Challenges of Predicting Arteriovenous Access Survival Prior to Conversion from Catheter.

OBJECTIVE: The decision to convert from catheter to arteriovenous access is difficult yet very important. The ability to accurately predict fistula survival prior to surgery would significantly improve the decision making process. Many previously investigated demographic and clinical features have been associated with fistula failure. However, it is not conclusively understood how reliable predictions based on these parameters are at an individual level. The aim of this study was to investigate the probability of arteriovenous fistula maturation and survival after conversion using machine learning workflows. METHODS: A retrospective cohort study on multicentre data from a large North American dialysis organisation was conducted. The study population comprised 73 031 chronic in centre haemodialysis patients. The dataset included 49 variables including demographic and clinical features. Two distinct feature selection and prediction pipelines were used: LASSO regression and Boruta followed by a random forest classifier. Predictions were facilitated for re-conversion to catheter within one year. Additionally, all cause mortality predictions were conducted to serve as a comparator. RESULTS: In total, 38 151 patients (52.2%) had complete data and made up the main cohort. Sensitivity analyses were conducted in 67 421 patients (92.3%) after eliminating variables with a high proportion of missing data points. Selected features diverged between datasets and workflows. A previously failed arteriovenous access appeared to be the most stable predictor for subsequent failure. Prediction of re-conversion based on the demographic and clinical information resulted in an area under the receiver operating characteristic curve (ROCAUC) between 0.541 and 0.571, whereas models predicting all cause mortality performed considerably better (ROCAUC 0.662 - 0.683). CONCLUSION: While group level depiction of major adverse outcomes after catheter to arteriovenous fistula or graft conversion is possible using the included variables, patient level predictions are associated with limited performance. Factors during and after fistula creation as well as biomolecular and genetic biomarkers might be more relevant predictors of fistula survival than baseline clinical conditions.

European Nephrologists' Attitudes toward the Application of Artificial Intelligence in Clinical Practice: A Comprehensive Survey.

INTRODUCTION: The rapid advancement of artificial intelligence and big data analytics, including descriptive, diagnostic, predictive, and prescriptive analytics, has the potential to revolutionize many areas of medicine, including nephrology and dialysis. Artificial intelligence and big data analytics can be used to analyze large amounts of patient medical records, including laboratory results and imaging studies, to improve the accuracy of diagnosis, enhance early detection, identify patterns and trends, and personalize treatment plans for patients with kidney disease. Additionally, artificial intelligence and big data analytics can be used to identify patients' treatment who are not receiving adequate care, highlighting care inefficiencies in the dialysis provider, optimizing patient outcomes, reducing healthcare costs, and consequently creating values for all the involved stakeholders. OBJECTIVES: We present the results of a comprehensive survey aimed at exploring the attitudes of European physicians from eight countries working within a major hemodialysis network (Fresenius Medical Care NephroCare) toward the application of artificial intelligence in clinical practice. METHODS: An electronic survey on the implementation of artificial intelligence in hemodialysis clinics was distributed to 1,067 physicians. Of the 1,067 individuals invited to participate in the study, 404 (37.9%) professionals agreed to participate in the survey. RESULTS: The survey showed that a substantial proportion of respondents believe that artificial intelligence has the potential to support physicians in reducing medical malpractice or mistakes. CONCLUSION: While artificial intelligence's potential benefits are recognized in reducing medical errors and improving decision-making, concerns about treatment plan consistency, personalization, privacy, and the human aspects of patient care persist. Addressing these concerns will be crucial for successfully integrating artificial intelligence solutions in nephrology practice.

Effectiveness of cold HD for the prevention of HD hypotension and mortality in the general HD population.

