The TorRS two component system regulates expression of TMAO reductase in response to high hydrostatic pressure in Vibrio fluvialis.

High hydrostatic pressure (HHP) regulated gene expression is one of the most commonly adopted strategies for microbial adaptation to the deep-sea environments. Previously we showed that the HHP-inducible trimethylamine N-oxide (TMAO) reductase improves the pressure tolerance of deep-sea strain Vibrio fluvialis QY27. Here, we investigated the molecular mechanism of HHP-responsive regulation of TMAO reductase TorA. By constructing torR and torS deletion mutants, we demonstrated that the two-component regulator TorR and sensor TorS are responsible for the HHP-responsive regulation of torA. Unlike known HHP-responsive regulatory system, the abundance of torR and torS was not affected by HHP. Complementation of the ΔtorS mutant with TorS altered at conserved phosphorylation sites revealed that the three sites were indispensable for substrate-induced regulation, but only the histidine located in the alternative transmitter domain was involved in pressure-responsive regulation. Taken together, we demonstrated that the induction of TMAO reductase by HHP is mediated through the TorRS system and proposed a bifurcation of signal transduction in pressure-responsive regulation from the substrate-induction. This work provides novel knowledge of the pressure regulated gene expression and will promote the understanding of the microbial adaptation to the deep-sea HHP environment.

[Clinical Outcome and Risk Factors of Treatment Failure of Peritoneal Dialysis Associated Peritonitis Caused by Klebsiella Pneumoniae:A Multicenter Study].

Objective To investigate the treatment outcomes,prognosis,and risk factors of treatment failure of peritoneal dialysis associated peritonitis (PDAP) caused by Klebsiella pneumoniae,and thus provide clinical evidence for the prevention and treatment of this disease. Methods The clinical data of PDAP patients at four peritoneal dialysis centers from January 1,2014 to December 31,2019 were collected retrospectively.The treatment outcomes and prognosis were compared between the patients with PDAP caused by Klebsiella.pneumoniae and that caused by Escherichia coli.Kaplan-Meier method was employed to establish the survival curve of technical failure,and multivariate Logistic regression to analyze the risk factors of the treatment failure of PADP caused by Klebsiella pneumoniae. Results In the 4 peritoneal dialysis centers,1034 cases of PDAP occurred in 586 patients from 2014 to 2019,including 21 cases caused by Klebsiella pneumoniae and 98 cases caused by Escherichia coli.The incidence of Klebsiella pneumoniae caused PDAP was 0.0048 times per patient per year on average,ranging from 0.0024 to 0.0124 times per patient per year during 2014-2019.According to the Kaplan-Meier survival curve,the technical failure rate of Klebsiella pneumoniae caused PDAP was higher than that of Escherichia coli caused PDAP (P=0.022).The multivariate Logistic regression model showed that long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP (OR=1.082,95%CI=1.011-1.158,P=0.023).Klebsiella pneumoniae was highly sensitive to amikacin,meropenem,imipenem,piperacillin,and cefotetan,and it was highly resistant to ampicillin (81.82%),cefazolin (53.33%),tetracycline (50.00%),cefotaxime (43.75%),and chloramphenicol (42.86%). Conclusion The PDAP caused by Klebsiella pneumoniae had worse prognosis than that caused by Escherichia coli,and long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP.

Impact of peritoneal dialysis modality on patient and PD survival: A systematic review.

We conducted a systematic review and meta-analysis to determine the effect of the peritoneal dialysis (PD) modality, automated peritoneal dialysis (APD) or continuous ambulatory peritoneal dialysis (CAPD), on all-cause mortality (ACM) and PD failure. Studies were identified in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure, Weipu and Wanfang databases from database inception until April 1, 2021. The inclusion and exclusion criteria were based on the Population, Intervention, Comparison, Outcome, and Study (PICOS) design. Adjusted hazard ratios (HRs) with 95% confidence intervals (CI) were used to pool outcome estimates. Seventeen studies (more than 230,000 patients) were included. Our meta-analysis showed that compared with CAPD, APD demonstrated a significantly lower ACM risk (HR 0.87 [95% CI 0.77-0.99], p = 0.04), especially in studies involving an as-treated analysis (HR 0.75 [95% CI, 0.63-0.90], p = 0.00), published in Asia (HR 0.76 [95% CI, 0.67-0.86], p < 0.001) or Europe (HR 0.81 [95% CI, 0.74-0.89], p < 0.00), or published after 2012 (HR 0.82 [95% CI, 0.68-0.99], p = 0.04). However, APD was as effective as CAPD for PD survival (HR, 0.87 [95% CI, 0.75 to 1.00], p = 0.05 or HR, 0.90 [95% CI, 0.60 to 1.35], p = 0.61). Our results demonstrate a significant survival benefit for APD and provide evidence for increasing the global use of APD, especially in developing nations, where APD use has been hampered by a lack of reimbursement for care.

Risk factors for mortality within 6 mo in patients with diabetes undergoing urgent-start peritoneal dialysis: A multicenter retrospective cohort study.

