Cardiovascular disease: priorities and outcomes in end stage kidney disease

Introduction End stage kidney disease (ESKD) accounts for 5-10 million deaths annually worldwide. The current treatment modalities for ESKD include dialysis, transplant and supportive care. The leading cause of death for people with ESKD is cardiovascular disease (CVD). CVD is a collective term for disease affecting the heart and blood vessels including coronary, cerebral and peripheral blood vessels. CVD causes significant morbidity and has a substantial impact on quality of life for people with ESKD. Improving cardiovascular outcomes for people living with ESKD is a priority. The escalating incidence of chronic kidney disease, its progression to ESKD and the high burden of cardiovascular disease has generated an increasing amount of research in the ESKD population. The ESKD population have previously been under-represented in clinical trials and current trials in ESKD have infrequently and inconsistently reported CVD outcomes. It is important to standardise outcomes used in research. When outcome reporting is standardised it enables comparisons of findings across trials, populations and eras. It is important that the outcomes reflect patient priorities and are relevant to patients and clinicians for use in shared decision making. The Standardised Outcomes in Nephrology Group (SONG) is an international initiative to establish a set of core outcomes and outcome measures across the spectrum of kidney disease for trials and other forms of research. The SONG-Haemodialysis (SONG - HD) initiative is developing a core outcome set for use in haemodialysis. As part of SONG-HD, CVD (as well as fatigue, vascular access and mortality) has been identified as important to all stakeholders and included in the core outcome set for haemodialysis. This requires appropriate measures of CVD to be identified and used. The first aim of this thesis was to achieve consensus on a CVD outcome measure for use in haemodialysis trials. In approaching this goal I first needed to ascertain the current use of cardiovascular outcomes (Chapter 2) and then determine which ones were important to all stakeholders (Chapter 3). Consensus over which is the most appropriate measure of CVD for use in trials in people on haemodialysis (Chapter 4) will allow improved standardisation of cardiovascular outcome reporting, reducing research wastage and will propel forward cardiovascular research to improve morbidity and mortality in this high risk population. The second aim of this thesis was to further examine some of the prioritised outcomes and to review the patterns and risks of CVD in the ESKD population. The magnitude of risk for cardiac events and cardiac deaths in people with ESKD relative to the general population and the changes over time are not well described. I hypothesised that the magnitude of risk remained high in the ESKD population and that epidemiological improvements seen in CVD outcomes in the general population have not been mirrored in the ESKD population (Chapters 5 and 6). CVD and more specifically cerebrovascular disease can lead to significant cognitive impairment which has a substantial impact on the ability of ESKD patients to understand their disease, interpret education and be involved in shared decision making. The patterns of cognitive deficit in the ESKD population are not well understood and I hypothesised that cognitive deficits in the ESKD population may be different to those found in the general population and may differ by modality of renal replacement therapy. Standardising CVD outcomes, examining the epidemiology of CVD in ESKD and comparing the trends and patterns to the general population can drive hypotheses into potential causative mechanisms and new treatments. I present this thesis as a hybrid of published work, work currently under peer review for publication and work submitted for publication on the theme of priorities and outcomes in ESKD

Cognition in chronic kidney disease: a systematic review and meta-analysis

Background Cognitive impairment is common in people with chronic kidney disease (CKD) and associated with increased morbidity and mortality. Subtle changes can impact engagement with healthcare, comprehension, decision-making, and medication adherence. We aimed to systematically summarise evidence of cognitive changes in CKD. Methods We searched MEDLINE (March 2016) for cross-sectional, cohort or randomised studies that measured cognitive function in people with CKD (PROSPERO, registration number CRD42014015226). The CKD population included people with eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, in any research setting. We conducted a meta-analysis using random effects, expressed as standardised mean differences (SMD) with 95% confidence intervals (CI). Outcomes were performance in eight cognitive domains. Bias was assessed with the Newcastle-Ottawa Scale (NOS). Results We identified 44 studies reporting sufficient data for synthesis (51,575 participants). Mean NOS score for cohort studies was 5.8/9 and for cross-sectional 5.4/10. Studies were deficient in NOS outcome and selection due to poor methods reporting and in comparison group validity of demographics and chronic disease status. CKD patients (eGFR < 60 mL/min/1.73 m2) performed worse than control groups (eGFR ≥ 60 mL/min/1.73 m2) on Orientation & Attention (SMD –0.79, 95% CI, –1.44 to –0.13), Language (SMD –0.63, 95% CI, –0.85 to –0.41), Concept Formation & Reasoning (SMD –0.63, 95% CI, –1.07 to –0.18), Executive Function (SMD –0.53, 95% CI, –0.85 to –0.21), Memory (SMD –0.48, 95% CI, –0.79 to –0.18), and Global Cognition (SMD –0.48, 95% CI, –0.72 to –0.24). Construction & Motor Praxis and Perception were unaffected (SMD –0.29, 95% CI, –0.90 to 0.32; SMD –1.12, 95% CI, –4.35 to 2.12). Language scores dropped with eGFR (<45 mL/min/1.73 m2 SMD –0.86, 95% CI, –1.25 to –46; 30 mL/min/1.73 m2 SMD –1.56, 95% CI, –2.27 to –0.84). Differences in Orientation & Attention were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.62, 95% CI, –4.68 to –4.55). Concept Formation & Reasoning differences were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.27, 95% CI, –4.23 to –4.27). Differences in Executive Functions were greatest at eGFR < 30 mL/min/1.73 m2 (SMD –0.54, 95% CI, –1.00 to –0.08). Conclusions Cognitive changes occur early in CKD, and skills decline at different rates. Orientation & Attention and Language are particularly affected. The cognitive impact of CKD is likely to diminish patients’ capacity to engage with healthcare decisions. An individual’s cognitive trajectory may deviate from average

Resveratrol: A Multifunctional Compound Improving Endothelial Function: Editorial to: “Resveratrol Supplementation Gender Independently Improves Endothelial Reactivity and Suppresses Superoxide Production in Healthy Rats” by S. Soylemez et al.

