Diabetic nephropathy: What does the future hold?

The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin–angiotensin–aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era

Audio-visual synchrony and spatial attention enhance processing of dynamic visual stimulation independently and in parallel: A frequency-tagging study

The neural processing of a visual stimulus can be facilitated by attending to its position or by a co-occurring auditory tone. Using frequency-tagging, we investigated whether facilitation by spatial attention and audio-visual synchrony rely on similar neural processes. Participants attended to one of two flickering Gabor patches (14.17 and 17 Hz) located in opposite lower visual fields. Gabor patches further “pulsed” (i.e. showed smooth spatial frequency variations) at distinct rates (3.14 and 3.63 Hz). Frequency-modulating an auditory stimulus at the pulse-rate of one of the visual stimuli established audio-visual synchrony. Flicker and pulsed stimulation elicited stimulus-locked rhythmic electrophysiological brain responses that allowed tracking the neural processing of simultaneously presented Gabor patches. These steady-state responses (SSRs) were quantified in the spectral domain to examine visual stimulus processing under conditions of synchronous vs. asynchronous tone presentation and when respective stimulus positions were attended vs. unattended. Strikingly, unique patterns of effects on pulse- and flicker driven SSRs indicated that spatial attention and audiovisual synchrony facilitated early visual processing in parallel and via different cortical processes. We found attention effects to resemble the classical top-down gain effect facilitating both, flicker and pulse-driven SSRs. Audio-visual synchrony, in turn, only amplified synchrony-producing stimulus aspects (i.e. pulse-driven SSRs) possibly highlighting the role of temporally co-occurring sights and sounds in bottom-up multisensory integration

Trace elements in end-stage renal disease – unfamiliar territory to be revealed

Although associated with unfavorable outcomes in the general population, abnormal blood levels of various trace elements have not been consistently studied in the end-stage renal disease population (with the notable exception of aluminum). This is surprising, as the uremic patient treated by chronic dialysis loses one major route of trace element excretion and is exposed systematically to a foreign environment (the dialysis fluid) possibly contaminated with significant amounts of potential deleterious trace elements. Moreover, some biological important trace elements may be lost through the dialysis membrane. Most studies to date demonstrated significantly altered blood levels of trace elements in ESRD patients compared to healthy controls. However, the biological impact of these abnormalities in renal disease is largely unknown and should be clarified by future studies. A further step would be the design of well-controlled randomized interventional studies, examining the potential therapeutic benefit of supplementing one or more trace elements in ESRD patients, a population characterized by an impressive mortality due to cardiovascular, infectious and neoplasic disease

Blueprint for a european calciphylaxis registry initiative. the european calciphylaxis network (eucalnet)

Calcific uraemic arteriolopathy (CUA) is a rare disease and continues to be a clinical challenge. The typical course of CUA is characterized by painful skin discolouration and induration evolving to necrotic ulcerations. Medial calcification of cutaneous arterioles and extensive extracellular matrix remodelling are the hallmarks of CUA. The epidemiology and risk factors associated with this disease are still not fully understood. Moreover, CUA treatment strategies vary significantly among centres and expert recommendations are heterogeneous. Registries may provide important insights and information to increase our knowledge about epidemiology and clinical aspects of CUA and may help to optimize its therapeutic management. In 2006, we established an internet-based registry in Germany (www.calciphylaxie.de) to allow online notification of patients with established or suspected CUA. The registry includes a comprehensive database with questions covering >70 parameters and items regarding patient-related and laboratory data, clinical background and presentation as well as therapeutic strategies. The next phase will be to allow international patient registration via www.calciphylaxis.net as part of the multinational EuCalNet (European Calciphylaxis Network) initiative, which is supported by the ERA-EDTA scientific working group 'CKD-MBD'. Based on the valuable experience with the previous German CUA registry, EuCalNet will be a useful tool to collect data on the rare disease CUA and may become a basis for prospective controlled trials in the near future

Circulating markers of bone turnover

Renal osteodystrophy is a feature of chronic kidney disease (CKD), with increasing prevalence as CKD progresses. This bone disease is responsible for major morbidity, including fractures, and a deterioration in the quality of life and its sequelae. Circulating biomarkers of renal osteodystrophy typically indicate bone turnover, but not other features of bone, like bone volume, mineralization, quality or strength. Bone turnover can be considered to be primarily a reflection of bone cell activity, in particular that of osteoblasts and osteoclasts. Since current treatments for bone disease usually target cellular activity, biomarkers are considered to be able to contribute to the decision-making for treatment and its follow-up. In CKD, one has to consider the impact of a diminished clearance of biomarkers or their altered metabolism, both potentially limiting its clinical use. Here, several aspects of the most frequently used biomarkers of bone turnover are reviewed, with an emphasis on the specific situation represented by CKD. This review is based on the overview lecture at the symposium held in Amsterdam, September 23, 2016: "The Bone In CKD", organized by the CKD-MBD working group of ERA-EDTA

Depression and anxiety in patients with rheumatoid arthritis: prevalence rates based on a comparison of the Depression, Anxiety and Stress Scale (DASS) and the hospital, Anxiety and Depression Scale (HADS)