BACKGROUND: Cold hemodialysis (HD) prevented intradialysis hypotension (IDH) in small, short-term, randomized trials in selected patients with IDH. Whether this treatments prevents IDH and mortality in the HD population at large is unknown. METHODS: We investigated the relationship between dialysate temperature and the risk of IDH, i.e. nadir blood pressure <90 mmHg (generalized estimating equation model) and all-cause mortality (Cox's regression) in an incident cohort of HD patients (n = 8071). To control for confounding by bias by indication and other factors we applied instrumental variables adjusting for case mix at facility level. RESULTS: Twenty-seven percent of patients in the study cohort were systematically treated with a dialysate temperature ≤35.5°C. Over a median follow-up of 13.6 months (interquartile range 5.2-26.1 months), a 0.5°C reduction of the dialysate temperature was associated with a small (-2.4%) reduction of the risk of IDH [odds ratio (OR) 0.976, 95% confidence interval (CI) 0.957-0.995, P = .013]. In case-mix, facility-level adjusted analysis, the association became much stronger (OR 0.67, 95% CI 0.63-0.72, risk reduction = 33%, P < .001). In contrast, colder dialysate temperature had no effect on mortality both in the unadjusted [hazard ratio (HR) (0.5°C decrease) 1.074, 95% CI 0.972-1.187, P = .16] and case-mix-adjusted analysis at facility level (HR 1.01, 95% CI 0.88-1.16, P = .84). Similar results were registered in additional analyses by instrumental variables applying the median dialysate temperature or the facility percentage of patients prescribed a dialysate temperature <36°C. Further analyses restricted to patients with recurrent IDH fully confirmed these findings. CONCLUSIONS: Cold HD was associated with IDH in the HD population but had no association with all-cause mortality.

High Protein Whole Food Snack and Albumin Outcomes in Patients With Dialysis-Dependent Chronic Kidney Disease.

OBJECTIVE: Protein-energy wasting is common among patients on hemodialysis (HD). This study sought to define effects that a novel, post-HD, high-calorie, high-protein whole food snack had on patients' serum albumin (serum alb), serum phosphorus and equilibrated normalized protein catabolic rate (enPCR). METHODS: A 12-month (6 months intervention, 6 months pre/post data collection), single-center, unblinded study was conducted. Participants (n = 67) consumed, ad libitum, a whole food snack post-HD for 6 treatments each month. Upon analysis, regression models identified relationships between serum alb and whole food snack consumption across follow up. Predefined effect size anticipated was + 0.2 g/dL. Patients were stratified by high (≥4 g/dL) or low (<4 g/dL) mean serum alb during a 3-month baseline period. Paired t-tests compared mean per patient difference in serum alb, enPCR and serum phosphorus from baseline to each month of follow up, stratified by high (≥640 g) or low (<640 g) consumption of the whole food snack (a priori caloric estimation). RESULTS: Linear regression models showed positive associations between higher serum alb and enPCR with higher whole food snack consumption across follow up (all P < .05). Assessments from baseline to each follow-up month show some increases in serum alb, yet t test comparisons were not significant. No significant changes were seen in serum phosphorus levels during follow-up. CONCLUSION: Albeit the catabolic effects of HD are well-known, effective nutritional interventions are scarce. Results showed that providing a whole food snack post-HD to individuals with serum alb <4.0 g/dL may be beneficial but further studies are recommended.

Medication Safety in Dialysis Care.

The outpatient dialysis setting presents unique challenges in the medication process. Dialysis staff conduct all steps in the medication process, including transcribing and verifying orders, preparing and administering medications, and monitoring for therapeutic and adverse effects. When addressing best medication practices, consideration should be given to education and resources provided to staff. This article explores the multiple strategies taken by a national dialysis network to support clinical staff and improve patient safety.

Virtual Screening for the Discovery of Microbiome ß-Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity.

