HEROIC: a 5-year observational cohort study aimed at identifying novel factors that drive diabetic kidney disease: rationale and study protocol

Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. INTRODUCTION: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease worldwide and a major cause of premature mortality in diabetes mellitus (DM). While improvements in care have reduced the incidence of kidney disease among those with DM, the increasing prevalence of DM means that the number of patients worldwide with DKD is increasing. Improved understanding of the biology of DKD and identification of novel therapeutic targets may lead to new treatments. A major challenge to progress has been the heterogeneity of the DKD phenotype and renal progression. To investigate the heterogeneity of DKD we have set up The East and North London Diabetes Cohort (HEROIC) Study, a secondary care-based, multiethnic observational study of patients with biopsy-proven DKD. Our primary objective is to identify histological features of DKD associated with kidney endpoints in a cohort of patients diagnosed with type 1 and type 2 DM, proteinuria and kidney impairment. METHODS AND ANALYSIS: HEROIC is a longitudinal observational study that aims to recruit 500 patients with DKD at high-risk of renal and cardiovascular events. Demographic, clinical and laboratory data will be collected and assessed annually for 5 years. Renal biopsy tissue will be collected and archived at recruitment. Blood and urine samples will be collected at baseline and during annual follow-up visits. Measured glomerular filtration rate (GFR), echocardiography, retinal optical coherence tomography angiography and kidney and cardiac MRI will be performed at baseline and twice more during follow-up. The study is 90% powered to detect an association between key histological and imaging parameters and a composite of death, renal replacement therapy or a 30% decline in estimated GFR. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Bloomsbury Research Ethics Committee (REC 18-LO-1921). Any patient identifiable data will be stored on a password-protected National Health Services N3 network with full audit trail. Anonymised imaging data will be stored in a ISO27001-certificated data warehouse.Results will be reported through peer-reviewed manuscripts and conferences and disseminated to participants, patients and the public using web-based and social media engagement tools as well as through public events

Multiparametric Magnetic Resonance Imaging Allows Non-Invasive Functional and Structural Evaluation of Diabetic Kidney Disease

BackgroundWe sought to develop a novel non-contrast multi-parametric MRI (mpMRI) protocol employing several complementary techniques in a single scan session for a comprehensive functional and structural evaluation of diabetic kidney disease (DKD).MethodsIn the cross-sectional part of this prospective observational study, 38 subjects aged 18‒79 years with type 2 diabetes and DKD (estimated glomerular filtration rate [eGFR] 15‒60 ml/min/1.73 m2), and 20 age- and gender-matched healthy volunteers (HV) underwent mpMRI. Repeat mpMRI was performed in 23 DKD subjects and 10 HV. By measured GFR (mGFR), 2 DKD subjects had GFR stage G2, 16 stage G3, and 20 stage G4/5. A wide range of MRI-biomarkers associated with kidney hemodynamics, oxygenation, and macro/micro-structure were evaluated. Their optimal sensitivity, specificity and repeatability to differentiate diabetic versus healthy kidneys, and categorize various stages of disease as well as their correlation with mGFR/albuminuria was assessed.ResultsSeveral MRI-biomarkers differentiated diabetic from healthy kidneys and distinct GFR stages (G3 versus G4/5); mean arterial flow (MAF) was the strongest predictor (sensitivity = 0.94 and 1.0, specificity = 1.00 and 0.69, p = 0.04 and 0.004, respectively). Parameters significantly correlating with mGFR were specific measures of kidney hemodynamics, oxygenation, microstructure and macrostructure, with MAF being the strongest univariate predictor (r = 0.92, p<0.0001).ConclusionsA comprehensive and repeatable non-contrast mpMRI protocol was developed that as a single, non-invasive tool allows functional and structural assessment of DKD, which has the potential to provide valuable insights into underlying pathophysiology, disease progression and analysis of efficacy/mode of action of therapeutic interventions in DKD

