Defining myocardial infarction in trials of people receiving hemodialysis: consensus report from the SONG-HD MI Expert Working group.

Cardiovascular disease is the leading cause of death in patients receiving hemodialysis. Currently, there is no standardized definition of myocardial infarction (MI) for patients receiving hemodialysis. Through an international consensus process MI was established as the core CVD measure for this population in clinical trials. The Standardised Outcomes in Nephrology Group-Hemodialysis (SONG-HD) initiative convened a multidisciplinary, international working group to address the definition of MI in this population. On the basis of current evidence, the working group recommends using the Fourth Universal Definition of Myocardial Infarction with specific caveats with regard to the interpretation of "ischemic symptoms" and performing a baseline 12-lead electrocardiogram to facilitate interpretation of acute changes on subsequent tracings. The working group does not recommend obtaining baseline cardiac troponin values, though does recommend obtaining serial cardiac biomarkers in settings where ischemia is suspected. The application of an evidence-based uniform definition should increase the reliability and accuracy of trial results.

Conversion from Aranesp® to NESP® in dialysis patients-Exploration of dosing strategies and the feasibility of extending the dosing interval.

AIM: Darbepoetin alpha is available as Aranesp® and NESP®, which differ in the inactive component and maximum dose-strength of prefilled syringes. We conducted an observational cohort study to investigate optimal conversion strategies and the feasibility of extending dosing intervals with higher-dose preparations in dialysis patients converting from Aranesp® to NESP®. METHODS: Adult dialysis patients on Aranesp® with stable haemoglobin of 9-12 g/dL were converted to NESP® at the same monthly total dose according to one of three conversion regimens. Group A included patients on ≤80 mcg/month of Aranesp® who converted with dosing regimen unchanged. Group B patients converted to NESP® with extended dosing intervals using higher individual dose preparations. Group C were patients on 100 mcg Aranesp® who converted to NESP® 120 mcg with extended dosing intervals. Patients were observed for 6 months. RESULTS: Fifty patients were included. All 24 Group A patients maintained stable haemoglobin. In Group B, 10 patients (50%) maintained stable haemoglobin with extension of dosing interval from 1.04 ± 0.14 to 3.03 ± 1.28 weeks. Factors associated with success in extending dosing interval included a lower prevalence of cardiovascular disease and a higher Kt/Vurea in peritoneal dialysis patients. Four patients (80%) in Group C maintained stable haemoglobin after conversion to NESP® 120 mcg with extended dosing interval. The use of NESP® 120 mcg was well tolerated, and was associated with reduced patient-reported pain score and 38% reduction of drug cost. CONCLUSION: Dialysis patients on Aranesp® can be successfully converted to NESP® and the dosing interval can be extended successfully in a significant proportion of patients, which could reduce discomfort and drug cost.

Eating During Hemodialysis Treatment: A Consensus Statement From the International Society of Renal Nutrition and Metabolism.

Poor nutritional status and protein-energy wasting are common among maintenance dialysis patients and associated with unfavorable outcomes. Providing foods, meal trays, snack boxes, and/or oral nutritional supplements during hemodialysis can improve nutritional status and might also reduce inflammation, enhance health-related quality of life, boost patient satisfaction, and improve survival. Potential challenges include postprandial hypotension and other hemodynamic instabilities, aspiration risk, gastrointestinal symptoms, hygiene issues, staff burden, reduced solute removal, and increased costs. Differing in-center nutrition policies exist within organizations and countries around the world. Recent studies have demonstrated clinical benefits and highlight the need to work toward clear guidelines. Meals or supplements during hemodialysis may be an effective strategy to improve nutritional status with limited reports of complications in real-world scenarios. Whereas larger multicenter randomized trials are needed, meals and supplements during hemodialysis should be considered as a part of the standard-of-care practice for patients without contraindications.

Global Prevalence of Protein-Energy Wasting in Kidney Disease: A Meta-analysis of Contemporary Observational Studies From the International Society of Renal Nutrition and Metabolism.

OBJECTIVE: To better define the prevalence of protein-energy wasting (PEW) in kidney disease is poorly defined. METHODS: We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability. RESULTS: Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified. CONCLUSION: By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.

First Report of Human Infection by Agromyces mediolanus, a Gram-Positive Organism Found in Soil.

We report the first human infection by a member of the Agromyces genus, a group of Gram-positive bacteria found in soil. A patient with a long-term venous catheter developed bacteremia due to a non-vancomycin-susceptible isolate of Agromyces mediolanus. Rapid identification was possible by matrix-assisted laser desorption ionization-time of flight mass spectrometry.

The Alzheimer's Disease Neuroimaging Initiative 2 PET Core: 2015.