Despite the potency of most first-line anti-cancer drugs, nonadherence to these drug regimens remains high and is attributable to the prevalence of "off-target" drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5'-diphospho-glucuronosyltransferases through homeostatic host metabolism to form drug-glucuronide conjugates. These sugar-conjugated metabolites are generally inactive and can be safely excreted via the biliary system into the gastrointestinal tract. However, ß-glucuronidase (ßGUS) enzymes expressed by commensal gut bacteria can remove the glucuronic acid moiety, producing the reactivated drug and triggering dose-limiting side effects. Small-molecule ßGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of novel chemical series of ßGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for ßGUS and applied them to large-scale vHTS against nearly 400,000 compounds within the chemical libraries of the National Center for Advancing Translational Sciences at the National Institutes of Health. From the vHTS results, we cherry-picked 291 compounds via a multifactor prioritization procedure, providing 69 diverse compounds that exhibited positive inhibitory activity in a follow-up ßGUS biochemical assay in vitro. Our findings correspond to a hit rate of 24% and could inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with first-line, standard-of-care anti-cancer drugs.

Predictors of shorter- and longer-term mortality after COVID-19 presentation among dialysis patients: parallel use of machine learning models in Latin and North American countries.

BACKGROUND: We developed machine learning models to understand the predictors of shorter-, intermediate-, and longer-term mortality among hemodialysis (HD) patients affected by COVID-19 in four countries in the Americas. METHODS: We used data from adult HD patients treated at regional institutions of a global provider in Latin America (LatAm) and North America who contracted COVID-19 in 2020 before SARS-CoV-2 vaccines were available. Using 93 commonly captured variables, we developed machine learning models that predicted the likelihood of death overall, as well as during 0-14, 15-30, > 30 days after COVID-19 presentation and identified the importance of predictors. XGBoost models were built in parallel using the same programming with a 60%:20%:20% random split for training, validation, & testing data for the datasets from LatAm (Argentina, Columbia, Ecuador) and North America (United States) countries. RESULTS: Among HD patients with COVID-19, 28.8% (1,001/3,473) died in LatAm and 20.5% (4,426/21,624) died in North America. Mortality occurred earlier in LatAm versus North America; 15.0% and 7.3% of patients died within 0-14 days, 7.9% and 4.6% of patients died within 15-30 days, and 5.9% and 8.6% of patients died > 30 days after COVID-19 presentation, respectively. Area under curve ranged from 0.73 to 0.83 across prediction models in both regions. Top predictors of death after COVID-19 consistently included older age, longer vintage, markers of poor nutrition and more inflammation in both regions at all timepoints. Unique patient attributes (higher BMI, male sex) were top predictors of mortality during 0-14 and 15-30 days after COVID-19, yet not mortality > 30 days after presentation. CONCLUSIONS: Findings showed distinct profiles of mortality in COVID-19 in LatAm and North America throughout 2020. Mortality rate was higher within 0-14 and 15-30 days after COVID-19 in LatAm, while mortality rate was higher in North America > 30 days after presentation. Nonetheless, a remarkable proportion of HD patients died > 30 days after COVID-19 presentation in both regions. We were able to develop a series of suitable prognostic prediction models and establish the top predictors of death in COVID-19 during shorter-, intermediate-, and longer-term follow up periods.

Hepatitis B Vaccination Response in Hemodialysis Patients: The Impact of Dialysis Shift.

BACKGROUND/AIMS: Hepatitis B (HB) vaccination in hemodialysis patients is important as they are at a higher risk of contracting HB. However, hemodialysis patients have a lower HB seroconversion rate than their healthy counterparts. As better sleep has been associated with better seroconversion in healthy populations and early hemodialysis start has been linked to significant sleep-wake disturbances in hemodialysis patients, we examined if hemodialysis treatment start time is associated with HB vaccination response. METHODS: Demographics, standard-of-care clinical, laboratory, and treatment parameters, dialysis shift data, HB antigen status, HB vaccination status, and HB titers were collected from hemodialysis patients in Fresenius clinics from January 2010 to December 2015. Patients in our analysis received 90% of dialysis treatments either before or after 8:30 a.m., were negative for HB antigen, and received a complete series of HB vaccination (Engerix B® or Recombivax HB™). Univariate and multivariate regression models examined whether dialysis start time is a predictor of HB vaccination response. RESULTS: Patients were 65 years old, 57% male, and had a HD vintage of 10 months. Patients whose dialysis treatments started before 8:30 a.m. were more likely to be younger, male, and have a greater dialysis vintage. Patients receiving Engerix B® and starting dialysis before 8:30 a.m. had a significantly higher seroconversion rate compared to patients who started dialysis after 8:30 a.m. Early dialysis start was a significant predictor of seroconversion in univariate and multivariate regression including male gender, but not in multivariate regression including age, neutrophil-to-lymphocyte ratio, and vintage. CONCLUSION: While better sleep following vaccination is associated with seroconversion in the general population, this is not the case in hemodialysis patients after multivariate adjustment. In the context of end-stage kidney disease, early dialysis start is not a significant predictor of HB vaccination response. The association between objectively measured postvaccination sleep duration and seroconversion rate should be investigated.