On the importance of LDL particle size and antibodies against oxidized LDL for early atherosclerosis development. Ultrasound studies in patients with hypercholesterolemia

The main aim of the study was to test the hypothesis that small LDL particle size or high antibody titers against Ox-LDL were related to atherosclerosis development as measured by ultrasound in the carotid artery. Before these studies began the value of intima-media thickness as a surrogate variable for coronary atherosclerosis was evaluated by investigating the relationship between coronary atherosclerosis and ultrasound measurement of intima-media thickness in three different segments of the carotid- and femoral arteries. Furthermore, a new computerized method for a thorough evaluation of LDL particle size was developed.Results of the methodological development and evaluation showed a significant correlation between the ultrasound measurement of intima-media thickness of the carotid bulb and diameter stenosis in the coronary arteries and of carotid plaques and diameter stenosis. The evaluation of the computerized LDL particle size method showed that the method was easy to work with, the reproducibility was satisfactory with an excellent precision in the measurement of LDL peak particle size and other characteristics of the LDL particle size distribution. There were no significant differences in antibody titers against Ox-LDL or MDA-LDL between the group of patients with familial hypercholesterolemia and the controls. No significant associations were observed between intima-media thickness of the carotid or femoral arteries and antibody titers against Ox-LDL or between plaque occurrence and these titers. An unexpected finding was that patients with a history of myocardial infarction had significantly lower IgM titers against Ox-LDL compared with patients without a history of myocardial infarction, and also compared to controls. In the group of patients with primary hypercholesterolemia and signs of early atherosclerotic changes in the carotid artery, patients had significantly smaller LDL particles compared to healthy controls. However, the difference in LDL peak particle size between patients and controls disappeared when adjusting for serum triglycerides. There was no association between increasing intima-media thickness of the carotid bulb and decreasing LDL peak particle size or between the occurrence of moderate to large plaques in the carotid artery and small LDL peak particle size. In conclusion, the results of this study showed that atherosclerosis in the carotid artery bulb, as measured by ultrasound, is significantly associated with coronary atherosclerosis, as measured by quantitative angiography. The lack of correlation between carotid atherosclerosis and high antibody titers against Ox-LDL, and also the finding that patients with a history of previous myocardial infarction had lower IgM titers against Ox-LDL than patients with a negative history of myocardial infarction indicate that the relationship between the autoimmune response to Ox-LDL and the extent of atherosclerosis is more complex than previously anticipated. There was no association between atherosclerosis development in the carotid artery and small LDL peak particle size in patients with hypercholesterolemia. These data do not support the hypothesis that small LDL particles are of importance for atherosclerosis development in primary hypercholesterolemia

Preclinical atherosclerosis and inflammation in 61-year-old men with newly diagnosed diabetes and established diabetes.

OBJECTIVE The aim of this study was to investigate the occurrence of subclinical atherosclerosis and underlying mechanisms in men with newly diagnosed diabetes and established diabetes compared with healthy control subjects. RESEARCH DESIGN AND METHODS In a population-based study of 61-year-old Caucasian men (n = 271) with established diabetes (n = 50) and newly diagnosed diabetes (n = 24) and healthy control subjects (n = 197), standard risk factors and highly sensitive (hs) C-reactive protein (CRP) were measured. Ultrasound measurements of intima-media thickness (IMT) were performed bilaterally in the common carotid artery, and a composite measure was calculated from common carotid and carotid bulb IMT (composite IMT). The plaque status was assessed. RESULTS Composite IMT and carotid plaque size increased gradually among the healthy control subjects, newly diagnosed diabetic patients, and established diabetic patients (P for trend < or =0.001, respectively). CRP was higher in newly and established diabetes (NS between diabetes groups) compared with healthy control subjects (P < 0.001). Total cholesterol levels were lower in newly diagnosed diabetes (5.51 +/- 1.13 mmol/l, P < 0.05) and established diabetes (5.45 +/- 1.15 mmol/l, P < 0.01) compared with those of healthy control subjects (5.77 +/- 1.03 mmol/l). In men with diabetes (n = 74), diabetes onset status (newly diagnosed versus established), waist-to-hip ratio (WHR), and serum triglycerides, but not CRP, explained 16% of the variance in composite IMT. CONCLUSIONS This is the first study to show increased preclinical atherosclerotic changes (IMT and plaque size) and increased inflammation (hs-CRP) in men with newly diagnosed diabetes as well as in patients with established diabetes compared with healthy control subjects. WHR, diabetes onset status (newly diagnosed versus established), and triglycerides, but not CRP, were independent correlates of carotid artery IMT in men with diabetes

