Showing papers by "David W. Johnson published in 2016"
The Chinese University of Hong Kong1, University of Pittsburgh2, The Catholic University of America3, Barts Health NHS Trust4, Pontifícia Universidade Católica do Rio Grande do Sul5, University of Montana6, Cliniques Universitaires Saint-Luc7, Kyungpook National University8, University of Missouri9, University of Amsterdam10, University of Colorado Hospital11, Princess Alexandra Hospital12
TL;DR: Recommendations under the auspices of the International Society for Peritoneal Dialysis (ISPD) were first published in 1983 and revised in 1993, 1996, 2000, 2005, and 2010 are revised.
Abstract: Peritonitis is a common and serious complication of peritoneal dialysis (PD). Although less than 5% of peritonitis episodes result in death, peritonitis is the direct or major contributing cause of death in around 16% of PD patients (1-6). In addition, severe or prolonged peritonitis leads to structural and functional alterations of the peritoneal membrane, eventually leading to membrane failure. Peritonitis is a major cause of PD technique failure and conversion to long-term hemodialysis (1,5,7,8). Recommendations under the auspices of the International Society for Peritoneal Dialysis (ISPD) were first published in 1983 and revised in 1993, 1996, 2000, 2005, and 2010 (9-14). The present recommendations are organized into 5 sections: 1. Peritonitis rate 2. Prevention of peritonitis 3. Initial presentation and management of peritonitis 4. Subsequent management of peritonitis 5.
724 citations
TL;DR: Technical innovations in peritoneal dialysis have significantly reduced therapy-related complications, allowing patients to be maintained on PD for longer periods, and the survival rate for patients treated with PD is now equivalent to that with in-center hemodialysis.
Abstract: Technical innovations in peritoneal dialysis (PD), now used widely for the long-term treatment of ESRD, have significantly reduced therapy-related complications, allowing patients to be maintained on PD for longer periods. Indeed, the survival rate for patients treated with PD is now equivalent to that with in-center hemodialysis. In parallel, changes in public policy have spurred an unprecedented expansion in the use of PD in many parts of the world. Meanwhile, our improved understanding of the molecular mechanisms involved in solute and water transport across the peritoneum and of the pathobiology of structural and functional changes in the peritoneum with long-term PD has provided new targets for improving efficiency and for intervention. As with hemodialysis, almost half of all deaths on PD occur because of cardiovascular events, and there is great interest in identifying modality-specific factors contributing to these events. Notably, tremendous progress has been made in developing interventions that substantially reduce the risk of PD-related peritonitis. Yet the gains have been unequal among individual centers, primarily because of unequal clinical application of knowledge gained from research. The work to date has further highlighted the areas in need of innovation as we continue to strive to improve the health and outcomes of patients treated with PD.
329 citations
University of Otago1, RMIT University2, University of Ioannina3, Princess Alexandra Hospital4, University of Queensland5, University of Calgary6, University of Sydney7, University of Eastern Piedmont8, The George Institute for Global Health9, Université de Montréal10, Alexandra Hospital11, University of Alberta12, University of Bari13
TL;DR: Findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.
Abstract: Importance Numerous glucose-lowering drugs are used to treat type 2 diabetes. Objective To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. Data Sources Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016. Study Selection Randomized clinical trials of 24 weeks’ or longer duration. Data Extraction and Synthesis Random-effects network meta-analysis. Main Outcomes and Measures The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A 1c (HbA 1C ) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight. Results A total of 301 clinical trials (1 417 367 patient-months) were included; 177 trials (56 598 patients) of drugs given as monotherapy; 109 trials (53 030 patients) of drugs added to metformin (dual therapy); and 29 trials (10 598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA 1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA 1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, −22% [−27% to −18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, −10% [95% CI, −18% to −2%]). Conclusions and Relevance Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA 1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.
313 citations
TL;DR: In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae.
Abstract: Background and objectives The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome–generated uremic toxins, IS and PCS, in patients with CKD. Design, setting, participants, & measurements Predialysis adult participants with CKD (eGFR=10–30 ml/min per 1.73 m2) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double–blind, placebo–controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect. Results Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m2), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (−2 μmol/L; 95% confidence interval [95% CI], −5 to 1 μmol/L) but did significantly reduce serum PCS (−14 μmol/L; 95% CI, −27 to −2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, −25 μmol/L; 95% CI, −38 to −12 μmol/L; serum IS, −5 μmol/L; 95% CI, −8 to −1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes. Conclusion In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large–scale clinical trials are justified.