Transmission of SARS-CoV-2 considering shared chairs in outpatient dialysis: a real-world case-control study.

BACKGROUND: SARS-CoV-2 can remain transiently viable on surfaces. We examined if use of shared chairs in outpatient hemodialysis associates with a risk for indirect patient-to-patient transmission of SARS-CoV-2. METHODS: We used data from adults treated at 2,600 hemodialysis facilities in United States between February 1st and June 8th, 2020. We performed a retrospective case-control study matching each SARS-CoV-2 positive patient (case) to a non-SARS-CoV-2 patient (control) treated in the same dialysis shift. Cases and controls were matched on age, sex, race, facility, shift date, and treatment count. For each case-control pair, we traced backward 14 days to assess possible prior exposure from a 'shedding' SARS-CoV-2 positive patient who sat in the same chair immediately before the case or control. Conditional logistic regression models tested whether chair exposure after a shedding SARS-CoV-2 positive patient conferred a higher risk of SARS-CoV-2 infection to the immediate subsequent patient. RESULTS: Among 170,234 hemodialysis patients, 4,782 (2.8 %) tested positive for SARS-CoV-2 (mean age 64 years, 44 % female). Most facilities (68.5 %) had 0 to 1 positive SARS-CoV-2 patient. We matched 2,379 SARS-CoV-2 positive cases to 2,379 non-SARS-CoV-2 controls; 1.30 % (95 %CI 0.90 %, 1.87 %) of cases and 1.39 % (95 %CI 0.97 %, 1.97 %) of controls were exposed to a chair previously sat in by a shedding SARS-CoV-2 patient. Transmission risk among cases was not significantly different from controls (OR = 0.94; 95 %CI 0.57 to 1.54; p = 0.80). Results remained consistent in adjusted and sensitivity analyses. CONCLUSIONS: The risk of indirect patient-to-patient transmission of SARS-CoV-2 infection from dialysis chairs appears to be low.

Real-time prediction of intradialytic relative blood volume: a proof-of-concept for integrated cloud computing infrastructure.

BACKGROUND: Inadequate refilling from extravascular compartments during hemodialysis can lead to intradialytic symptoms, such as hypotension, nausea, vomiting, and cramping/myalgia. Relative blood volume (RBV) plays an important role in adapting the ultrafiltration rate which in turn has a positive effect on intradialytic symptoms. It has been clinically challenging to identify changes RBV in real time to proactively intervene and reduce potential negative consequences of volume depletion. Leveraging advanced technologies to process large volumes of dialysis and machine data in real time and developing prediction models using machine learning (ML) is critical in identifying these signals. METHOD: We conducted a proof-of-concept analysis to retrospectively assess near real-time dialysis treatment data from in-center patients in six clinics using Optical Sensing Device (OSD), during December 2018 to August 2019. The goal of this analysis was to use real-time OSD data to predict if a patient's relative blood volume (RBV) decreases at a rate of at least - 6.5 % per hour within the next 15 min during a dialysis treatment, based on 10-second windows of data in the previous 15 min. A dashboard application was constructed to demonstrate how reporting structures may be developed to alert clinicians in real time of at-risk cases. Data was derived from three sources: (1) OSDs, (2) hemodialysis machines, and (3) patient electronic health records. RESULTS: Treatment data from 616 in-center dialysis patients in the six clinics was curated into a big data store and fed into a Machine Learning (ML) model developed and deployed within the cloud. The threshold for classifying observations as positive or negative was set at 0.08. Precision for the model at this threshold was 0.33 and recall was 0.94. The area under the receiver operating curve (AUROC) for the ML model was 0.89 using test data. CONCLUSIONS: The findings from our proof-of concept analysis demonstrate the design of a cloud-based framework that can be used for making real-time predictions of events during dialysis treatments. Making real-time predictions has the potential to assist clinicians at the point of care during hemodialysis.

