Phage therapy is emerging as a promising alternative to antibiotics for treating various infections. However, there have been no prior studies on using bacteriophages for peritonitis in patients undergoing peritoneal dialysis. This report presents the successful treatment of refractory peritonitis in a 71-year-old male peritoneal dialysis patient using bacteriophages combined with antibiotics. The patient has a history of refractory and repeat peritonitis caused by Staphylococcus haemolyticus, which was resolved through simultaneous catheter replacement (SCR). Subsequently, the patient experiences another episode of refractory peritonitis due to Klebsiella pneumoniae. Although this strain is found to be susceptible to amikacin and imipenem, a 14-day course of treatment with these antibiotics in the abdominal cavity fails to resolve the peritonitis. Combined with antibiotic therapy, the patient is successfully treated with intraperitoneal phage therapy targeting his bacterial isolate. We monitor the longitudinal progression of phage loads, phage-neutralizing antibodies, interleukin-6 levels, and lipopolysaccharide concentrations in the dialysate effluent during the bacteriophage therapy. The combination of a phage cocktail and imipenem (IPM) demonstrates a greater effect in killing bacteria than either treatment alone, which indicates that a synergistic effect exists between the phage cocktail and IPM. Intraperitoneal IPM is discontinued after a 3-week course of treatment. At the same time, oral fluconazole is given to prevent fungal infections. The patient is discharged without any antibiotics. After this round of treatment, the patient remains healthy during the one-month follow-up. Our study suggests that personalized phage therapy combined with sensitive antibiotics can play a significant role in managing refractory peritonitis in patients undergoing peritoneal dialysis, showing promise for future applications.

BACKGROUND:Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2. METHODS:The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin. RESULTS:Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells. CONCLUSION:Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.

INTRODUCTION:Peritoneal dialysis (PD)-associated peritonitis is a major complication in PD patients, leading to increased morbidity and technique failure. Identifying reliable biomarkers for predicting peritonitis risk is crucial for early intervention. Monocyte-to-lymphocyte ratio (MLR) is an emerging inflammatory marker associated with adverse outcomes in end-stage renal disease, but its predictive value for peritonitis remains unclear. METHODS:This retrospective cohort study included PD patients from a single center who had undergone PD for at least 3 months. MLR was assessed at the time of PD catheter insertion, and patients were followed for 36 months. Peritonitis was defined according to the International Society for Peritoneal Dialysis criteria. Cox proportional hazards models were used to analyze the association between MLR (continuous and tertile-based) and peritonitis, adjusting for demographic, clinical, and laboratory factors. Restricted cubic spline (RCS) regression was applied to evaluate nonlinearity, and subgroup analysis was conducted to examine whether the association between MLR and peritonitis was consistent across different subgroups. RESULTS:A total of 108 patients were included, with 33 (30.6%) developing peritonitis. MLR was significantly higher in the peritonitis group (p = 0.032). Cox regression showed that higher MLR was independently associated with an increased risk of peritonitis (adjusted hazard ratio = 1.85, 95% confidence interval: 1.01-3.40, p = 0.048). Patients in the highest MLR tertile had a sixfold increased peritonitis risk compared to those in the lowest tertile (p for trend = 0.002). RCS analysis revealed a nonlinear association, with a threshold at natural logarithm-transformed MLR = -0.9. Subgroup analysis suggested a stronger association in patients with lower body mass index (<24 kg/m2). CONCLUSION:Higher MLR at PD initiation is an independent predictor of long-term peritonitis risk. MLR may serve as a simple, cost-effective biomarker for early peritonitis risk stratification, particularly in leaner patients.