INTRODUCTION: This article reviews the work done in the Alzheimer's Disease Neuroimaging Initiative positron emission tomography (ADNI PET) core over the past 5 years, largely concerning techniques, methods, and results related to amyloid imaging in ADNI. METHODS: The PET Core has used [(18)F]florbetapir routinely on ADNI participants, with over 1600 scans available for download. Four different laboratories are involved in data analysis, and have examined factors such as longitudinal florbetapir analysis, use of [(18)F]fluorodeoxyglucose (FDG)-PET in clinical trials, and relationships between different biomarkers and cognition. RESULTS: Converging evidence from the PET Core has indicated that cross-sectional and longitudinal florbetapir analyses require different reference regions. Studies have also examined the relationship between florbetapir data obtained immediately after injection, which reflects perfusion, and FDG-PET results. Finally, standardization has included the translation of florbetapir PET data to a centiloid scale. CONCLUSION: The PET Core has demonstrated a variety of methods for the standardization of biomarkers such as florbetapir PET in a multicenter setting.

Etiology of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM).

Protein-energy wasting (PEW), a term proposed by the International Society of Renal Nutrition and Metabolism (ISRNM), refers to the multiple nutritional and catabolic alterations that occur in chronic kidney disease (CKD) and associate with morbidity and mortality. To increase awareness, identify research needs, and provide the basis for future work to understand therapies and consequences of PEW, ISRNM provides this consensus statement of current knowledge on the etiology of PEW syndrome in CKD. Although insufficient food intake (true undernutrition) due to poor appetite and dietary restrictions contribute, other highly prevalent factors are required for the full syndrome to develop. These include uremia-induced alterations such as increased energy expenditure, persistent inflammation, acidosis, and multiple endocrine disorders that render a state of hypermetabolism leading to excess catabolism of muscle and fat. In addition, comorbid conditions associated with CKD, poor physical activity, frailty, and the dialysis procedure per se further contribute to PEW.

Changes in the Auditory Association Cortex in Dementing Illnesses.

OBJECTIVE: To evaluate the relationship between degree of cognitive impairment and gray-matter density changes in the auditory cortex. STUDY DESIGN: Retrospective case-control. PATIENTS: Six hundred sixty-three patients of a tertiary referral center cognitive disorders clinic. INTERVENTION: Magnetic resonance imaging. MAIN OUTCOME MEASURES: Ratios of gray matter density of the primary auditory cortex (A1) to whole brain and auditory association cortex (AAC) to whole brain in patients with Alzheimer's disease (AD) compared with mild cognitive impairment (MCI) and patients with a mini-mental state exam (MMSE) scores ≤25 versus >25. RESULTS: After multivariate analysis, a statistically significant difference between AAC to brain ratios for patients with a MMSE ≤25 (n = 325) compared with >25 (n = 269) was found, with values -0.03 (95% CI -0.04 to -0.02, p < 0.0001) on the left and -0.04 (95% CI -0.06 to -0.03, p < 0.0001) on the right. The adjusted average difference of left and right AAC to brain ratios between AD patients (n = 218) compared with MCI patients (n = 121) was also statistically significant, at -0.03 (95% CI -0.05 to -0.01, p = 0.004) and -0.05 (95% CI -0.07 to -0.03, p < 0.0001), respectively. There was no statistically significant difference in the left or right A1 to brain ratios between the MMSE groups or between the AD and MCI groups. CONCLUSIONS: The AAC for patients with MMSE ≤25 and for those with AD shows decreased gray matter density when compared with patients with better cognitive function. No difference was detected in A1, raising the possibility that patients may have intact neural hearing, but impaired ability to interpret sounds.

Left Atrial Remodeling Assessed by Cardiac MRI after Conversion from Conventional Hemodialysis to In-Centre Nocturnal Hemodialysis.

BACKGROUND: Left atrial (LA) volume is a well-established cardiovascular prognosticator in patients with end-stage renal disease. Although dialysis intensification is associated with left ventricular mass regression, there are limited data regarding LA remodeling. Using cardiac magnetic resonance imaging (CMR), we examined changes in LA size and function relative to ventricular remodeling and cardiac biomarkers after dialysis intensification. METHODS: In this prospective 2-centre cohort study, 37 patients receiving conventional hemodialysis (CHD, 4 h/session, 3×/week) were converted to in-centre nocturnal hemodialysis (INHD 7-8 h/session, 3×/week); 30 patients remained on CHD. CMR and biomarkers were performed at baseline and repeated at 52 weeks. RESULTS: After 52 weeks, there were no significant changes in the LA volumes or LA ejection fraction (EF) within either the CHD or INHD group, and no significant differences between the two groups. Correlations existed between changes in LA and LV end-diastolic volume index (EDVi, Spearman's r = 0.69, p < 0.001), LA and LV end-systolic volume index (ESVi, r = 0.44, p = 0.001), LAEF and LVEF (r = 0.28, p = 0.04), LA and RV EDVi (r = 0.51, p < 0.001), LA and RV ESVi (r = 0.29, p = 0.039), and LA ESVi and LV mass index (r = 0.31, p = 0.02). At baseline, indexed LA volumes positively correlated with NT-proBNP, whereas LAEF negatively correlated with NT-proBNP and Troponin I. After 52 weeks, changes in biomarker levels did not correlate with changes in LA volume or EF. CONCLUSION: There was no significant change in LA size or systolic function after conversion to INHD. The significant correlations between LA and ventricular remodeling and cardiac biomarkers suggest common underlying pathophysiologic mechanisms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00718848.