Switching from Epoetin Alfa (Epogen®) to Epoetin Alfa-Epbx (RetacritTM) Using a Specified Dosing Algorithm: A Randomized, Non-Inferiority Study in Adults on Hemodialysis.

BACKGROUND: For patients with anemia undergoing hemodialysis, erythropoiesis-stimulating agents (ESAs) are typically dosed via precise algorithms. Using one such algorithm, we assessed the maintenance of hemoglobin levels in patients switched from epoetin alfa reference product (Epogen®) to epoetin alfa-epbx (RetacritTM; a biosimilar to US-licensed Epogen®/Procrit®). METHODS: This randomized, open-label, non-inferiority study was conducted at Fresenius Medical Care North America (FMCNA) hemodialysis centers. Patients with anemia and chronic kidney disease undergoing maintenance hemodialysis and receiving routine intravenous (IV) Epogen® were randomized 1: 1 to switch to IV RetacritTM or continue standard-of-care (Epogen®) for 24 weeks, using analogous versions of the FMCNA ESA-dosing algorithm. The primary endpoint was the proportion of time patients' hemoglobin was 9-11 g/dL during weeks 17-24. RESULTS: Of 432 randomized patients, 418 received treatment (RetacritTM, n = 212; standard-of-care, n = 206) and comprised the full analysis set. A similar proportion of patients discontinued from each arm. The proportion of time patients' hemoglobin was within the target range was 61.9% (95% CI 57.5-66.2) in the RetacritTM arm and 63.3% (95% CI 58.7-67.7) in the standard-of-care arm. The difference in proportions between treatment arms was -1.4% (95% CI -7.6 to 4.9), and the lower bound of the confidence interval was within the pre-specified non-inferiority margin of -12.5%. There was no statistically significant difference between arms in the mean change from baseline in the weekly mean ESA dose during weeks 17-24, and no clinically relevant differences in safety outcomes. CONCLUSIONS: Switching to RetacritTM was non-inferior to continuing -Epogen® in maintaining hemoglobin levels in patients receiving hemodialysis, when both ESAs were dosed using a specified algorithm (ClinicalTrials.gov, NCT02504294).

Dialysis Catheter-Related Bloodstream Infections: A Cluster-Randomized Trial of the ClearGuard HD Antimicrobial Barrier Cap.

BACKGROUND: The rate of bloodstream infections (BSIs) is disproportionately high in hemodialysis (HD) patients with central venous catheters (CVCs) versus those with permanent accesses, contributing to poorer outcomes, such as increased rates of death and hospitalizations. STUDY DESIGN: 12-month, prospective, cluster-randomized, multicenter, open-label trial. SETTING & PARTICIPANTS: 40 Fresenius Medical Care North America dialysis facilities were matched and paired by positive blood culture rate and number of patients with CVCs and then cluster-randomized with 20 in each study group. 2,470 patients participated in the study (1,245, intervention group; 1,225, control group), accruing approximately 350,000 CVC-days. INTERVENTION: Use of ClearGuard HD Antimicrobial Barrier Caps versus use of standard CVC caps; assigned at the facility level. OUTCOME: Primary end point was positive blood culture rate as an indicator of BSI rate. MEASUREMENTS: Positive blood cultures, hospital admissions for BSI, hospitalization-days for BSI, intravenous antibiotic starts, and CVC-days. RESULTS: Baseline positive blood culture rates were similar (P=0.8) between groups. Use of ClearGuard HD caps for 12 months was associated with a 56% lower BSI rate versus use of standard CVC caps (0.26 vs 0.59/1,000 CVC-days, respectively; P=0.01). When considering sustained use (defined as last 6 months of the study), the intervention versus the control was associated with a 69% lower BSI rate (0.22 vs 0.72/1,000 CVC-days, respectively; P=0.01), 43% fewer hospital admissions for BSI (0.28 vs 0.48/1,000 CVC-days, respectively; P=0.04), and 51% fewer hospitalization days for BSI (2.42 vs 4.94/1,000 CVC-days, respectively; P=0.04). No device-related adverse events were reported. LIMITATIONS: Study was open label; patients occasionally received HD at nonresearch facilities; patients did not receive the intervention when hospitalized. CONCLUSIONS: The findings show that use of ClearGuard HD Antimicrobial Barrier Caps, when compared with standard CVC caps, significantly lowers rates of catheter-related BSIs and hospital admissions for BSI in HD patients using CVCs.