265 citations
Children's Hospital at Westmead1, University of Sydney2, University of Calgary3, Monash University, Clayton campus4, Westmead Hospital5, University of Alberta6, University College London7, Ghent University Hospital8, Baylor College of Medicine9, Translational Research Institute10, Princess Alexandra Hospital11
TL;DR: Patients tend to prioritize outcomes that are more relevant to their daily living and well-being, and researchers need to consider interventions that are likely to improve these outcomes and measure and report patient-relevant outcomes in trials.
205 citations
TL;DR: Overall, use of antibiotics was not associated with an increased risk of developing HUS; however, after excluding studies at high risk of bias and those that did not employ an acceptable definition of HUS, there was a significant association.
Abstract: Background Antibiotic administration to individuals with Shiga toxin-producing Escherichia coli (STEC) infection remains controversial. We assessed if antibiotic administration to individuals with STEC infection is associated with development of hemolytic uremic syndrome (HUS). Methods The analysis included studies published up to 29 April 2015, that provided data from patients (1) with STEC infection, (2) who received antibiotics, (3) who developed HUS, and (4) for whom data reported timing of antibiotic administration in relation to HUS. Risk of bias was assessed; strength of evidence was adjudicated. HUS was the primary outcome. Secondary outcomes restricted the analysis to low-risk-of-bias studies employing commonly used HUS criteria. Pooled estimates of the odds ratio (OR) were obtained using random-effects models. Results Seventeen reports and 1896 patients met eligibility; 8 (47%) studies were retrospective, 5 (29%) were prospective cohort, 3 (18%) were case-control, and 1 was a trial. The pooled OR, including all studies, associating antibiotic administration and development of HUS was 1.33 (95% confidence interval [CI], .89-1.99; I(2) = 42%). The repeat analysis including only studies with a low risk of bias and those employing an appropriate definition of HUS yielded an OR of 2.24 (95% CI, 1.45-3.46; I(2) = 0%). Conclusions Overall, use of antibiotics was not associated with an increased risk of developing HUS; however, after excluding studies at high risk of bias and those that did not employ an acceptable definition of HUS, there was a significant association. Consequently, the use of antibiotics in individuals with STEC infections is not recommended.
164 citations
Journal Article•
TL;DR: In this paper, a Delphi survey was conducted to generate a consensus-based, prioritized list of core outcomes for trials in haemodialysis trials, where participants rated the importance of outcomes using a 9-point Likert scale.
Abstract: AIM: To generate a consensus-based, prioritized list of core outcomes for trials in haemodialysis.
BACKGROUND: Survival and quality of life for patients on haemodialysis remain poor despite substantial research efforts. Existing trials often report surrogate outcomes that may not be relevant to patients and clinicians. A core outcome set that reflects stakeholder priorities would improve the relevance, efficiency, and comparability of haemodialysis trials.
METHODS: In an online Delphi survey, participants rated the importance of outcomes using a 9-point Likert scale. In Round 2 and 3, participants reviewed the scores and comments of other respondents and re-rated the outcomes. For each outcome, we calculated the median, mean, and proportion rating 7-9 (“critically important”).
RESULTS: 1,181 participants (202 [17%] patients/caregivers, 979 health professionals) from 73 countries completed Round 1 and 838 (150 [18%] patients/caregivers) completed Round 3 (71% response rate). Outcomes achieving consensus as high priorities across both groups were: vascular access complications, cardiovascular disease, mortality, dialysis adequacy and fatigue. Patients/caregivers rated four outcomes higher than health professionals: ability to travel (mean difference 0.9), dialysis-free time (0.5), dialysis adequacy (0.3), and washed out after dialysis (0.2). Health professionals rated 11 outcomes higher: mortality (1.0), hospitalization (1.0), drop in blood pressure (1.0), vascular access complications (0.9), depression (0.9), cardiovascular disease (0.8), target weight (0.7), infection (0.4), potassium (0.4), ability to work (0.3), and pain (0.3).
