutic targets of Salvia miltiorrhiza in AKI treatment. The in vivo studies had demonstrated that TanIIA improved renal function and inflammation by reducing necrosis and promoting the proliferation of tubular epithelial cells. Improved renal arterial perfusion in AKI mice with TanIIA treatment was also recorded by ultrasonography. In vitro studies had shown that TanIIA ameliorated renal inflammation by activating the PXR while inhibiting PXR-mediated NF-κB signaling. The results had suggested a role of PXR activation against AKI-induced renal inflammation. Conclusion: Salvia miltiorrhiza Bunge (Danshen) may protect the kidneys against AKI by regulating nuclear receptors. TanIIA improved cell necrosis proliferation and reduced renal inflammation by upregulating the expression of the PXR and inhibiting NF-κB signaling in a PXR-dependent manner. The PXR may be a potential therapeutic target for AKI treatment.

Current apparent treatment-resistant hypertension in patients undergoing peritoneal dialysis: A multi-center cross-sectional study.

Apparent treatment-resistant hypertension (aTRH) is the most commonly used term to report resistant hypertension (RH) and is considered as a common problem in dialysis population. However, few reports have focused on peritoneal dialysis (PD) hypertensive patients. The authors conducted a multi-center cross-sectional study involving 1789 PD patients from nine centers in Guangdong, China. The prevalence of aTRH was estimated by home blood pressure (BP) monitoring. Evaluating drug adherence through Eight-item Morisky Medication Adherence Scale (MMAS-8) and pill counting was performed to assess RH in one PD center. Related factors of aTRH were analyzed using logistic regression analysis. The prevalence of aTRH in PD patients was estimated at 42.2% (755 out of 1789 hypertensive patients) based on home BP. Of those, 91.4% patients were classified as uncontrolled RH, 2.0% as controlled RH, and 6.6% as refractory hypertension. The prevalence of RH was 40.6% and 41.9% among those with medium/high adherence based on the MMAS-8 scores and the pill counting rate, respectively. PD patients who were younger, with higher body mass index, with lower serum albumin and poorer dialysis adequacy were significantly associated with higher aTRH incident. In conclusion, the present study demonstrates a high prevalence of aTRH in PD population, which occurs in about two in five treated hypertensive patients. Nutritional status and dialysis adequacy might tightly associate with aTRH.

Characterization of the complete mitochondrial genome of Haemadipsa tianmushana Song 1977 (Hirudiniformes, Haemadipsidae) and its phylogenetic analysis.

The complete mitochondrial genome of Haemadipsa tianmushana Song 1977 from China has been determined and reported for the first time in this study. It was 14,625 bp in length and consisted of 22 tRNA genes, 2 rRNA genes, 13 protein-coding genes (PCGs), and 3 control regions. The nucleotide base content of the complete mitogenome for this species was 35.1% A, 10.5% C, 11.6% G, and 42.8% T. The tRNA genes were ranged from 57 bp (SerTCT) to 66 bp (GlnTTG) in length. The phylogenetic analyses indicated that Hirudinea is a mono-phyletic clade. And it includes Whitmania acranulata, Whitmania pigra, Whitmania laevis, Zeylanicobdella arugamensis, Ozobranchus jantseanus and Placobdella lamothei. In Hirudiniformes, H. tianmushana and three species of Haemopidae were obviously clustered into two independent branches. This result is consistent with a taxonomy that they all belong to the same suborder. This study adds to the genetic resources currently available for the species.

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.

Propensity-matched comparison of mortality between peritoneal dialysis and hemodialysis in patients with type 2 diabetes.

