32 results on '"Townend, Jonathan N"'
Search Results
2. Management of heart failure in patients with kidney disease-updates from the 2021 ESC guidelines.
- Author
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Edwards NC, Price AM, Steeds RP, Ferro CJ, and Townend JN
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- Humans, Stroke Volume, Syndrome, Disease Management, Guidelines as Topic, Angiotensin Receptor Antagonists therapeutic use, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Defibrillators, Implantable, Heart Failure therapy, Renal Insufficiency, Chronic complications
- Abstract
The wide overlap between the syndromes of chronic kidney disease (CKD) and chronic heart failure (HF) means that familiarity with the 2021 European Society of Cardiology guidelines is of importance to nephrologists. The common risk factors for the two syndromes together with the adverse cardiac structural remodelling associated with CKD means that many kidney disease patients experience breathlessness and fall within the HF phenotypes categorized in the guidelines. The management of HF is evolving rapidly leading to significant changes in the latest guideline iteration. The 2021 guidelines have changed from the 2016 version firstly by an increased focus on identifying the three phenotypes of HF to guide appropriate evidence-based management. Secondly, a new and simplified treatment algorithm for HF with reduced ejection fraction involving the rapid sequential initiation and up-titration of four 'pillars' of drug treatment-angiotensin-converting enzyme inhibitors or angiotensin-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and now, thanks to convincing trial data, sodium-glucose co-transporter 2 inhibitors. Thirdly, guidelines for device therapy have been changed with down-graded advice on indications for primary prevention implantable cardioverter defibrillator therapy for patients with non-ischaemic HF and for cardiac resynchronization therapy with left bundle branch block (LBBB) and a QRS duration <150 ms. There are updated treatment plans for HF associated with non-cardiovascular comorbidities including CKD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2023
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3. Hypertension and cardiomyopathy associated with chronic kidney disease: epidemiology, pathogenesis and treatment considerations.
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Law JP, Pickup L, Pavlovic D, Townend JN, and Ferro CJ
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- Humans, Kidney, Hypertrophy, Left Ventricular epidemiology, Hypertrophy, Left Ventricular etiology, Hypertrophy, Left Ventricular therapy, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic therapy, Hypertension complications, Hypertension epidemiology, Hypertension therapy, Cardiomyopathies epidemiology, Cardiomyopathies etiology, Cardiomyopathies therapy, Ventricular Dysfunction, Left
- Abstract
Chronic kidney disease (CKD) is a complex condition with a prevalence of 10-15% worldwide. An inverse-graded relationship exists between cardiovascular events and mortality with kidney function which is independent of age, sex, and other risk factors. The proportion of deaths due to heart failure and sudden cardiac death increase with progression of chronic kidney disease with relatively fewer deaths from atheromatous, vasculo-occlusive processes. This phenomenon can largely be explained by the increased prevalence of CKD-associated cardiomyopathy with worsening kidney function. The key features of CKD-associated cardiomyopathy are increased left ventricular mass and left ventricular hypertrophy, diastolic and systolic left ventricular dysfunction, and profound cardiac fibrosis on histology. While these features have predominantly been described in patients with advanced kidney disease on dialysis treatment, patients with only mild to moderate renal impairment already exhibit structural and functional changes consistent with CKD-associated cardiomyopathy. In this review we discuss the key drivers of CKD-associated cardiomyopathy and the key role of hypertension in its pathogenesis. We also evaluate existing, as well as developing therapies in the treatment of CKD-associated cardiomyopathy., (© 2022. The Author(s).)
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- 2023
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4. Effects of Spironolactone and Chlorthalidone on Cardiovascular Structure and Function in Chronic Kidney Disease: A Randomized, Open-Label Trial.
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Edwards NC, Price AM, Mehta S, Hiemstra TF, Kaur A, Greasley PJ, Webb DJ, Dhaun N, MacIntyre IM, Farrah T, Melville V, Herrey AS, Slinn G, Wale R, Ives N, Wheeler DC, Wilkinson I, Steeds RP, Ferro CJ, and Townend JN
- Subjects
- Adult, Aged, Blood Pressure drug effects, Cardiovascular Diseases diagnosis, Cardiovascular Diseases physiopathology, Chlorthalidone adverse effects, Double-Blind Method, Female, Glomerular Filtration Rate drug effects, Humans, Male, Middle Aged, Mineralocorticoid Receptor Antagonists adverse effects, Prospective Studies, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic physiopathology, Sodium Chloride Symporter Inhibitors adverse effects, Spironolactone adverse effects, Time Factors, Treatment Outcome, United Kingdom, Vascular Stiffness drug effects, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects, Cardiovascular Diseases drug therapy, Chlorthalidone therapeutic use, Mineralocorticoid Receptor Antagonists therapeutic use, Renal Insufficiency, Chronic drug therapy, Sodium Chloride Symporter Inhibitors therapeutic use, Spironolactone therapeutic use
- Abstract
Background and Objectives: In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone., Design, Setting, Participants, & Measurements: A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m
2 ). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg)., Results: There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g, P =0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s, P =0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, P =0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, P =0.07)., Conclusions: Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD., (Copyright © 2021 by the American Society of Nephrology.)- Published
- 2021
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5. Sudden cardiac death in chronic renal disease: aetiology and risk reduction strategies.