CONCLUSIONS: The top stakeholder prioritized outcomes were vascular access problems, cardiovascular disease, mortality, dialysis adequacy and fatigue. Patients/caregivers gave higher priority to lifestyle-related outcomes than health professionals. This prioritized set of outcomes can inform the establishment of a core outcome set, to improve the value of trial evidence to support decision-making for people on haemodialysis.
149 citations
Institute of Cancer Research1, University of Arkansas for Medical Sciences2, Heidelberg University3, German Cancer Research Center4, Lund University5, Erasmus University Rotterdam6, deCODE genetics7, University of Iceland8, University of Leeds9, University of Basel10, University of Bonn11, Royal Victoria Infirmary12, Sahlgrenska University Hospital13, Karolinska Institutet14, Uppsala University15, University of Southampton16, Norwegian University of Science and Technology17, University of Ulm18, Broad Institute19
TL;DR: Eight new loci are discovered at 6p22.3, which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1, providing additional support for a polygenic model of MM and insight into the biological basis of tumour development.
Abstract: Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
140 citations
TL;DR: Iron-based binders show evidence of greater phosphate lowering that warrants further examination in randomized trials, and there is currently no evidence that phosphate-binder treatment reduces mortality compared to placebo in adults with CKD.
121 citations
TL;DR: The PDOPPS is the first large, international study to follow PD patients longitudinally to capture clinical practice and provide a means to understand variation in PD practices and outcomes, to identify optimal practices, and to ultimately improve outcomes for PD patients.
Abstract: BackgroundExtending technique survival on peritoneal dialysis (PD) remains a major challenge in optimizing outcomes for PD patients while increasing PD utilization. The primary objective of the Per...
103 citations
TL;DR: Electron microscopy provides atomically resolved images of a uniform distribution of individual POM species soft landed directly on complex technologically relevant CNT electrodes, established as a versatile approach for the controlled design of novel surfaces for both fundamental and applied research in energy storage.
Abstract: The rational design of improved electrode-electrolyte interfaces (EEI) for energy storage is critically dependent on a molecular-level understanding of ionic interactions and nanoscale phenomena. The presence of non-redox active species at EEI has been shown to strongly influence Faradaic efficiency and long-term operational stability during energy storage processes. Herein, we achieve substantially higher performance and long-term stability of EEI prepared with highly dispersed discrete redox-active cluster anions (50 ng of pure ∼0.75 nm size molybdenum polyoxometalate (POM) anions on 25 μg (∼0.2 wt%) carbon nanotube (CNT) electrodes) by complete elimination of strongly coordinating non-redox species through ion soft landing (SL). Electron microscopy provides atomically resolved images of a uniform distribution of individual POM species soft landed directly on complex technologically relevant CNT electrodes. In this context, SL is established as a versatile approach for the controlled design of novel surfaces for both fundamental and applied research in energy storage.
TL;DR: The results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison are presented in this paper.
Abstract: Purpose: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.
Experimental Design: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.
Results: In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX . The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.
Conclusions: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 1–12. ©2016 AACR.
TL;DR: It is proposed that peritoneal dialysis technique failure be defined by a composite endpoint of death or transfer to hemodialysis using both 30-day and 180-day definitions.
Abstract: ♦ BACKGROUND: Although technique failure is a key outcome in peritoneal dialysis (PD), there is currently no agreement on a uniform definition. We explored different definitions of PD technique failure using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. ♦ METHODS: We included 16,612 incident PD patients in Australia and New Zealand from January 1998 to December 2012. Different definitions of technique failure were applied according to the minimum number of days (30, 60, 90, 180, or 365) the patient received hemodialysis after cessation of PD. ♦ RESULTS: Median technique survival varied from 2.0 years with the 30-day definition to 2.4 years with the 365-day definition. For all definitions, the most common causes of technique failure were death, followed by infectious complications. The likelihood of a patient returning to PD within 12 months of technique failure was highest in the 30-day definition (24%), and was very small when using the 180- and 365-day definitions (3% and 0.8%, respectively). Patients whose technique failed due to mechanical reasons were the most likely to return to PD (46% within 12 months using the 30-day definition). ♦ CONCLUSIONS: Both 30- and 180-day definitions have clinical relevance but offer different perspectives with very different prognostic implications for further PD. Therefore, we propose that PD technique failure be defined by a composite endpoint of death or transfer to hemodialysis using both 30-day and 180-day definitions.