BACKGROUND: The optimal choice of dialysis modality for diabetic patients remains controversial. This study aimed to compare mortality between peritoneal dialysis (PD) and hemodialysis (HD) in end-stage renal disease (ESRD) patients with type 2 diabetes (T2D). METHODS: Our observational, longitudinal cohort consisted of all incident ESRD patients with T2D who received either PD or HD in our center from January 2012 to December 2017 and were followed until December 2019. Propensity scores were used to select a 1:1 matched cohort. Mortality was compared between dialysis modalities using Kaplan-Meier survival analysis, and risk factors for mortality were estimated using multivariate Cox regression analyses. RESULTS: The median follow-up times were 35.5 months in the PD group (n = 134) and 41.6 months in the HD group (n = 134, p = 0.0381). The 1-, 2-, 3-, 5-, and 7-year patient survival rates were 98%, 91%, 77%, 61%, and 35% for diabetic PD patients and 96%, 88%, 81%, 60%, and 57% for diabetic HD patients. Kaplan-Meier survival analysis showed that overall mortality did not significantly differ between modalities (log-rank = 0.9473, p = 0.6575). Using a multivariate Cox regression model, advanced age and increased cholesterol at the initiation of PD treatment were independent risk factors associated with mortality, whereas under HD therapy, the risk factors associated with mortality were lower BMI and higher HbA1c. CONCLUSIONS: These results suggest that in patients with T2D, mortality is comparable between PD and HD irrespective of whether there are the first 2 years or over the 2-year period, and that different mortality predictor patterns exist between patients treated with PD versus HD.

The "Half-Perc" technique using a simple modified metal trocar for peritoneal dialysis catheter placement: results of a 3-year follow-up of 280 patients and a literature review.

PURPOSE: There is an ongoing debate about the ideal technique for peritoneal dialysis (PD) catheter insertion in patients with end-stage renal disease (ESRD). A half-percutaneous ("Half-Perc") technique shares some of the advantages of both percutaneous technique and traditional open surgery. This retrospective study aimed to evaluate the clinical feasibility, safety, and effects of the "Half-Perc" technique for PD catheter placement, and to compare the clinical outcomes of the "Half-Perc" technique with various imaging-assisted percutaneous techniques from the current literature. METHODS: We included 280 consecutive patients with ESRD who underwent the "Half-Perc" insertion of the first PD catheter between September 2016 and September 2019. We recorded baseline characteristics, operative parameters, catheter-related complications, catheter survival, and the reason behind PD cessation. RESULTS: We included 174 men and 106 women, with a mean age of 50.4 years (range, 11-85 years). The mean operative time was 28.8 min (range, 15-38 min) and technical success rate was observed in 278 patients (99.3%). There were 28 episodes (10%) of mechanical complications with initial catheters occurring during the follow-up. Catheter malfunctions were the most common mechanical complication and were observed in 15 patients. Peritonitis was the most frequent catheter-related complication, with 32 episodes of peritonitis observed in 29 (10.4%) patients. After a mean follow-up period of 15.4 months (range, 2-36 months), 235 patients (83.9%) survived with their initial PD catheter by the end of the study. Of the 280 patients analyzed, 35 patients (12.5%) ceased PD at some stage during follow-up. The most common reason for PD cessation was kidney transplantation (18 patients (6.4%)), followed by death (9 patients (3.2%)) and switch to hemodialysis (HD) (7 patients (2.5%)), and recovery of renal failure (1 patient (0.4%)). CONCLUSION: The "Half-Perc" technique, including a modified metal trocar, is a simple, safe, and effective method for PD catheter placement that can be used for patients with ESRD.

The Role of Gut Microbiota and Microbiota-Related Serum Metabolites in the Progression of Diabetic Kidney Disease.