Realizing the potential of positron emission tomography with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer's disease.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG-PET) thus far rarely has been used to advance the development of new treatments for Alzheimer's disease (AD). Now that FDG-PET with standard acquisition protocols for dementia is widely available, change in cerebral glucose metabolism is a feasible outcome variable for clinical drug trials. Individual analysis of FDG-PET results also might prove valuable. FDG-PET can detect metabolic changes very early in the course of AD and identify subjects for earlier treatment. FDG-PET reliably distinguishes AD from frontotemporal dementia so that only those most likely to benefit are enrolled in trials. Finally, objectively identifying phenotypic variations of AD with FDG-PET might have pathogenic and prognostic implications that can be used for personalized treatment approaches. The judicious use of FDG-PET is needed to accelerate the evaluation of promising new drugs and more rationally target treatments for dementing diseases.

Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD): Study Protocol for Establishing a Core Outcome Set in PD.

BACKGROUND: Worldwide, approximately 11% of patients on dialysis receive peritoneal dialysis (PD). Whilst PD may offer more autonomy to patients compared with hemodialysis, patient and caregiver burnout, technique failure, and peritonitis remain major challenges to the success of PD. Improvements in care and outcomes are likely to be mediated by randomized trials of innovative therapies, but will be limited if the outcomes measured and reported are not important for patients and clinicians. The aim of the Standardised Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) study is to establish a set of core outcomes for trials in patients on PD based on the shared priorities of all stakeholders, so that outcomes of most relevance for decision-making can be evaluated, and that interventions can be compared reliably. METHODS: The 5 phases in the SONG-PD project are: a systematic review to identify outcomes and outcome measures that have been reported in randomized trials involving patients on PD; focus groups using nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choice of outcomes; semi-structured key informant interviews with health professionals; a 3-round international Delphi survey involving a multi-stakeholder panel; and a consensus workshop to review and endorse the proposed set of core outcome domains for PD trials. DISCUSSION: The establishment of 3 to 5 high-priority core outcomes, to be measured and reported consistently in all trials in PD, will enable patients and clinicians to make informed decisions about the relative effectiveness of interventions, based upon outcomes of common importance.

Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value.

OBJECTIVES: The aim of this study was to ascertain if left ventricular mitral annulus velocities measured by tissue Doppler imaging (TDI) are more powerful predictors of outcome compared with clinical data and standard Doppler-echocardiographic parameters. BACKGROUND: Tissue Doppler imaging of basal or mitral annulus velocities provides rapid assessment of ventricular long axis function. But it is not known if TDI-derived velocities in systole and diastole add incremental value and are superior to the standard Doppler-echocardiographic measurements as a predictor of outcome. METHODS: The study population consisted of 518 subjects, 353 with cardiac disease and 165 normal subjects who had full Doppler two-dimensional-echocardiographic studies with measurement of mitral inflow velocities in early and late diastole, E-wave deceleration time (DT), peak systolic mitral annular velocity (Sm) early and late diastolic mitral annular velocity (Em and Am) by TDI, early diastolic flow propagation velocity, and standard chamber dimensions. All subjects were followed up for two years. The end point was cardiac death. RESULTS: Tissue Doppler imaging mitral annulus systolic and diastolic velocities were all significantly lower in the non-survivors (all p < 0.05) as was DT (p = 0.024). In the Cox model the best predictors of mortality were Em, Sm, Am, left ventricular ejection fraction, left ventricular mass, and left atrial diameter in systole (LADs). By backward stepwise analysis Em and LADs were the strongest predictors. After forcing the TDI measurements into the covariate model with clinical and mitral DT <0.16 s, Em provided significant incremental value for predicting cardiac mortality (p = 0.004). CONCLUSIONS: Mitral annulus velocity measured by TDI in early diastole gives incremental predictive power for cardiac mortality compared to clinical data and standard echocardiographic measurements. This easily available measurement adds significant value in the clinical management of cardiac patients.