The complexity of the tumor microenvironment (TME) is a crucial factor in lung adenocarcinoma (LUAD) progression. To gain deeper insights into molecular mechanisms of LUAD, we perform an integrative single-cell RNA sequencing (scRNA-seq) data analysis of 377,574 cells from 117 LUAD patient samples. By linking scRNA-seq data with bulk gene expression data, we identify a cluster of prognostic-related UPP1 high tumor cells. These cells, primarily situated at the invasive front of tumors, display a stronger association with the immunosuppressive components in the TME. Our cytokine array analysis reveals that the upregulation of UPP1 in tumor cells leads to the increased release of various immunosuppressive cytokines, with TGF-β1 being particularly prominent. Furthermore, this UPP1 upregulation also elevates the expression of PD-L1 through the PI3K/AKT/mTOR pathway, which contributes to the suppression of CD8 + T cells. Cytometry by time-of-flight (CyTOF) analysis provides additional evidence of the role of UPP1 in shaping the immunosuppressive nature of the TME. Using patient-derived organoids (PDOs), we discover that UPP1 high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

Cisplatin is a chemotherapeutic agent that is used extensively to treat solid tumors; however, its clinical application is limited by side effects, especially nephrotoxicity. Cisplatin-induced acute kidney injury (AKI) is characterized by DNA damage, cell-cycle arrest, and mitochondrial oxidative stress. Recent research demonstrated that 14-3-3ζ plays an important role in cancers, nerve disease, and kidney disease, although the regulatory mechanisms underlying cisplatin-induced AKI have yet to be fully elucidated. In the present study, we found that 14-3-3ζ mRNA was upregulated in human kidney organoids (GSE145085) when treated with cisplatin; subsequently, this was confirmed in experimental mice. The application of a protein interaction inhibitor for 14-3-3 (BV02) resulted in a decline in renal function, along with apoptosis, mitochondrial dysfunction, and oxidative stress in cisplatin-induced AKI. Accordingly, the knockdown of 14-3-3ζ in cisplatin-treated NRK-52E cells led to increased apoptosis, cell-cycle arrest, the production of reactive oxygen species (ROS), and lipid dysbolism. Furthermore, the blockade of 14-3-3ζ, both in vivo and in vitro, suppressed β-catenin and its nuclear translocation, thus downregulating expression of the downstream gene cyclin D1 in cisplatin-induced damage. In contrast, the overexpression of 14-3-3ζ alleviated the injury caused by cisplatin both in vivo and in vitro. Furthermore, a non-specific agonist of β-catenin, BIO, reversed the effects of 14-3-3ζ knockdown in terms of cisplatin-induced damage in NRK-52E cells by activating β-catenin. Next, we verified the direct interaction between 14 - 3-3ζ and β-catenin by CO-IP and immunofluorescence. Collectively, these findings indicate that 14-3-3ζ protects against cisplatin-induced AKI by improving mitochondrial function and the balance between proliferation and apoptosis by facilitating the nuclear translocation of β-catenin.

Abstract Background Gut dysbiosis in peritoneal dialysis (PD) patients causes chronic inflammation and metabolic disorders which result in a series of complications, probably playing an important role in PD technique failure. The reduction in gut microbial diversity was a common feature of gut dysbiosis. The objective was to explore the relationship between gut microbial diversity and technique failure in PD patients. Methods The gut microbiota was analyzed by 16s ribosomal RNA gene amplicon sequencing. Cox proportional hazards models were used to identify association between gut microbial diversity and technique failure in PD patients. Results In this study, a total of 101 PD patients were enrolled. During a median follow-up of 38 months, we found that lower diversity was independently associated with a higher risk of technique failure (hazard ratio [HR], 2.682; 95% confidence interval [CI], 1.319–5.456; p = 0.006). In addition, older age (HR, 1.034; 95% CI, 1.005–1.063; p = 0.020) and the history of diabetes (HR, 5.547; 95% CI, 2.218–13.876; p < 0.001) were also independent predictors for technique failure of PD patients. The prediction model constructed on the basis of three independent risk factors above performed well in predicting technique failure at 36 and 48 months (36 months: area under the curve [AUC] = 0.861; 95% CI, 0.836–0.886; 48 months: AUC = 0.815; 95% CI, 0.774–0.857). Conclusion Gut microbial diversity was independently correlated with technique failure in PD patients, and some specific microbial taxa may serve as a potential therapeutic target for decreasing PD technique failure.