A Nationally Representative Study of Calcific Uremic Arteriolopathy Risk Factors.

Accurate identification of risk factors for calcific uremic arteriolopathy (CUA) is necessary to develop preventive strategies for this morbid disease. We investigated whether baseline factors recorded at hemodialysis initiation would identify patients at risk for future CUA in a matched case-control study using data from a large dialysis organization. Hemodialysis patients with newly diagnosed CUA (n=1030) between January 1, 2010, and December 31, 2014, were matched by age, sex, and race in a 1:2 ratio to hemodialysis patients without CUA (n=2060). Mean ages for patients and controls were 54 and 55 years, respectively; 67% of participants were women and 49% were white. Median duration between hemodialysis initiation and subsequent CUA development was 925 days (interquartile range, 273-2185 days). In multivariable conditional logistic regression analyses, diabetes mellitus; higher body mass index; higher levels of serum calcium, phosphorous, and parathyroid hormone; and nutritional vitamin D, cinacalcet, and warfarin treatments were associated with increased odds of subsequent CUA development. Compared with patients with diabetes receiving no insulin injections, those receiving insulin injections had a dose-response increase in the odds of CUA involving lower abdomen and/or upper thigh areas (odds ratio, 1.49; 95% confidence interval, 1.03 to 2.51 for one or two injections per day; odds ratio, 1.88; 95% confidence interval, 1.30 to 3.43 for 3 injections per day; odds ratio, 3.74; 95% confidence interval, 2.28 to 6.25 for more than three injections per day), suggesting a dose-effect relationship between recurrent skin trauma and CUA risk. The presence of risk factors months to years before CUA development observed in this study will direct the design of preventive strategies and inform CUA pathobiology.

Improvements in MBD lab outcomes associated with improved pharmaceutical care in hemodialysis patients.

End stage renal disease (ESRD) patients require a large number of medications and are known to have high rates of nonadherence. It is estimated that >50% of ESRD patients do not take their phosphate binders as prescribed. The renal pharmacy FreseniusRx provides coordinated ESRD medication delivery and adherence support for enrolled patients. We investigated whether coordinated pharmacy care of mineral and bone disorder (MBD) therapies is associated with improvements in laboratory. outcomes. We used data from hemodialysis patients treated at Fresenius Medical Care North America (FMCNA) clinics from February 2014 to January 2015. We included patients who were residing in a state with >100 patients in the FMCNA network, not in a nursing home, and prescribed a phosphate binder and/or calcimimetic. We found 15,287 pharmacy patients who met the study criteria. Concurrent control patients not in the pharmacy were matched to pharmacy patients on a monthly basis that was based off the first date of receipt of therapy from FreseniusRx using 1:1 nearest neighbor matching on the logit of the propensity score for an array of clinical and non-clinical parameters. Logistic regression was used to measure the association between pharmacy care and patients achieving their laboratory goals for phosphorus (PO4) and intact parathyroid hormone (iPTH), and combined goals for total calcium (Ca), PO4, and iPTH. We analyzed data from 30,574 patients (15,287 pharmacy and control). In unadjusted and adjusted analyses, we consistently observed that pharmacy patients were more likely to achieve their MBD laboratory goals as compared to controls. In an adjusted analysis, we found pharmacy patients were more likely to achieve their MBD laboratory targets at 3, 6, 9, and 12 months for PO4 (11.1%, 10.5%, 11.8% and 12.7% respectively), iPTH (8.9%, 17.5%, 23.4% and 27.9% respectively) and combined goals for Ca, PO4, and. iPTH (12.1%, 13.4%, 16.7% and 21.2% respectivelv) versus controls (n<0.01 for all comparisons). These findings indicate that coordinated pharmaceutical care may be associated with improvements in patients achieving their MBD laboratory goals.