BACKGROUND: The risk of early mortality of patients who start dialysis urgently is high; however, in patients with diabetes undergoing urgent-start peritoneal dialysis (USPD), the risk of, and risk factors for, early mortality are unknown. AIM: To identify risk factors for mortality during high-risk periods in patients with diabetes undergoing USPD. METHODS: This retrospective cohort study enrolled 568 patients with diabetes, aged ≥ 18 years, who underwent USPD at one of five Chinese centers between 2013 and 2019. We divided the follow-up period into two survival phases: The first 6 mo of USPD therapy and the months thereafter. We compared demographic and baseline clinical data of living and deceased patients during each period. Kaplan-Meier survival curves were generated for all-cause mortality according to the New York Heart Association (NYHA) classification. A multivariate Cox proportional hazard regression model was used to identify risk factors for mortality within the first 6 mo and after 6 mo of USPD. RESULTS: Forty-one patients died within the first 6 mo, accounting for the highest proportion of mortalities (26.62%) during the entire follow-up period. Cardiovascular disease was the leading cause of mortality within 6 mo (26.83%) and after 6 mo (31.86%). The risk of mortality not only within the first 6 mo but also after the first 6 mo was higher for patients with obvious baseline heart failure symptoms than for those with mild or no heart failure symptoms. Independent risk factors for mortality within the first 6 mo were advanced age [hazard ratio (HR: 1.908; 95%CI: 1.400-2.600; P < 0.001), lower baseline serum creatinine level (HR: 0.727; 95%CI: 0.614-0.860; P < 0.001), higher baseline serum phosphorus level (HR: 3.162; 95%CI: 1.848-5.409; P < 0.001), and baseline NYHA class III-IV (HR: 2.148; 95%CI: 1.063-4.340; P = 0.033). Independent risk factors for mortality after 6 mo were advanced age (HR: 1.246; 95%CI: 1.033-1.504; P = 0.022) and baseline NYHA class III-IV (HR: 2.015; 95%CI: 1.298-3.130; P = 0.002). CONCLUSION: To reduce the risk of mortality within the first 6 mo of USPD in patients with diabetes, controlling the serum phosphorus level and improving cardiac function are recommended.

[Clinical Characteristics and Treatment Outcome of Pseudomonas Peritoneal Dialysis-associated Peritonitis].

Objective To explore the clinical characteristics and treatment of Pseudomonas peritoneal dialysis-associated peritonitis(PsP). Methods The data of patients receiving peritoneal dialysis in four tertiary hospitals in Jilin province from 2015 to 2019 were retrospectively analyzed.According to the etiological classification,the patients with peritoneal dialysis-associated peritonitis(PDAP)were classified into PsP group and non-PsP group.The incidence of PsP was calculated,and the clinical characteristics and treatment outcomes of the two groups were compared.Kaplan-Meier method was used to draw the survival curve,and Cox regression was performed to analyze the risk factors affecting the technical failure of PsP.The treatment options of Pseudomonas aeruginosa-caused PDAP and the drug sensitivity of PsP were summarized. Results A total of 1530 peritoneal dialysis patients with complete data were included in this study,among which 439 patients had 664 times of PDAP.The incidence of PsP was 0.007 episodes/patient-year.PsP group had higher proportion of refractory peritonitis(41.38% vs.19.69%,P=0.005),lower cure rate(55.17% vs.80.79%, P=0.001),and higher extubation rate(24.14% vs.7.09%,P=0.003)than non-PsP group.The technical survival rate of PsP group was lower than that of non-PsP group(P<0.001).Multivariate Cox regression analysis showed that Pseudomonas aeruginosa was an independent risk factor for technical failure in patients with PsP(HR=9.020,95%CI=1.141-71.279,P=0.037).Pseudomonas was highly sensitive to amikacin,meropenem,and piperacillin-tazobactam while highly resistant to compound sulfamethoxazole,cefazolin,and ampicillin. Conclusion The treatment outcome of PsP is worse than that of non-PsP,and Pseudomonas aeruginosa is an independent risk factor for technical failure of PsP.

[Research Progress on Role and Mechanism of Elabela in Organ Fibrosis].

Elabela is a newly discovered peptide in recent years.It is the endogenous ligand of Apelin receptor(APJ)and plays an important role in embryonic development and adult organs.Elabela-APJ axis is closely related to organ fibrosis.Elabela can protect the functions of heart and kidney by antagonizing renin-angiotensin system and regulating blood pressure.In addition,it can prevent kidney and heart fibrosis by down-regulating the expression of fibrosis and inflammatory factors.However,there is a positive correlation between the level of Elabela and the degree of liver fibrosis,suggesting that Elabela may play a role in promoting liver fibrosis.This review aims to explore the role of Elabela-APJ axis in renal fibrosis,cardiac fibrosis,and liver fibrosis,and to provide a new therapeutic target for organ fibrosis.

Comparison of clinical features and outcomes in peritoneal dialysis-associated peritonitis patients with and without diabetes: A multicenter retrospective cohort study.