Peritoneal dialysis (PD) is a renal replacement therapy for end-stage renal disease. Gut microbiota-derived uremic solutes, indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine-N-oxide (TMAO) accumulate in PD patients. The objective was to explore the gut microbiota and their influence on uremic toxins in PD patients and healthy controls (HC). Fecal samples were collected from PD patients (n = 105) and HC (n = 102). 16S rRNA gene regions were sequenced for gut microbiota analysis. IS, PCS, and TMAO levels were measured using HPLC-MS. PD patients exhibited lower alpha diversity and altered gut microbiota composition compared to HC. At the genus level, PD patients showed increased abundance of opportunistic pathogenic bacteria, and decreased abundance of beneficial bacteria. Three Operational Taxonomic Units discriminated PD patients from HC. Phenylalanine metabolism increased in PD, whereas tryptophan metabolism was unaltered. Low serum PCS did not necessarily mean healthier due to the loss of alpha diversity, increased Proteobacteria and opportunistic pathogenic bacteria. High serum PCS was mainly caused by elevated p-cresol-producing bacteria, enriched amino acid related enzymes, and enhanced sulfur metabolism, rather than declined residual renal function. In patients with different urine volumes, the gut microbiota alpha diversity and composition were unaltered, but serum IS and TMAO were significantly elevated in anuric patients. In conclusion, the gut microbiota abundance, composition, and function were altered in PD patients, which increased the PCS levels. We provided a better understanding of the microbiota-metabolite-kidney axis in PD patients. Targeting certain bacteria could decrease the PCS levels, whereas preserving the residual renal function could reduce the IS and TMAO levels.

Cisplatin, an extensively used chemotherapeutic agent for solid tumors, is limited in clinical use due to its side effects, especially nephrotoxicity. Cisplatin-induced acute kidney injury (AKI) is characterized by DNA damage, cell cycle arrest and mitochondrial oxidative stress. Recent work demonstrated that 14-3-3ζ plays important role in cancers, nerve disease and kidney disease, but the role and regulatory mechanism in cisplatin AKI remain to be further clarified. Here, we found that the transcriptional level of 14-3-3ζ was upregulated in human kidney organoids (GSE145085) when treated with cisplatin, which was confirmed in experimental mice. Then the use of a small molecule inhibitor for 14-3-3 (BV02) aggregated drop of renal function, apoptosis, mitochondrial dysfunction and oxidative stress in cisplatin-induced AKI. Among these, mitochondria dysfunction was intensified as exhibited by worsened mitochondria in morphology, more accumulation of lipid droplets, decreasing ATP synthesis and downregulation of CPT-1α and PGC-1α mRNAs. Accordingly, increased apoptosis, cell cycle arrest, ROS production and lipid dysbolism in cisplatin-treated NRK-52E cells were exacerbated in cells knocking down 14-3-3ζ. Strikingly, blocking 14-3-3ζ both in vivo and in vitro suppressed β-catenin and its nuclear translocation, downregulating the expression of cyclin D1 in cisplatin-induced damage. In contrast, overexpression of 14-3-3ζ relieved injury caused by cisplatin and promoted the transportation of β-catenin to the nucleus. Further, a non-specific agonist of β-catenin BIO reversed the effects of knocking down 14-3-3ζ in cisplatin-induced damage in NRK-52E by activating β-catenin. Taken together, these findings indicate that 14-3-3ζ protects against cisplatin-induced AKI by improving proliferation, mitochondrial function and lipid metabolism through facilitating β-catenin nuclear translocation.