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Pickup LC, Law JP, Townend JN, and Ferro CJ
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- Death, Sudden, Cardiac etiology, Death, Sudden, Cardiac prevention & control, Humans, Risk Factors, Risk Reduction Behavior, Kidney Failure, Chronic complications, Renal Insufficiency, Chronic complications
- Published
- 2021
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6. Finerenone and Chronic Kidney Disease Outcomes in Type 2 Diabetes.
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Edwards NC, Ferro CJ, and Townend JN
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- Humans, Naphthyridines, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Renal Insufficiency, Chronic complications
- Published
- 2021
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7. Defining Myocardial Abnormalities Across the Stages of Chronic Kidney Disease: A Cardiac Magnetic Resonance Imaging Study.
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Hayer MK, Radhakrishnan A, Price AM, Liu B, Baig S, Weston CJ, Biasiolli L, Ferro CJ, Townend JN, Steeds RP, and Edwards NC
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- Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Contrast Media, Cross-Sectional Studies, Fibrosis, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Myocardium pathology, Predictive Value of Tests, Ventricular Function, Left, Gadolinium, Renal Insufficiency, Chronic
- Abstract
Objectives: A proof of concept cross-sectional study investigating changes in myocardial abnormalities across stages of chronic kidney disease (CKD). Characterizing noninvasive markers of myocardial fibrosis on cardiac magnetic resonance, echocardiography, and correlating with biomarkers of fibrosis, myocardial injury, and functional correlates including exercise tolerance., Background: CKD is associated with an increased risk of cardiovascular death. Much of the excess mortality is attributed to uremic cardiomyopathy, defined by increased left ventricular hypertrophy, myocardial dysfunction, and fibrosis. The prevalence of these abnormalities across stages of CKD and their impact on cardiovascular performance is unknown., Methods: A total of 134 nondiabetic, pre-dialysis subjects with CKD stages 2 to 5 without myocardial ischemia underwent cardiac magnetic resonance (1.5-T) including; T
1 mapping (biomarker of diffuse fibrosis), T2 mapping (edema), late gadolinium enhancement, and assessment of aortic distensibility. Serum biomarkers including collagen turnover (P1NP, P3NP), troponin T, and N-terminal pro-B-type natriuretic peptide were measured. Cardiovascular performance was quantified by bicycle cardiopulmonary exercise testing and echocardiography., Results: Native myocardial T1 times increased incrementally from stage 2 to 5 (966 ± 21 ms vs. 994 ± 33 ms; p < 0.001), independent of hypertension and aortic distensibility. Left atrial volume, E/e', N-terminal pro-B-type natriuretic peptide, P1NP, and P3NP increased with CKD stage (p < 0.05), while effort tolerance (% predicted VO2 Peak, %VO2 VT) decreased (p < 0.001). In multivariable linear regression models, estimated glomerular filtration rate was the strongest predictor of native myocardial T1 time (p < 0.001). Native myocardial T1 time, left atrial dilatation, and high-sensitivity troponin T were independent predictors of % predicted VO2 Peak (p < 0.001)., Conclusions: Imaging and serum biomarkers of myocardial fibrosis increase with advancing CKD independent of effects of left ventricular afterload and might be a key intermediary in the development of uremic cardiomyopathy. Further studies are needed to determine whether these changes lead to the increased rates of heart failure and death in CKD. (Left Ventricular Fibrosis in Chronic Kidney Disease [FibroCKD]; NCT03176862)., Competing Interests: Author Relationship With Industry This study is supported by the British Heart Foundation (PG/15/117/31961). Dr. Weston is funded by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. All other authors have reported that they have no relationships relevant to the contents of this paper. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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8. Clinical Potential of Targeting Fibroblast Growth Factor-23 and αKlotho in the Treatment of Uremic Cardiomyopathy.