Washington University in St. Louis1, Vanderbilt University2, University of California, San Francisco3, University of Connecticut4, University of Wisconsin-Madison5, Cleveland Clinic6, Mayo Clinic7, University of Iowa8, Rush University Medical Center9, University of Pennsylvania10, University at Buffalo11, University of Virginia12, University of Michigan13, Regions Hospital14, University of North Carolina at Chapel Hill15, Ohio State University16, Thomas Jefferson University17, Children's Hospital of Philadelphia18, Princeton University19, University of Western Ontario20, University of California, Los Angeles21, Hospital for Special Surgery22, University of Pittsburgh23, Lenox Hill Hospital24, University of Colorado Boulder25, University of British Columbia26, Brown University27, Harvard University28, New York University29, University of Vermont30, United States Department of the Army31, Albany Medical College32, Washington State University33, University of Missouri34, Chesapeake Energy35
TL;DR: Prior lateral meniscectomy and current grade 3 to 4 changes of the trochlea were associated with worse outcomes in terms of decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision ACL reconstruction, but they had no effect on activity levels.
Abstract: Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes compared with primary ACL reconstructions. Purpose/Hypothesis: The purpose of this study was to determine if the prevalence, location, and/or degree of meniscal and chondral damage noted at the time of revision ACL reconstruction predicts activity level, sports function, and osteoarthritis symptoms at 2-year follow-up. The hypothesis was that meniscal loss and high-grade chondral damage noted at the time of revision ACL reconstruction will result in lower activity levels, decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery. Study Design: Cohort study; Level of evidence, 2. Methods: Between 2006 and 2011, a total of 1205 patients who underwent revision ACL reconstruction by 83 surgeons at 52 hospitals were accumulated for study of the relationship of meniscal and articular cartilage damage to outcome. Baseline demographic and intraoperative data, including the International Knee Documentation Committee (IKDC) subjective knee evaluation, Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity score, were collected initially and at 2-year follow-up to test the hypothesis. Regression analysis was used to control for age, sex, body mass index, smoking status, activity level, baseline outcome scores, revision number, time since last ACL reconstruction, incidence of having a previous ACL reconstruction on the contralateral knee, previous and current meniscal and articular cartilage injury, graft choice, and surgeon years of experience to assess the meniscal and articular cartilage risk factors for clinical outcomes 2 years after revision ACL reconstruction. Results: At 2-year follow-up, 82% (989/1205) of the patients returned their questionnaires. It was found that previous meniscal injury and current articular cartilage damage were associated with the poorest outcomes, with prior lateral meniscectomy and current grade 3 to 4 trochlear articular cartilage changes having the worst outcome scores. Activity levels at 2 years were not affected by meniscal or articular cartilage pathologic changes. Conclusion: Prior lateral meniscectomy and current grade 3 to 4 changes of the trochlea were associated with worse outcomes in terms of decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery, but they had no effect on activity levels. Registration: NCT00625885
TL;DR: This review focuses on indoxyl sulphate (IS), a protein‐bound, tryptophan‐derived metabolite that is generated by intestinal micro‐organisms (microbiota) and demonstrates an association between IS accumulation and increased fibrosis, and oxidative stress.
Abstract: In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m(2) ) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest-growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein-bound, tryptophan-derived metabolite that is generated by intestinal micro-organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) report effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney.
TL;DR: Evidence comparing the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, to manage acute nonsurgical pain in children treated in ambulatory settings highlights challenges in assessing medication safety, including lack of more detailed information in registry data, and inconsistent reporting in trials.