Acute kidney injury (AKI) is a serious condition with high mortality. The most common cause is kidney ischemia/reperfusion (IR) injury, which is thought to be closely related to pyroptosis. Disulfiram is a well-known alcohol abuse drug, and recent studies have shown its ability to mitigate pyroptosis in mouse macrophages. This study investigated whether disulfiram could improve IR-induced AKI and elucidated the possible molecular mechanism. We generated an IR model in mouse kidneys and a hypoxia/reoxygenation (HR) injury model with murine tubular epithelial cells (MTECs). The results showed that IR caused renal dysfunction in mice and triggered pyroptosis in renal tubular epithelial cells, and disulfiram improved renal impairment after IR. The expression of proteins associated with the classical pyroptosis pathway (Nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3), apoptosis-related specific protein (ASC), caspase-1, N-GSDMD) and nonclassical pyroptosis pathway (caspase-11, N-GSDMD) were upregulated after IR. Disulfiram blocked the upregulation of nonclassical but not all classical pyroptosis pathway proteins (NLRP3 and ASC), suggesting that disulfiram might reduce pyroptosis by inhibiting the caspase-11-GSDMD pathway. In vitro, HR increased intracellular ROS levels, the positive rate of PI staining and LDH levels in MTECs, all of which were reversed by disulfiram pretreatment. Furthermore, we performed a computer simulation of the TIR domain of TLR4 using homology modeling and identified a small molecular binding energy between disulfiram and the TIR domain. We concluded that disulfiram might inhibit pyroptosis by antagonizing TLR4 and inhibiting the caspase-11-GSDMD pathway.

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）作为针对细胞毒性T淋巴细胞相关抗原4（cytotoxic T-lymphocyte-associated protein 4，CTLA-4）和程序性死亡蛋白1（programmed death 1，PD-1）或其配体PD-L1研制的系列抗体，在肿瘤治疗中取得良好效果，但其在提高生存率的同时，也带来了一系列不良反应。对于肾脏而言，最常见的不良反应是急性间质性肾炎（acute interstitial nephritis，AIN）。本文将从发病机制、临床表现、诊断和防治这几个方面对ICIs所致肾脏不良反应进行综述，以期更好地认识和处理肾脏相关免疫不良反应，改善患者的预后。

Introduction: The immune senescence marked by the inflation of memory T cell is established in end-stage renal disease (ESRD) patients with peritoneal dialysis (PD). These patients suffer high incidence of infectious disease, which has been relevant to immune dysfunction. However the association of immune senescence with infection in PD patients is not clear. This prospective study aimed to investigate the relationship between proportion of T cell subsets and infection event in patients on PD. Methods: We enrolled patients on PD >6 months from January 1, 2016 to December 30, 2016 and followed them until April 30, 2020. Baseline T cell subsets from blood were collected at the time of recruitment. The primary end point was infection event including peritonitis, exit site infection, pneumonia, urinary tract infection, and other infection. Results: There were 94 patients (46 male) with a mean age of 56.1 ± 14.9 years old enrolled during the follow-up period, and 26 patients suffered infection events. A higher proportion of effector memory (EM) CD8+ T cells was found in patients with infection than in those without infection. There was no difference in the distribution of EM CD8+ T cells between PD-related and non-dialysis infection. Increased level of EM CD8+ T cells was risk factor for first infection event in PD patients. Conclusion: High level of EM CD8+ T cells could be a significant predictor of infection event in patients on PD.

对于腹膜透析(peritoneal dialysis,PD)(简称腹透)患者的难治性腹膜炎,国际腹膜透析协会(International Society for Peritoneal Dialysis,ISPD)腹膜炎诊治指南建议早期拔管,期间给予血液透析(简称血透)过渡,而何时进行腹透管重置目前尚缺乏明确的循证医学证据.本文报道1例PD患者拔管与置管同时进行成功治疗复发性合并难治性腹膜炎,避免血透过渡时新建血管通路以及血透相关风险,结合其诊治过程,加深对复发性及难治性腹膜炎的认识,为PD相关腹膜炎的预防和治疗提供可借鉴的经验.