Objective: Diabetic kidney disease (DKD) has become the major cause of end-stage renal disease (ESRD) associated with the progression of renal fibrosis. As gut microbiota dysbiosis is closely related to renal damage and fibrosis, we investigated the role of gut microbiota and microbiota-related serum metabolites in DKD progression in this study. Methods: Fecal and serum samples obtained from predialysis DKD patients from January 2017 to December 2019 were detected using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry, respectively. Forty-one predialysis patients were divided into two groups according to their estimated glomerular filtration rate (eGFR): the DKD non-ESRD group (eGFR ≥ 15 ml/min/1.73 m2) (n = 22), and the DKD ESRD group (eGFR < 15 ml/min/1.73 m2) (n = 19). The metabolic pathways related to differential serum metabolites were obtained by the KEGG pathway analysis. Differences between the two groups relative to gut microbiota profiles and serum metabolites were investigated, and associations between gut microbiota and metabolite concentrations were assessed. Correlations between clinical indicators and both microbiota-related metabolites and gut microbiota were calculated by Spearman rank correlation coefficient and visualized by heatmap. Results: Eleven different intestinal floras and 239 different serum metabolites were identified between the two groups. Of 239 serum metabolites, 192 related to the 11 different intestinal flora were mainly enriched in six metabolic pathways, among which, phenylalanine and tryptophan metabolic pathways were most associated with DKD progression. Four microbiota-related metabolites in the phenylalanine metabolic pathway [hippuric acid (HA), L-(-)-3-phenylactic acid, trans-3-hydroxy-cinnamate, and dihydro-3-coumaric acid] and indole-3 acetic acid (IAA) in the tryptophan metabolic pathway positively correlated with DKD progression, whereas L-tryptophan in the tryptophan metabolic pathway had a negative correlation. Intestinal flora g_Abiotrophia and g_norank_f_Peptococcaceae were positively correlated with the increase in renal function indicators and serum metabolite HA. G_Lachnospiraceae_NC2004_Group was negatively correlated with the increase in renal function indicators and serum metabolites [L-(-)-3-phenyllactic acid and IAA]. Conclusions: This study highlights the interaction among gut microbiota, serum metabolites, and clinical indicators in predialysis DKD patients, and provides new insights into the role of gut microbiota and microbiota-related serum metabolites that were enriched in the phenylalanine and tryptophan metabolic pathways, which correlated with the progression of DKD.

Characteristics Analysis, Clinical Outcome and Risk Factors for Fungal Peritonitis in Peritoneal Dialysis Patients: A 10-Year Case-Control Study.

Background: Fungal peritonitis (FP) is a rare but severe complication that can appear in patients receiving peritoneal dialysis (PD). This study aimed to investigate the incidence rate and clinical characteristics of FP, evaluate clinical outcomes between FP and bacterial peritonitis (BP) patients on PD, and especially estimate the risk factors for FP outbreak. Methods: All episodes of FP diagnosed in our hospital from January 1, 2011, to December 31, 2020, were reviewed in this single-center study. FP cases were analyzed and compared with patients diagnosed with BP in a 1:6 ratio matching for case-control study. Patient information, including clinical information, biochemical analysis, and outcomes, was recorded. Univariate and multivariate logistic regression model were used to analyze the risk factors for FP. Results: A total of 15 FP episodes were observed in 15 PD patients, with an FP rate of 0.0071 episodes per patient-year. Seventeen strains of fungi were isolated and identified. Candida was the most common pathogen (15 strains, 88.2%), followed by Aspergillus fumigatus (2 strains, 11.8%). Between the groups, FP group showed a higher rate of HD transfer and catheter removal, and a lower rate of PD resumption in the short-term outcome (all P < 0.01), while no significant difference in the mortality was noted during the whole study period. The multivariate logistic regression analysis showed that longer PD duration (odds ratio [OR] 1.042, 95% confidence interval [CI] 1.012-1.073, P < 0.01), higher serum potassium (OR 3.373, 95% CI 1.068-10.649, P < 0.05), elevated estimated glomerular filtration rate (eGFR) (OR 1.845, 95% CI 1.151-2.955, P < 0.05), reduced serum albumin level (OR 0.820, 95% CI 0.695-0.968, P < 0.05) and peritoneal effluent polymorphonuclear (PMN) count (OR 0.940, 95%CI 0.900-0.981, P < 0.01) were significantly increased the risk for FP. Conclusion: These results suggested that FP leads to higher rate of catheter removal and HD transfer, and a lower rate of PD resumption than BP, and that additional attention should be paid to hypoalbuminemia, increased serum potassium, long PD duration, and low peritoneal effluent PMN in PD patients.

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.