Abstract: Background. Fear of adverse events and occurrence of side effects are commonly cited by families and physicians as obstructive to appropriate use of pain medication in children. We examined evidence comparing the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, to manage acute nonsurgical pain in children (<18 years) treated in ambulatory settings. Methods. A comprehensive search was performed to July 2015, including review of national data registries. Two reviewers screened articles for inclusion, assessed methodological quality, and extracted data. Risks (incidence rates) were pooled using a random effects model. Results. Forty-four studies were included; 23 reported on adverse events. Based on limited current evidence, acetaminophen, ibuprofen, and opioids have similar nausea and vomiting profiles. Opioids have the greatest risk of central nervous system adverse events. Dual therapy with a nonopioid/opioid combination resulted in a lower risk of adverse events than opioids alone. Conclusions. Ibuprofen and acetaminophen have similar reported adverse effects and notably less adverse events than opioids. Dual therapy with a nonopioid/opioid combination confers a protective effect for adverse events over opioids alone. This research highlights challenges in assessing medication safety, including lack of more detailed information in registry data, and inconsistent reporting in trials.
TL;DR: Center-level predictors of lower peritonitis rates included smaller center size, high proportion of PD, low peritoneal equilibration test use at PD start, and low proportion of hospitalization forPeritonitis.
Abstract: BackgroundPrevious studies have reported significant variation in peritonitis rates across dialysis centers. Limited evidence is available to explain this variability. The aim of this study was to ...
University of Otago1, University of Bari2, University of Sydney3, Monash University4, University of Western Australia5, Charles Darwin University6, University of Queensland7, Princess Alexandra Hospital8, Ottawa Hospital Research Institute9, University of Ottawa10, The George Institute for Global Health11, Unitec Institute of Technology12, Cochrane Collaboration13
TL;DR: There was no clear and consistent association between intervention-induced LVM change and mortality and evidence for LVM as a valid surrogate end point in CKD is currently lacking.
TL;DR: This article present a conceptual argument that by engaging in the processes of democracy over and over again for as long as they are in school that children, adolescents, and young adults internalize the values, attitudes, and patterns of behavior necessary to be involved and contributing citizens in a democracy.
TL;DR: Analysis of local and systemic immune responses in peritoneal dialysis patients presenting with acute bacterial peritonitis and monitoring individuals before and during defined infectious episodes shows a crucial role for Vγ9/Vδ2 T cells and mucosal-associated invariant T cells in bacterial infection, and suggests that they represent a useful predictive marker for important clinical outcomes, which may inform future stratification and patient management.
Abstract: The antimicrobial responsiveness and function of unconventional human T cells are poorly understood, with only limited access to relevant specimens from sites of infection. Peritonitis is a common and serious complication in individuals with end-stage kidney disease receiving peritoneal dialysis. By analyzing local and systemic immune responses in peritoneal dialysis patients presenting with acute bacterial peritonitis and monitoring individuals before and during defined infectious episodes, our data show that Vγ9/Vδ2+ γδ T cells and mucosal-associated invariant T cells accumulate at the site of infection with organisms producing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and vitamin B2, respectively. Such unconventional human T cells are major producers of IFN-γ and TNF-α in response to these ligands that are shared by many microbial pathogens and affect the cells lining the peritoneal cavity by triggering local inflammation and inducing tissue remodeling with consequences for peritoneal membrane integrity. Our data uncover a crucial role for Vγ9/Vδ2 T cells and mucosal-associated invariant T cells in bacterial infection and suggest that they represent a useful predictive marker for important clinical outcomes, which may inform future stratification and patient management. These findings are likely to be applicable to other acute infections where local activation of unconventional T cells contributes to the antimicrobial inflammatory response.
TL;DR: TheESKD of lupus nephritis was associated with worse dialysis and transplant patient survival but comparable renal allograft survival compared with other causes of ESKD.
TL;DR: An end point of 30 or 40% decline in estimated glomerular filtration rate (eGFR) over 2-3 years can substitute for serum creatinine doubling in the composite end point and these alternate kidney end points were significantly associated with subsequent risks of ESKD and death.