Disulfiram (DSF), a promising caspase-11 inhibitor, is a widely used U.S. Food and Drug Administration (FDA)-approved drug for alcohol-abuse prevention. It is also recently confirmed to be a copper (Cu2+)-dependent antineoplastic medicine. We now propose a mechanism by which DSF may alleviate renal damage from I/R AKI. We confirmed that DSF attenuated the pyroptosis of tubular epithelial cells through the inhibition of caspase-11-GSDMD pathway instead of classical pyroptosis pathwayin vitro and in vivo .

全球约有10%的成年人患有慢性肾脏疾病，不断攀升的肾脏疾病发病率对临床与公共卫生事业都是一个巨大的挑战。本文综述了近年来肾脏类器官的构建过程及其在肾脏疾病中的应用进展。类器官模型不仅在构建肾脏疾病模型中兼顾了动物模型和细胞培养的优点，还能对疾病进行治疗药物筛选和药物肾毒性检测。在未来，肾脏类器官也有望成为肾移植的供肾来源。

Peritoneal dialysis (PD) is a replacement therapy for end-stage renal disease patients. In the first 4-8 weeks of PD, the patients were given an empirical dialysis prescription due to unknown peritoneal transport characteristics. Proteomic analysis could be used to identify serum biomarkers. In a discovery set, patients were divided into three groups according to the peritoneal equilibration test (PET) results: high (H), high average (HA), low average and low (LA&L) groups. A total of 1051 identified proteins were screened by Nano HPLC-MS/MS. The top two proteins among different peritoneal transport characteristics were Orosomucoid 2 (ORM2) and Creactive protein (CRP). In a validation set, CRP was significantly elevated in H group than LA&L group, consistent with proteomic analysis. Serum ORM2 was enhanced in LA&L group compared with H and HA group. The expression of ORM2 in peritoneum was also enriched in LA&L group. At last, supplying exogenous ORM could reduce peritoneal proteins loss, without causing a pro-inflammatory response in mice. ORM2 and CRP could be used as biomarkers to predict the baseline peritoneal transport characteristics, and guide the early PD treatment. ORM may serve as a novel therapeutic target for decreasing peritoneal proteins loss in PD patients. Significance: Peritoneal dialysis (PD) is associated with the functional alterations of the peritoneum. PD patients were often given an empirical dialysis prescription due to the unknown peritoneal transport characteristics in the first 4-8 weeks since PD started. Therefore, it is urgently needed to find biomarkers to predict the baseline peritoneal transport characteristics. In this study, we employed a proteomic analysis to identify serum biomarkers in a training set and verified the screened biomarkers in a validation set. We also found that Orosomucoid (ORM) has the potential to decrease peritoneal proteins loss in PD therapy.

Glycation plays a pathogenic role in many age-related degenerative pathological conditions, such as diabetes, end-stage renal diseases, and cardiovascular diseases. Mass spectrometry-based qualitative and quantitative analysis methods have been greatly developed and contribute to our understanding of protein glycation. However, it is still challenging to sensitively and accurately quantify endogenous glycated proteome in biological samples. Herein, we proposed an integrated and robust quantitative strategy for comprehensive profiling of early-stage glycated proteome. In this strategy, a filter-assisted sample preparation method was applied to reduce sample loss and improve reproducibility of sample preparation, contributing to high-throughput analysis and accurate quantification of endogenous glycated proteins with low abundance. Standard glycated peptides were spiked and performed the subsequent process together with complex samples both in label-free quantification and multiple reaction monitoring (MRM) analysis, contributing to the improvement of quantitative accuracy. In parallel, a novel approach was developed for the synthesis of heavy isotope-labeled glycated peptides used in MRM analysis. By this way, a total of 1128 endogenous glycated peptides corresponding to 203 serum proteins were identified from 60 runs of 10 pairs of hemodialysis patients with and without cardiovascular complications, and 234 glycated peptides corresponding to 63 proteins existed in >70% runs, among which 17 peptides were discovered to be differentially glycated (P < 0.05, fold-change > 1.5 or <0.67). Furthermore, we validated the glycation difference of four target peptides in 46 serum samples using MRM analysis, which were consistent with our results of label-free quantification.

