Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

Introduction: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis: Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination: The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications

Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial)

Introduction: The primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A 1c (HbA 1c)39-47 mmol/mol/5.7%-6.4%). The secondary aims are to investigate the effects of the interventions on body composition and cardiometabolic risk factors. Methods and analysis: The Pre-D Trial is an investigator-initiated, randomised, controlled, parallel, open-label, superiority trial. The study aims to assign 120 participants in a 1:1:1:1 ratio to receive one of four interventions for 13 weeks: (1) dapagliflozin (10 mg once daily); (2) metformin (850 mg twice daily); (3) exercise (interval training, 5 days a week, 30 min per session); or (4) control (lifestyle advice). After the 13 weeks of intervention, a follow-up period of 13 weeks will follow to study the long-term effects of the interventions. The primary endpoint is reduction from baseline to end-of treatment (13 weeks) in mean amplitude of glycaemic excursions measured by continuous glucose monitoring. The secondary endpoints include concomitant changes in various measures of glucose metabolism, body weight, cardiorespiratory fitness, blood pressure, plasma lipids, objectively measured physical activity and dietary intake. Ethics and dissemination: The study protocol has been approved by the Ethics Committee of the Capital Region and the Danish Medicines Agency. Approval of data and biobank storage has been obtained from the Danish Data Protection Board. The study will be carried out according to the Declaration of Helsinki and to the regulations for good clinical practice. The results from this trial will allow a number of research questions concerning the effect of exercise versus dapagliflozin or metformin in HbA 1c -defined prediabetes to be addressed.</p

Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes:A systematic review

Hypothesis/objectives: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can prevent development of microalbuminuria. Materials and methods: We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) to placebo. Studies had to have at least 50 participants in each arm and one year of follow-up. Random and fixed effect models were performed as well as trial sequential analysis. Results: Six trials were included in the analysis ( n=16,921). Overall risk of bias was variable. In a fixed model analysis ACE or ARB treatment was superior to placebo in relation to prevention of development of microalbuminuria, risk ratio 0.84 (95% confidence interval (CI) 0.79–0.88) p&lt;0.001, I2=23%, similar to random model results. Treatment also showed a trend towards a reduction in all-cause mortality( p=0.07). Conclusions: We conclude that in patients with type 2 diabetes and normoalbuminuria, early intervention with ACEis or ARBs reduces the risk for development of microalbuminuria. </jats:sec

Multifactorial intervention to prevent cardiovascular disease in patients with early rheumatoid arthritis:protocol for a multicentre randomised controlled trial

INTRODUCTION: Cardiovascular morbidity is a major burden in patients with rheumatoid arthritis (RA). In this study, we compare the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment of modifiable risk factors for cardiovascular disease (CVD) in patients with early RA fulfilling the 2010 American College of Rheumatology European League Against Rheumatism (ACR/EULAR) criteria. METHODS AND ANALYSIS: The study is a prospective, randomised, open label trial with blinded end point assessment and balanced randomisation (1:1) conducted in 10 outpatient clinics in Denmark. The primary end point after 5 years of follow-up is a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke and cardiac revascularisation. Secondary outcomes are: the proportion of patients achieving low-density lipoprotein cholesterol <2.5 mmol/L, glycated haemoglobin <48 mmol/mol, blood pressure <140/90 mm  Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes and normoalbuminuria (urinary albumin creatinine ratio <30 mg/g) after 1 year of follow-up and the proportion of patients in each treatment group achieving low RA disease activity after 1 year, defined as a disease activity score C-reactive protein (DAS28-CRP) <3.2 and a DAS28-CRP score <2.6 after 12, 24 and 60 months. Furthermore, all hospitalisations for acute and elective reasons will be adjudicated by the event committee after 12, 24 and 60 months. Three hundred treatment-naive patients with early RA will be randomly assigned (1:1) to receive either conventional treatment administered and monitored by their general practitioner according to national guidelines (control group) or a stepwise implementation administered and monitored in a quarterly rheumatological nurse-administered set-up of behaviour modification and pharmacological therapy targeting (1) hyperlipidaemia, (2) hypertension, (3) hyperglycaemia and (4) microalbuminuria (intervention group). ETHICS AND DISSEMINATION: This protocol is approved by the local ethics committee (DK-S-2014007) and The Danish Health and Medicines Authority. Dissemination will occur through presentations at National and International conferences and publications in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT0224625

Non-linear control of a hydraulic piezo-valve using a generalized Prandtl-Ishlinskii hysteresis model