Abstract: Chronic kidney disease (CKD) is strongly associated with increased risks of progression to end-stage kidney disease (ESKD) and mortality. Clinical trials evaluating CKD progression commonly use a composite end point of death, ESKD or serum creatinine doubling. However, due to low event rates, such trials require large sample sizes and long-term follow-up for adequate statistical power. As a result, very few interventions targeting CKD progression have been tested in randomized controlled trials. To overcome this problem, the National Kidney Foundation and Food and Drug Administration conducted a series of analyses to determine whether an end point of 30 or 40% decline in estimated glomerular filtration rate (eGFR) over 2-3 years can substitute for serum creatinine doubling in the composite end point. These analyses demonstrated that these alternate kidney end points were significantly associated with subsequent risks of ESKD and death. However, the association between, and consistency of treatment effects on eGFR decline and clinical end points were influenced by baseline eGFR, follow-up duration and acute hemodynamic effects. The investigators concluded that a 40% eGFR decline is broadly acceptable as a kidney end point across a wide baseline eGFR range and that a 30% eGFR decline may be acceptable in some situations. Although these alternate kidney end points could potentially allow investigators to conduct shorter duration clinical trials with smaller sample sizes thereby generating evidence to guide clinical decision-making in a timely manner, it is uncertain whether these end points will improve trial efficiency and feasibility. This review critically appraises the evidence, strengths and limitations pertaining to eGFR end points.
TL;DR: A meta-analysis of four patient series of European ancestry concludes that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors and identifies a locus at 6q25.1 marked by rs12374648 associated with MM-OS.
Abstract: Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.
TL;DR: It is shown that suppression of CD CA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival, which indicates how germline variation might confer susceptibility to MM.
Abstract: Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10-25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10-36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM.
TL;DR: This paper updates a previous ‘Call to Action’ paper that reviewed key outcome data for Australian and New Zealand peritoneal dialysis patients and made recommendations to improve care and includes additional practical recommendations based on published evidence and emerging initiatives to further improve outcomes.
Abstract: This paper updates a previous 'Call to Action' paper (Nephrology 2011; 16: 19-29) that reviewed key outcome data for Australian and New Zealand peritoneal dialysis patients and made recommendations to improve care. Since its publication, peritonitis rates have improved significantly, although they have plateaued more recently. Peritoneal dialysis patient and technique survival in Australian and New Zealand have also improved, with a reduction in the proportion of technique failures attributed to 'social reasons'. Despite these improvements, technique survival rates overall remain lower than in many other parts of the world. This update includes additional practical recommendations based on published evidence and emerging initiatives to further improve outcomes.
TL;DR: This review will outline the processes undertaken to achieve a sustained reduction in peritonitis rates in Australia and New Zealand over the last 5 years and the initiatives being put in place to ensure continued improvement.
Abstract: Peritonitis represents a major factor limiting the uptake and retention of patients on peritoneal dialysis (PD) in Australia and New Zealand. Until recently, peritonitis was an all-too-frequent complication, with peritonitis rates static at approximately 0.6 – 0.75 episodes per patient-year for 15 years between 1994 and 2008 and 40% of Australian PD units and 60% of New Zealand PD units failing to meet the maximum acceptable peritonitis rate of 0.67 episodes per patient-year recommended by the 2005 International Society for Peritoneal Dialysis (ISPD) Guidelines (1). There was an extraordinary 10-fold variation in peritonitis rates between centers, predominantly associated with center-level characteristics (2). For every 100 patients experiencing peritonitis, 14 would experience a relapse, 22 would have their catheter removed, 18 would be permanently transferred to hemodialysis, and 3 would die (3). Peritonitis represented the second commonest cause of PD technique failure after death (4), and nearly 60% of Australian pre-dialysis patients indicated that they were concerned or very concerned about PD-related peritonitis (5). In response to the seemingly entrenched and refractory nature of the peritonitis problem in Australia and New Zealand, a coordinated, multi-pronged approach has been undertaken by PD clinicians over the last decade to address this issue by (i) generating better evidence to inform peritonitis guidelines and clinical practice; (ii) improving translation of evidence and guidelines into clinical practice; and, (iii) improving peritonitis rates and outcomes through the establishment of continuous quality improvement (CQI) processes at local, state, and national levels. This review will outline the processes undertaken to achieve a sustained reduction in peritonitis rates in Australia and New Zealand over the last 5 years and the initiatives being put in place to ensure continued improvement.
TL;DR: Mammalian target of rapamycin inhibitor use was associated with a higher risk of all-cause mortality but not allograft loss, and patients using mammalian target ofRapamycin inhibitors were more likely to be white and have a history of pretransplant cancer.