AIMS:Cisplatin is an anticancer agent marred by nephrotoxicity. Limiting this adverse effect may allow the use of higher doses to improve its efficacy. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis and repair of renal diseases. BIO, a small molecule agonist of this pathway, exerted a protective effect in adriamycin nephropathy and promoted nephrogenesis. The aim of this study, therefore, was to investigate whether Wnt/β-catenin agonist BIO could protect against cisplatin-induced nephrotoxicity in vivo and in vitro, as well as its possible mechanism.MAIN METHODS:Male mice and human renal proximal tubular cells (HK-2) were subjected to cisplatin to study reno-protective effect of BIO. Renal function, cell viability, tubular apoptosis, production of reactive oxygen species (ROS) and proliferative level were analyzed respectively. Additionally, xenograft model was induced to investigate if BIO would impair the antitumor effect of cisplatin.KEY FINDINGS:Cisplatin increased serum creatinine levels and promoted histological renal injury as well as oxidative stress levels. Besides, renal apoptotic level and the expression of pro-apoptotic proteins, Bax/bcl-2 and cleaved-caspase3 included, in the kidney were increased. All these features were decreased by BIO, which also activated Wnt/β-catenin pathway in cisplatin-induced nephrotoxicity. Similarly, accompanied by the motivation of Wnt/β-catenin pathway, BIO exerted a positively protective effect on HK-2 challenged cisplatin. Last, the chemotherapeutic effects of cisplatin in xenograft mice of ovary tumor models and in lung cancer cells weren't compromised by BIO.SIGNIFICANCE:Wnt/β-catenin agonist BIO has the potential to prevent cisplatin nephrotoxicity without compromising its anti-proliferation efficacy.

Renal tubule-interstitial fibrosis is related to chronic kidney disease progression and a typical feature of the aging kidney. Epigenetic modifications of fibrosis-prone genes regulate the development of renal fibrosis. As a kind of “epigenetic diet”, soy isoflavone genistein was reported to have renal protective action and epigenetic-modulating effects. However, its renal protection role and underlying mechanisms are yet to be fully clarified. Herein, we showed that genistein exhibits a demonstrable anti-fibrotic effect on kidney in vivo UUO (unilateral ureteral occlusion) model and renal epithelial cells in vitro model. The mechanism is strongly associated with epithelial-to-mesenchymal transition and m6A RNA demethylase ALKBH5. Mouse fibrotic kidneys induced by UUO exhibited adverse expression of renal fibrosis-related proteins and significant increases in the total m6A level. As an eraser, ALKBH5 showed severer suppression in the renal fibrosis process. However, genistein pretreatment restored ALKBH5 loss remarkably and reduced renal fibrosis, abnormal protein, and inflammatory markers. The examination of possible mechanisms revealed that genistein promoted ALKBH5 and maybe induced the level of mRNA m6A methylation in some epithelial-to-mesenchymal transition-related transcription factors. We found snail was the critical regulator and critical for the protective role of genistein. To verify the relationship between ALKBH5 and snail, we generated knockdown and overexpression of ALKBH5 cells in vitro. ALKBH5 knockdown enhanced the mesenchymal phenotype marker α-smooth muscle actin and snail expression. In agreement, overexpression ALKBH5 increased epithelial adhesion molecule E-cadherin and reduced snail expression. In conclusion, genistein increased renal ALKBH5 expression in UUO-induced renal fibrosis and reduced RNA m6A levels and ameliorates renal damages.