The red wine polyphenol resveratrol boosts endothelium-dependent and -independent vasorelaxations. The improvement of endothelial function by resveratrol is largely attributable to nitric oxide (NO) derived from endothelial NO synthase (eNOS). By stimulating eNOS expression, eNOS phosphorylation and eNOS deacetylation, resveratrol enhances endothelial NO production. By upregulating antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) and suppressing the expression and activity of NADPH oxidases, resveratrol inhibits superoxide-mediated NO inactivation. Some resveratrol effects are mediated by sirtuin 1 (SIRT1) or estrogen receptors, respectively

Importance of investigating epigenetic alterations for industry and regulators: An appraisal of current efforts by the Health and Environmental Sciences Institute

AbstractRecent technological advances have led to rapid progress in the characterization of epigenetic modifications that control gene expression in a generally heritable way, and are likely involved in defining cellular phenotypes, developmental stages and disease status from one generation to the next. On November 18, 2013, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) held a symposium entitled “Advances in Assessing Adverse Epigenetic Effects of Drugs and Chemicals” in Washington, D.C. The goal of the symposium was to identify gaps in knowledge and highlight promising areas of progress that represent opportunities to utilize epigenomic profiling for risk assessment of drugs and chemicals. Epigenomic profiling has the potential to provide mechanistic information in toxicological safety assessments; this is especially relevant for the evaluation of carcinogenic or teratogenic potential and also for drugs that directly target epigenetic modifiers, like DNA methyltransferases or histone modifying enzymes. Furthermore, it can serve as an endpoint or marker for hazard characterization in chemical safety assessment. The assessment of epigenetic effects may also be approached with new model systems that could directly assess transgenerational effects or potentially sensitive stem cell populations. These would enhance the range of safety assessment tools for evaluating xenobiotics that perturb the epigenome. Here we provide a brief synopsis of the symposium, update findings since that time and then highlight potential directions for future collaborative efforts to incorporate epigenetic profiling into risk assessment

Loss of estrogen receptor β decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice

Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estrogen receptor beta (βER) are more thrombogenic than those from age-matched wild-type (WT) mice. Intracellular processes contributing to this increased thrombogenicity are not known. Experiments were designed to identify subcellular localization of estrogen receptors and evaluate both glycolytic and mitochondrial energetic processes which might affect platelet activation. Platelets and blood from aged (22–24 months) WT and estrogen receptor β knockout (βERKO) female mice were used in this study. Body, spleen weight, and serum concentrations of follicle-stimulating hormone and 17β-estradiol were comparable between WT and βERKO mice. Number of spontaneous deaths was greater in the βERKO colony (50% compared to 30% in WT) over the course of 24 months. In resting (nonactivated) platelets, estrogen receptors did not appear to colocalize with mitochondria by immunostaining. Lactate production and mitochondrial membrane potential of intact platelets were similar in both groups of mice. However, activities of NADH dehydrogenase, cytochrome bc1 complex, and cytochrome c oxidase of the electron transport chain were reduced in mitochondria isolated from platelets from βERKO compared to WT mice. There were a significantly higher number of phosphatidylserine-expressing platelet-derived microvesicles in the plasma and a greater thrombin-generating capacity in βERKO compared to WT mice. These results suggest that deficiencies in βER affect energy metabolism of platelets resulting in greater production of circulating thrombogenic microvesicles and could potentially explain increased predisposition to thromboembolism in some elderly females

Sex-specific pathways in early cardiac response to pressure overload in mice

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (α-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFβ2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF

Multiple-frequency bioimpedance devices for fluid management in people with chronic kidney disease receiving dialysis : a systematic review and economic evaluation

The National Institute for Health Research Health Technology Assessment programme. Acknowledgements The authors are grateful to Lara Kemp for her secretarial support. The authors would also like to thank the members of the specialist committee assembled to support this assessment: Dr Andrew Davenport (Royal Free Hospital, London), Dr Simon Roe (Nottingham University Hospitals NHS Trust), Dr Elizabeth Lindley (St James’s University Hospital), Dr Wesley Hayes (Great Ormond Street Hospital), Ms Joanne Prince (Central Manchester University Hospitals NHS Foundation Trust), Mr Nick McAleer (Royal Devon & Exeter NHS Foundation Trust), Dr Kay Tyerman (Leeds General Infirmary), Dr Graham Woodrow (St James’s University Hospital) and Mr Paul Taylor (lay specialist committee member). The Health Services Research Unit, Health Economics Research Unit and Institute of Applied Health Sciences, University of Aberdeen are all core funded by the Chief Scientist Office of the Scottish Government Health DirectoratesPeer reviewedPublisher PD