Plasma phospholipid EPA and DHA in relation to atherosclerosis in 61-year-old men

Introduction: Increased intake of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been shown to decrease the risk for cardiovascular death and to reduce CVD risk factors. It has also been suggested that EPA and DHA reduce atherosclerosis progression, but data are inconclusive. Carotid intima-media thickness (IMT) is a well-established surrogate measure for sub-clinical atherosclerosis. Our aim was to examine if plasma phospholipid EPA and DHA are associated with IMT and plaque occurrence and size in the carotid and femoral arteries. Methods: IMT and plaque occurrence in carotid and femoral arteries was measured by ultrasound in 487 sixty-one-year-old men in this cross-sectional study. Plasma phospholipid levels of EPA and DHA, serum lipids, cell adhesion molecules, and blood pressure were measured, and occurrence of diabetes and socioeconomic factors were assessed. Results: Plasma phospholipid EPA was negatively associated with IMT in carotid and femoral arteries, and with cigarette years and cell adhesion proteins. EPA was positively associated with HDL, total cholesterol, blood pressure, plasma insulin and years of education. The association between EPA and carotid IMT remained after adjustment for blood pressure, but not for other covariates. Plasma phospholipid DHA was negatively associated with cigarette years and several endothelial markers, and positively associated with years of education and systolic blood pressure. In contrast to other studies, EPA content was higher in diabetic patients compared with patients without diabetes. Conclusion: Plasma phospholipid EPA, but not DHA, was inversely associated with carotid and femoral IMT, as well as several endothelial markers supporting the concept of an effect of EPA on the vascular wall. This association was independent of blood pressure, but not for other covariates. There was no association between plasma phospholipid EPA or DHA and plaque occurrence in the carotid and femoral arteries. \ua9 2008 Elsevier Ireland Ltd. All rights reserved

Circulating oxidized low-density lipoprotein is associated with echolucent plaques in the femoral artery independently of hsCRP in 61-year-old men.

OBJECTIVES The aim of the study was to test the hypothesis that circulating markers of inflammation (high-sensitive C-reactive protein, hsCRP) and oxidative modification of lipids (oxidized low-density lipoprotein, oxLDL) were associated with the occurrence of echolucent rather than echogenic femoral artery plaques in a cross-sectional population based cohort of 513, 61-year-old men. BACKGROUND The relationships between circulating oxLDL, hsCRP and the occurrence of echolucent plaques in the femoral artery have not previously been investigated. METHODS The levels of circulating oxLDL and hsCRP were determined in plasma by ELISA. Plaque occurrence, size and echogenicity were measured by B-mode ultrasound in the right femoral artery. Assessment of plaque echogenicity was based on the classification (grades 1-4) proposed by Gray-Weale et al. RESULTS A higher frequency of echolucent femoral plaques was observed in subjects with the metabolic syndrome and current smokers (p=0.01 and p<0.001, respectively) as well as with increasing levels of oxLDL and hsCRP (p=0.002 and p=0.005, respectively). In a multiple logistic regression analysis oxLDL and current smokers turned out to be independent associated with the presence of echolucent femoral artery plaques. CONCLUSIONS The results of the present study support our hypothesis that circulating oxLDL is a marker of an unstable echolucent plaque phenotype in the femoral artery in man