Prognostic value of C-reactive protein for heart disease in dialysis patients.

C-reactive protein (CRP) is considered to be the prototype marker of inflammation. In the general population, there are ample clinical and epidemiological data that indicate its usefulness both in predicting the prognosis for various forms of cardiovascular disease, and in monitoring response to treatment. There is also evolving evidence that CRP may be directly involved in the pathological disease process itself. In end-stage renal disease (ESRD) patients, cardiovascular disease remains the leading cause of morbidity and mortality, and is accounted for by a clustering of both traditional and non-traditional risk factors. Of these, inflammation is considered one of the important risk factors and is usually denoted by the presence of elevated CRP. However, since it is a non-specific inflammatory marker and acute-phase reactant, CRP may become elevated as a result of other dialysis-related (such as graft and fistula infections, bio-incompatible dialysis membrane or dialysate, endotoxin exposure and back filtration) and dialysis-unrelated factors (such as chronic infections and malnutrition). This raises an important question as to whether CRP serves as a useful prognostic biomarker in the dialysis population. This review provides an updated view of the use of CRP as a prognostic marker of cardiovascular disease in ESRD patients on maintenance dialysis.

Amyloid deposition and cognition in older adults: the effects of premorbid intellect.

Although amyloid deposition remains a marker of the development of Alzheimer's disease, results linking amyloid and cognition have been equivocal. Twenty-five community-dwelling non-demented older adults were examined with (18)F-flutemetamol, an amyloid imaging agent, and a cognitive battery, including an estimate of premorbid intellect and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In the first model, (18)F-flutemetamol uptake significantly correlated with the Delayed Memory Index of the RBANS (r = -.51, p = .02) and premorbid intellect (r = .43, p = .03). In the second model, the relationship between (18)F-flutemetamol and cognition was notably stronger when controlling for premorbid intellect (e.g., three of the five RBANS Indexes and its Total score significantly correlated with (18)F-flutemetamol, r's = -.41 to -.58). Associations were found between amyloid-binding (18)F-flutemetamol and cognitive functioning in non-demented older adults. These associations were greatest with delayed memory and stronger when premorbid intellect was considered, suggesting that cognitive reserve partly compensates for the symptomatic expression of amyloid pathology in community-dwelling elderly.

Genetic, structural and functional imaging biomarkers for early detection of conversion from MCI to AD.

With the advent of advanced imaging techniques, genotyping, and methods to assess clinical and biological progression, there is a growing need for a unified framework that could exploit information available from multiple sources to aid diagnosis and the identification of early signs of Alzheimer's disease (AD). We propose a modeling strategy using supervised feature extraction to optimally combine high-dimensional imaging modalities with several other low-dimensional disease risk factors. The motivation is to discover new imaging biomarkers and use them in conjunction with other known biomarkers for prognosis of individuals at high risk of developing AD. Our framework also has the ability to assess the relative importance of imaging modalities for predicting AD conversion. We evaluate the proposed methodology on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to predict conversion of individuals with mild cognitive impairment (MCI) to AD, only using information available at baseline.

Left ventricular filling pressure by Doppler echocardiography in patients with end-stage renal disease.

Left ventricular hypertrophy and systolic dysfunction predict mortality in patients with end-stage renal disease. However, the prognostic value of left ventricular filling pressure has remained uncertain in this population. We evaluated whether the early mitral inflow velocity to peak mitral annulus velocity (E/Em) ratio, an estimate of left ventricular filling pressure by tissue Doppler imaging, has significant additional prognostic value to conventional echocardiographic parameters and other clinical and biochemical parameters in 220 patients with end-stage renal disease. The E/Em ratio was elevated (>15) in 62% of the patients. Multivariate analysis showed that an elevated E/Em ratio had the highest correlation with left ventricular volume index, followed by loss of residual glomerular filtration rate, increasing age, worsening ejection fraction, and diabetes. During the median follow-up of 48 months, the E/Em ratio emerged as an independent predictor of all-cause mortality (adjusted hazard ratio: 1.027; 95% CI: 1.003 to 1.051; P=0.026) and cardiovascular death (adjusted hazard ratio: 1.033; 95% CI: 1.002 to 1.065; P=0.035) in the multivariable Cox regression analysis. In addition, the E/Em ratio added significant incremental prognostic value for all-cause mortality (P=0.035) and cardiovascular death (P=0.035) beyond the standard clinical, biochemical, and dialysis parameters and echocardiographic measurements. In conclusion, the E/Em ratio displayed important additional long-term prognostic information above and beyond that of left ventricular mass and systolic function. Our data suggest that left ventricular filling pressure should be estimated during echocardiographic examination for additional prognostication in patients with end-stage renal disease.