Abstract: Background and objectives Emerging evidence from recently published observational studies and an individual patient data meta–analysis shows that mammalian target of rapamycin inhibitor use in kidney transplantation is associated with increased mortality. Therefore, all-cause mortality and allograft loss were compared between use and nonuse of mammalian target of rapamycin inhibitors in patients from Australia and New Zealand, where mammalian target of rapamycin inhibitor use has been greater because of heightened skin cancer risk. Design, setting, participants, & measurements Our longitudinal cohort study included 9353 adult patients who underwent 9558 kidney transplants between January 1, 1996 and December 31, 2012 and had allograft survival ≥1 year. Risk factors for all-cause death and all–cause and death–censored allograft loss were analyzed by multivariable Cox regression using mammalian target of rapamycin inhibitor as a time-varying covariate. Additional analyses evaluated mammalian target of rapamycin inhibitor use at fixed time points of baseline and 1 year. Results Patients using mammalian target of rapamycin inhibitors were more likely to be white and have a history of pretransplant cancer. Over a median follow-up of 7 years, 1416 (15%) patients died, and 2268 (24%) allografts were lost. There was a higher risk of all-cause mortality with time–varying mammalian target of rapamycin inhibitor use (hazard ratio, 1.47; 95% confidence interval, 1.23 to 1.76) as well as in the fixed time model analyses comparing mammalian target of rapamycin inhibitor use at baseline (hazard ratio, 1.54; 95% confidence interval, 1.22 to 1.93) and 1 year (hazard ratio, 1.63; 95% confidence interval, 1.32 to 2.01). Time–varying mammalian target of rapamycin inhibitor use was associated with higher risk of death because of malignancy (hazard ratio, 1.37; 95% confidence interval, 1.09 to 1.71). There were no statistically significant differences in the risk of all–cause (hazard ratio, 0.98; 95% confidence interval, 0.85 to 1.12) and death–censored (hazard ratio, 0.85; 95% confidence interval, 0.69 to 1.03) allograft loss between the mammalian target of rapamycin inhibitor use and nonuse groups in the time-varying model as well as the fixed time models. Conclusions Mammalian target of rapamycin inhibitor use was associated with a higher risk of all-cause mortality but not allograft loss.
TL;DR: This review will discuss NO pathways that are linked to the progression of CKD and CVD and therapeutic options for targeting these pathways.
TL;DR: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score.
Abstract: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl) intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acute gastroenteritis (AGE). Prospective, randomized, double-blind study conducted at eight pediatric emergency departments (EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h. Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 % NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged ≥6 months to <11 years with AGE-induced moderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level ≤22 mEq/L formed the modified intent to treat (mITT) group. At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, the PLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean ± SD at 4 h: 18 ± 3.74 vs 18.0 ± 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groups received similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2 (both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening of laboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatment group developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3). In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score. NCT#01234883
(Registration Date: November 3, 2010).
TL;DR: It is concluded that regulation of cGMP-cGK1-PDE signaling might provide novel, therapeutic strategies for the worsening global public health problem of CKD.
Abstract: Cyclic nucleotide signal transduction pathways are an emerging research field in kidney disease. Activated cell surface receptors transduce their signals via intracellular second messengers such as cAMP and cGMP. There is increasing evidence that regulation of the cGMP-cGMP-dependent protein kinase 1-phosphodiesterase (cGMP-cGK1-PDE) signaling pathway may be renoprotective. Selective PDE5 inhibitors have shown potential in treating kidney fibrosis in patients with chronic kidney disease (CKD), via their downstream signaling, and these inhibitors also have known activity as antithrombotic and anticancer agents. This review gives an outline of the cGMP-cGK1-PDE signaling pathways and details the downstream signaling and regulatory functions that are modulated by cGK1 and PDE inhibitors with regard to antifibrotic, antithrombotic, and antitumor activity. Current evidence that supports the renoprotective effects of regulating cGMP-cGK1-PDE signaling is also summarized. Finally, the effects of icariin, a natural plant extract with PDE5 inhibitory function, are discussed. We conclude that regulation of cGMP-cGK1-PDE signaling might provide novel, therapeutic strategies for the worsening global public health problem of CKD.