The potential to actuate proportional flow control valves using piezoelectric ceramics or other smart materials has been investigated for a number of years. Although performance advantages compared to electromagnetic actuation have been demonstrated, a major obstacle has proven to be ferroelectric hysteresis, which is typically 20% for a piezoelectric actuator. In this paper, a detailed study of valve control methods incorporating hysteresis compensation is made for the first time. Experimental results are obtained from a novel spool valve actuated by a multi-layer piezoelectric ring bender. A generalized Prandtl-Ishlinskii model, fitted to experimental training data from the prototype valve, is used to model hysteresis empirically. This form of model is analytically invertible and is used to compensate for hysteresis in the prototype valve both open loop, and in several configurations of closed loop real time control system. The closed loop control configurations use PID (Proportional Integral Derivative) control with either the inverse hysteresis model in the forward path or in a command feedforward path. Performance is compared to both open and closed loop control without hysteresis compensation via step and frequency response results. Results show a significant improvement in accuracy and dynamic performance using hysteresis compensation in open loop, but where valve position feedback is available for closed loop control the improvements are smaller, and so conventional PID control may well be sufficient. It is concluded that the ability to combine state-of-the-art multi-layer piezoelectric bending actuators with either sophisticated hysteresis compensation or closed loop control provides a route for the creation of a new generation of high performance piezoelectric valves.<br/

Progressive decline in estimated glomerular filtration rate in patients with diabetes after moderate loss in kidney functiond even without albuminuria

Objective: Persons with diabetes but no chronic kidney disease (CKD) and without albuminuria have the same age-related decline in kidney function as the background population. Whether this also applies following moderate loss in kidney function is unknown. We quantified the impact of albuminuria status on the development of estimated glomerular filtration rate (eGFR) trajectories following CKD stage 3 (CKD3) and assessed potential heterogeneous development patterns among the subgroup with normoalbuminuria. Research Design and Methods: We used repeated clinical measures during up to 16 years of follow-up in 935 persons with type 1 diabetes and 1,984 with type 2 diabetes. Trajectories of eGFR by diabetes type and albuminuria status following CKD3 were estimated with spline mixed-effects models with adjustment for relevant confounders. Latent class trajectory modeling was used to find distinct patterns of eGFR development in the subgroups with normoalbuminuria. Results: Mean annual declines in eGFR for normo-, micro- and macroalbuminuria the first 10 years following CKD3 were 1.9, 2.3, and 3.3 mL/min/1.73 m 2 in type 1 diabetes and 1.9, 2.1, and 3.0 in type 2 diabetes, respectively. For normoalbuminuria, two distinct eGFR patterns were found, one with accelerated declining eGFR levels. This specific progression pattern was associated with less use of lipid-lowering treatment, renin-angiotensin system blockers, and other antihypertensive treatment. Conclusions: Our results support a diabetes-dependent decline in kidney function without albuminuria following CKD3, with a subgroup showing a progressive decline. Furthermore, this group seems to be undertreated in terms of cardioprotective and renal protective treatment and suggests that increased attention should be drawn to normoalbuminuric diabetic kidney disease. </p

Effect of large weight reductions on measured and estimated kidney function

BACKGROUND: When patients experience large weight loss, muscle mass may be affected followed by changes in plasma creatinine (pCr). The MDRD and CKD-EPI equations for estimated GFR (eGFR) include pCr. We hypothesised that a large weight loss reduces muscle mass and pCr causing increase in eGFR (creatinine-based equations), whereas measured GFR (mGFR) and cystatin C-based eGFR would be unaffected if adjusted for body surface area. METHODS: Prospective, intervention study including 19 patients. All attended a baseline visit before gastric bypass surgery followed by a visit six months post-surgery. mGFR was assessed during four hours plasma (51)Cr-EDTA clearance. GFR was estimated by four equations (MDRD, CKD-EPI-pCr, CKD-EPI-cysC and CKD-EPI-pCr-cysC). DXA-scans were performed at baseline and six months post-surgery to measure changes in lean limb mass, as a surrogate for muscle mass. RESULTS: Patients were (mean ± SD) 40.0 ± 9.3 years, 14 (74%) were female and 5 (26%) had type 2 diabetes, baseline weight was 128 ± 19 kg, body mass index 41 ± 6 kg/m2 and absolute mGFR 122 ± 24 ml/min. Six months post-surgery weight loss was 27 (95% CI: 23; 30) kg, mGFR decreased by 9 (−17; −2) from 122 ± 24 to 113 ± 21 ml/min (p = 0.024), but corrected for current body surface area (BSA) mGFR was unchanged by 2 (−5; 9) ml/min/1.73 m(2) (p = 0.52). CKD-EPI-pCr increased by 12 (6; 17) and MDRD by 13 (8; 18) (p < 0.001 for both), while CKD-EPI-cysC was unchanged by 2 (−8; 4) ml/min/1.73 m(2) (p = 0.51). Lean limb mass was reduced by 3.5 (−4.4;−2.6; p < 0.001) kg and change in lean limb mass correlated with change in plasma creatinine (R (2) = 0.28, p = 0.032). CONCLUSIONS: Major weight reductions are associated with a reduction in absolute mGFR, which may reflect resolution of glomerular hyperfiltration, while mGFR adjusted for body surface area was unchanged. Estimates of GFR based on creatinine overestimate renal function likely due to changes in muscle mass, whereas cystatin C based estimates are unaffected. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02138565. Date of registration: March 24, 2014

Urinary albumin and 8-oxo-7,8-dihydroguanosine as markers of mortality and cardiovascular disease during 19 years after diagnosis of type 2 diabetes:A comparative study of two markers to identify high risk patients

Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death