Functional Analysis of an S-Layer-Associated Fibronectin-Binding Protein in Lactobacillus acidophilus NCFM.

Bacterial surface layers (S-layers) are crystalline arrays of self-assembling proteinaceous subunits called S-layer proteins (Slps) that comprise the outermost layer of the cell envelope. Many additional proteins that are associated with or embedded within the S-layer have been identified in Lactobacillus acidophilus NCFM, an S-layer-forming bacterium that is widely used in fermented dairy products and probiotic supplements. One putative S-layer-associated protein (SLAP), LBA0191, was predicted to mediate adhesion to fibronectin based on the in silico detection of a fibronectin-binding domain. Fibronectin is a major component of the extracellular matrix (ECM) of intestinal epithelial cells. Adhesion to intestinal epithelial cells is considered an important trait for probiotic microorganisms during transit and potential association with the intestinal mucosa. To investigate the functional role of LBA0191 (designated FbpB) in L. acidophilus NCFM, an fbpB-deficient strain was constructed. The L. acidophilus mutant with a deletion off bpB lost the ability to adhere to mucin and fibronectin in vitro Homologues off bpB were identified in five additional putative S-layer-forming species, but no homologues were detected in species outside theL. acidophilus homology group.

Conserved S-Layer-Associated Proteins Revealed by Exoproteomic Survey of S-Layer-Forming Lactobacilli.

The Lactobacillus acidophilus homology group comprises Gram-positive species that include L. acidophilus, L. helveticus, L. crispatus, L. amylovorus, L. gallinarum, L. delbrueckii subsp. bulgaricus, L. gasseri, and L. johnsonii. While these bacteria are closely related, they have varied ecological lifestyles as dairy and food fermenters, allochthonous probiotics, or autochthonous commensals of the host gastrointestinal tract. Bacterial cell surface components play a critical role in the molecular dialogue between bacteria and interaction signaling with the intestinal mucosa. Notably, the L. acidophilus complex is distinguished in two clades by the presence or absence of S-layers, which are semiporous crystalline arrays of self-assembling proteinaceous subunits found as the outermost layer of the bacterial cell wall. In this study, S-layer-associated proteins (SLAPs) in the exoproteomes of various S-layer-forming Lactobacillus species were proteomically identified, genomically compared, and transcriptionally analyzed. Four gene regions encoding six putative SLAPs were conserved in the S-layer-forming Lactobacillus species but not identified in the extracts of the closely related progenitor, L. delbrueckii subsp. bulgaricus, which does not produce an S-layer. Therefore, the presence or absence of an S-layer has a clear impact on the exoproteomic composition of Lactobacillus species. This proteomic complexity and differences in the cell surface properties between S-layer- and non-S-layer-forming lactobacilli reveal the potential for SLAPs to mediate intimate probiotic interactions and signaling with the host intestinal mucosa.