BACKGROUND: The number of end-stage renal disease patients with diabetes mellitus (DM) who are undergoing peritoneal dialysis is increasing. Peritoneal dialysis-associated peritonitis (PDAP) is a serious complication of peritoneal dialysis leading to technical failure and increased mortality in patients undergoing peritoneal dialysis. The profile of clinical symptoms, distribution of pathogenic organisms, and response of PDAP to medical management in the subset of end-stage renal disease patients with DM have not been reported previously. Discrepant results have been found in long-term prognostic outcomes of PDAP in patients with DM. We inferred that DM is associated with bad outcomes in PDAP patients. AIM: To compare the clinical features and outcomes of PDAP between patients with DM and those without. METHODS: In this multicenter retrospective cohort study, we enrolled patients who had at least one episode of PDAP during the study period. The patients were followed for a median of 31.1 mo. They were divided into a DM group and a non-DM group. Clinical features, therapeutic outcomes, and long-term prognostic outcomes were compared between the two groups. Risk factors associated with therapeutic outcomes of PDAP were analyzed using multivariable logistic regression. A Cox proportional hazards model was constructed to examine the influence of DM on patient survival and incidence of technical failure. RESULTS: Overall, 373 episodes occurred in the DM group (n = 214) and 692 episodes occurred in the non-DM group (n = 395). The rates of abdominal pain and fever were similar in the two groups (P > 0.05). The DM group had more infections with coagulase-negative Staphylococcus and less infections with Escherichia coli (E. coli) as compared to the non-DM group (P < 0.05). Multivariate logistic regression analysis revealed no association between the presence of diabetes and rates of complete cure, catheter removal, PDAP-related death, or relapse of PDAP (P > 0.05). Patients in the DM group were older and had a higher burden of cardiovascular disease, with lower level of serum albumin, but a higher estimated glomerular filtration rate (P < 0.05). Cox proportional hazards model confirmed that the presence of diabetes was a significant predictor of all-cause mortality (hazard ratio = 1.531, 95% confidence interval: 1.091-2.148, P < 0.05), but did not predict the occurrence of technical failure (P > 0.05). CONCLUSION: PDAP patients with diabetes have similar symptomology and are predisposed to coagulase-negative Staphylococcus but not E. coli infection compared those without. Diabetes is associated with higher all-cause mortality but not therapeutic outcomes of PDAP.

Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy.

Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20-40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN.

Histone lysine methylation in diabetic nephropathy.

Diabetic nephropathy (DN) belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called "metabolic memory." The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN.

Advances in murine models of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the microvascular complications of both type 1 and type 2 diabetes, which is also associated with a poor life expectancy of diabetic patients. However, the pathogenesis of DN is still unclear. Thus, it is of great use to establish appropriate animal models of DN for doing research on pathogenesis and developing novel therapeutic strategies. Although a large number of murine models of DN including artificially induced, spontaneous, and genetically engineered (knockout and transgenic) animal models have been developed, none of them develops renal changes sufficiently reflecting those seen in humans. Here we review the identified murine models of DN from the aspects of genetic background, type of diabetes, method of induction, gene deficiency, animal age and gender, kidney histopathology, and phenotypic alterations in the hope of enhancing our comprehension of genetic susceptibility and molecular mechanisms responsible for this disease and providing new clues as to how to choose appropriate animal models of DN.

Is C677T polymorphism in methylenetetrahydrofolate reductase gene a risk factor for diabetic nephropathy or diabetes mellitus in a Chinese population?

BACKGROUND AND AIMS: To date, case-control studies on the association between C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene and diabetes mellitus (DM) or diabetic nephropathy (DN) in different populations have provided inconclusive results. To clarify the effect of the C677T polymorphism on the risk of both DM and DN in a Chinese population, a meta-analysis was performed. METHODS: A comprehensive literature search was conducted to collect data from all case-control observational studies that investigated association of C677T polymorphism in MTHFR gene with DM or DN in a Chinese population. RESULTS: Overall, 12 studies in a Chinese population published up to 2011 were combined, and the heterogeneity among them varied from none to moderate. The 677T allele showed significant association with DN (OR = 1.97, 95% CI [1.71, 2.28], p <0.00001), but no relationship with DM (OR = 1.03, 95% CI [0.89, 1.18], p = 0.70) compared with the 677C allele in a Chinese population. Similarly, evidence of significant association with DN was detected in the additive model, the recessive model and the dominant model for allele T (additive model: OR = 3.26, 95% CI [2.46, 4.31], p <0.00001; recessive model: OR = 2.32, 95% CI [1.81, 2.97], p <0.00001; dominant model: OR = 2.35, 95% CI [1.89, 2.91], p <0.00001); however, no relationship with DM was found (additive model: OR = 1.01, 95% CI [0.76, 1.35], p = 0.94; recessive model: OR = 0.98, 95% CI [0.76, 1.26], p = 0.87; dominant model: OR = 1.23, 95% CI [0.91, 1.65], p = 0.18). There were no sources of bias in the selected studies, and the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) suggested stability of this meta-analysis. CONCLUSIONS: C677T polymorphism in MTHFR gene may be a risk factor for DN, but not for DM, in a Chinese population.