<p>Abstract</p> <p>Background</p> <p>While it is recognised that depression is prevalent in Rheumatoid Arthritis (RA), recent studies have also highlighted significant levels of anxiety in RA patients. This study compared two commonly used scales, the Depression Anxiety and Stress Scale (DASS) and the Hospital Anxiety and Depression Scale (HADS), in relation to their measurement range and cut points to consider the relative prevalence of both constructs, and if prevalence rates may be due to scale-specific case definition.</p> <p>Methods</p> <p>Patients meeting the criteria for RA were recruited in Leeds, UK and Sydney, Australia and asked to complete a survey that included both scales. The data was analysed using the Rasch measurement model.</p> <p>Results</p> <p>A total of 169 RA patients were assessed, with a repeat subsample, resulting in 323 cases for analysis. Both scales met Rasch model expectations. Using the 'possible+probable' cut point from the HADS, 58.3% had neither anxiety nor depression; 13.5% had anxiety only; 6.4% depression only and 21.8% had both 'possible+probable' anxiety and depression. Cut points for depression were comparable across the two scales while a lower cut point for anxiety in the DASS was required to equate prevalence.</p> <p>Conclusions</p> <p>This study provides further support for high prevalence of depression and anxiety in RA. It also shows that while these two scales provide a good indication of possible depression and anxiety, the estimates of prevalence so derived could vary, particularly for anxiety. These findings are discussed in terms of comparisons across studies and selection of scales for clinical use.</p

Exploring differential item functioning in the SF-36 by demographic, clinical, psychological and social factors in an osteoarthritis population

The SF-36 is a very commonly used generic measure of health outcome in osteoarthritis (OA). An important, but frequently overlooked, aspect of validating health outcome measures is to establish if items work in the same way across subgroup of a population. That is, if respondents have the same 'true' level of outcome, does the item give the same score in different subgroups or is it biased towards one subgroup or another. Differential item functioning (DIF) can identify items that may be biased for one group or another and has been applied to measuring patient reported outcomes. Items may show DIF for different conditions and between cultures, however the SF-36 has not been specifically examined in an osteoarthritis population nor in a UK population. Hence, the aim of the study was to apply the DIF method to the SF-36 for a UK OA population. The sample comprised a community sample of 763 people with OA who participated in the Somerset and Avon Survey of Health. The SF-36 was explored for DIF with respect to demographic, social, clinical and psychological factors. Well developed ordinal regression models were used to identify DIF items. Results: DIF items were found by age (6 items), employment status (6 items), social class (2 items), mood (2 items), hip v knee (2 items), social deprivation (1 item) and body mass index (1 item). Although the impact of the DIF items rarely had a significant effect on the conclusions of group comparisons, in most cases there was a significant change in effect size. Overall, the SF-36 performed well with only a small number of DIF items identified, a reassuring finding in view of the frequent use of the SF-36 in OA. Nevertheless, where DIF items were identified it would be advisable to analyse data taking account of DIF items, especially when age effects are the focus of interest

Parmodulins Inhibit Thrombus Formation Without Inducing Endothelial Injury Caused by Vorapaxar

Protease-activated receptor-1 (PAR1) couples the coagulation cascade to platelet activation during myocardial infarction and to endothelial inflammation during sepsis. This receptor demonstrates marked signaling bias. Its activation by thrombin stimulates prothrombotic and proinflammatory signaling, whereas its activation by activated protein C (APC) stimulates cytoprotective and antiinflammatory signaling. A challenge in developing PAR1-targeted therapies is to inhibit detrimental signaling while sparing beneficial pathways. We now characterize a novel class of structurally unrelated small-molecule PAR1 antagonists, termed parmodulins, and compare the activity of these compounds to previously characterized compounds that act at the PAR1 ligand–binding site. We find that parmodulins target the cytoplasmic face of PAR1 without modifying the ligand-binding site, blocking signaling through Gαq but not Gα13 in vitro and thrombus formation in vivo. In endothelium, parmodulins inhibit prothrombotic and proinflammatory signaling without blocking APC-mediated pathways or inducing endothelial injury. In contrast, orthosteric PAR1 antagonists such as vorapaxar inhibit all signaling downstream of PAR1. Furthermore, exposure of endothelial cells to nanomolar concentrations of vorapaxar induces endothelial cell barrier dysfunction and apoptosis. These studies demonstrate how functionally selective antagonism can be achieved by targeting the cytoplasmic face of a G-protein–coupled receptor to selectively block pathologic signaling while preserving cytoprotective pathways

Variability in depression prevalence in early rheumatoid arthritis: a comparison of the CES-D and HAD-D Scales

<p>Abstract</p> <p>Background</p> <p>Depression is common in rheumatoid arthritis (RA), however reported prevalence varies considerably. Two frequently used instruments to identify depression are the Center for Epidemiological Studies Depression (CES-D) scale, and the Hospital Anxiety and Depression Scale (HADS). The objectives of this study were to test if the CES-D and HADS-D (a) satisfy current modern psychometric standards for unidimensional measurement in an early RA sample; (b) measure the same construct (i.e. depression); and (c) identify similar levels of depression.</p> <p>Methods</p> <p>Data from the two scales completed by patients with early RA were fitted to the Rasch measurement model to show that (a) each scale satisfies the criteria of fit to the model, including strict unidimensionality; (b) that the scales can be co-calibrated onto a single underlying continuum of depression and to (c) examine the location of the cut points on the underlying continuum as indication of the prevalence of depression.</p> <p>Results</p> <p>Ninety-two patients with early RA (62% female; mean age = 56.3, SD = 13.7) gave 141 sets of paired CES-D and HAD-D data. Fit of the data from the CES-D was found to be poor, and the scale had to be reduced to 13 items to satisfy Rasch measurement criteria whereas the HADS-D met model expectations from the outset. The 20 items combined (CES-D13 and HADS-D) satisfied Rasch model expectations. The CES-D gave a much higher prevalence of depression than the HADS-D.</p> <p>Conclusion</p> <p>The CES-D in its present form is unsuitable for use in patients with early RA, and needs to be reduced to a 13-item scale. The HADS-D is valid for early RA and the two scales measure the same underlying construct but their cut points lead to different estimates of the level of depression. Revised cut points on the CES-D13 provide comparative prevalence rates.</p

DIALYSIS MINERAL BONE DISEASE

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