A phase 3b, multicenter, open-label, single-arm study of roxadustat within a US dialysis organization: The DENALI study.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). DENALI, a phase 3b study, evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD receiving in-center or home dialysis. METHODS: Eligible patients received open-label roxadustat, dosed three times weekly for 24 weeks, with an optional extension of ≤1 year. Initial dosing depended on erythropoiesis-stimulating agent (ESA) dose at screening for patients receiving ESAs (≥6 weeks) and weight-based for those not (total <6 weeks). Primary efficacy endpoints were proportion of patients with mean hemoglobin (Hb) ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24. Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were assessed. FINDINGS: Of 281 patients screened, 203 were treated and 201 included in the full analysis set. Overall, 166 patients completed the 24-week treatment period and 126 continued into the extension period. Mean baseline Hb was 10.4 g/dL and 82.6% received in-center hemodialysis. Overall, 84.6% of patients achieved a mean Hb ≥ 10.0 g/dL averaged Weeks 16-24. Mean (standard deviation) Hb change from baseline averaged Weeks 16-24 was 0.5 (1.0) g/dL. Prespecified subgroup analyses were consistent with primary analyses. Dosing adherence was 94%. Overall, 3.0% of patients received a red blood cell transfusion at up to Week 24. TEAEs and TESAEs were reported by 71.4% and 25.6% of patients, respectively. The most frequently reported TESAEs were COVID-19 (n = 5; 2.5%), and acute myocardial infarction, pneumonia, and sepsis (each n = 4; 2.0%). DISCUSSION: Roxadustat effectively achieved and/or maintained mean Hb levels ≥10.0 g/dL in patients receiving dialysis. The feasibility of incorporating oral roxadustat into dialysis organizations was successfully demonstrated with high dosing adherence. No new safety signals were identified.

Antihypertensive drug treatment and the risk for intra-hemodialysis hypotension.

BACKGROUND: Antihypertensive medications are often prescribed to manage hypertension in hemodialysis (HD) patients, and intradialytic hypotension (IDH) is a common complication in these patients. We investigated the risk of IDH in incident HD patients who initiated treatment with antihypertensive drugs in monotherapy. METHODS: The study was conducted as an emulation of a randomized clinical trial in 4072 incident HD patients who started anti-hypertensive drug treatment between January 2016 to December 2019. The primary outcome was the occurrence of IDH during HD sessions. The Gener alised Estimating Equation (GEE) analysis was adjusted by inverse probability treatment weighting (IPTW). RESULTS: Calcium channel blocker (CCB) use was associated with an IDH incidence rate of 7.4 events per person-year (95% CI: 6.2-8.6). Compared to CCB use, use of beta and alpha-beta blockers was strongly associated with a higher likelihood of IDH (OR [95% CI] 2.27 [1.50-3.43]). Use of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (OR [95% CI] 1.71 [1.14-2.57]) and diuretics (OR [95% CI] 1.52 [1.07-2.16]) were also associated with higher likelihood of IDH compared to CCB use. CONCLUSION: The study suggests that using beta and alpha-beta blockers, ACE inhibitors or angiotensin II receptor blockers, and diuretics may increase the risk of IDH in HD patients compared to CCB use.

Prevalence and outcomes of antimicrobial treatment for Staphylococcus aureus bacteremia in outpatients with ESRD.

Staphylococcus bacteremia is a common and life-threatening medical emergency, but it is treatable with appropriate antibiotic therapy. To identify opportunities that may reduce morbidity and mortality associated with S. aureus, we analyzed data from 293,094 chronic hemodialysis outpatients to characterize practices of antibiotic selection. In the study population, the overall rate of bacteremia was 15.4 per 100 outpatient-years; the incidence rate for methicillin-sensitive (MSSA) was 2.1 per 100 outpatient-years, and the incidence rate for methicillin-resistant (MRSA) S. aureus was 1.9 per 100 outpatient-years. One week after the collection of the index blood culture, 56.1% of outpatients with MSSA bacteremia were receiving vancomycin, and 16.7% of outpatients with MSSA were receiving cefazolin. Among MSSA-bacteremic patients who did not die or get hospitalized 1 week after blood culture collection, use of cefazolin was associated with a 38% lower risk for hospitalization or death compared with vancomycin (adjusted HR=0.62, 95% CI=0.46-0.84). In conclusion, vancomycin is commonly used to treat MSSA bacteremia in outpatients receiving chronic dialysis, but there may be more risk of treatment failure than observed among those individuals who receive a ß-lactam antibiotic such as cefazolin.