- Author
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Law JP, Price AM, Pickup L, Radhakrishnan A, Weston C, Jones AM, McGettrick HM, Chua W, Steeds RP, Fabritz L, Kirchhof P, Pavlovic D, Townend JN, and Ferro CJ
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- Animals, Cardio-Renal Syndrome blood, Cardio-Renal Syndrome mortality, Cardio-Renal Syndrome physiopathology, Cardiomyopathies blood, Cardiomyopathies mortality, Cardiomyopathies physiopathology, Fibroblast Growth Factor-23, Fibroblast Growth Factors blood, Glucuronidase blood, Humans, Klotho Proteins, Molecular Targeted Therapy, Prognosis, Recombinant Proteins therapeutic use, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic mortality, Renal Insufficiency, Chronic physiopathology, Risk Assessment, Risk Factors, Uremia blood, Uremia mortality, Uremia physiopathology, Cardio-Renal Syndrome drug therapy, Cardiomyopathies drug therapy, Fibroblast Growth Factors antagonists & inhibitors, Glucuronidase therapeutic use, Renal Insufficiency, Chronic drug therapy, Uremia drug therapy
- Abstract
Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor-23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor-23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end-stage renal disease.
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- 2020
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9. Anticoagulant strategies for the patient with chronic kidney disease.
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Law JP, Pickup L, Townend JN, and Ferro CJ
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- Adult, Anticoagulants therapeutic use, Hemorrhage chemically induced, Humans, Renal Insufficiency, Chronic drug therapy, Thrombosis
- Abstract
Chronic kidney disease (CKD) is a global health problem affecting up to 14% of the adult population in developed countries. On the basis of current guidelines, patients with CKD will often fulfil criteria for both short-term and long-term anticoagulation. Paradoxically, patients with CKD are not only at a higher risk of thrombosis, they are also at increased risk of bleeding. Furthermore, the pharmacokinetics and pharmacodynamics of many anticoagulant therapies are significantly affected by renal dysfunction. In addition, patients with advanced CKD are often systematically excluded from major clinical trials. As such, the decision on whether to anticoagulate or not, and if so with what agent, poses significant challenges. A solid understanding of the condition in question and the available treatments is required to make an informed judgement call. An in-depth appreciation of the advantages and disadvantages of the currently available anticoagulants is a key element in the decision-making process., (© Royal College of Physicians 2020. All rights reserved.)
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- 2020
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10. Myocardial characterization in pre-dialysis chronic kidney disease: a study of prevalence, patterns and outcomes.
- Author
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Price AM, Hayer MK, Vijapurapu R, Fyyaz SA, Moody WE, Ferro CJ, Townend JN, Steeds RP, and Edwards NC
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- Adult, Aged, Cause of Death, Contrast Media administration & dosage, England epidemiology, Female, Fibrosis, Gadolinium DTPA administration & dosage, Humans, Hypertrophy, Left Ventricular mortality, Hypertrophy, Left Ventricular physiopathology, Male, Middle Aged, Organometallic Compounds administration & dosage, Predictive Value of Tests, Prevalence, Prognosis, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic mortality, Renal Insufficiency, Chronic physiopathology, Retrospective Studies, Risk Factors, Stroke Volume, Ventricular Dysfunction, Left mortality, Ventricular Dysfunction, Left physiopathology, Ventricular Function, Left, Ventricular Remodeling, Hypertrophy, Left Ventricular diagnostic imaging, Hypertrophy, Left Ventricular epidemiology, Magnetic Resonance Imaging, Renal Insufficiency, Chronic epidemiology, Ventricular Dysfunction, Left diagnostic imaging, Ventricular Dysfunction, Left epidemiology
- Abstract
Background: Late gadolinium enhancement (LGE) using cardiac magnetic resonance (CMR) characterizes myocardial disease and predicts an adverse cardiovascular (CV) prognosis. Myocardial abnormalities, are present in early chronic kidney disease (CKD). To date there are no data defining prevalence, pattern and clinical implications of LGE-CMR in CKD., Methods: Patients with pre-dialysis CKD (stage 2-5) attending specialist renal clinics at University Hospital Birmingham (UK) who underwent gadolinium enhanced CMR (1.5 T) between 2005 and 2017 were included. The patterns and presence (LGEpos) / absence (LGEneg) of LGE were assessed by two blinded observers. Association between LGE and CV outcomes were assessed., Results: In total, 159 patients received gadolinium (male 61%, mean age 55 years, mean left ventricular ejection fraction 69%, left ventricular hypertrophy 5%) with a median follow up period of 3.8 years [1.04-11.59]. LGEpos was present in 55 (34%) subjects; the patterns were: right ventricular insertion point n = 28 (51%), mid wall n = 18 (33%), sub-endocardial n = 5 (9%) and sub-epicardial n = 4 (7%). There were no differences in left ventricular structural or functional parameters with LGEpos. There were 12 adverse CV outcomes over follow up; 7 of 55 with LGEpos and 5 of 104 LGEneg. LGEpos was not predicted by age, gender, glomerular filtration rate or electrocardiographic abnormalities., Conclusions: In a selected cohort of subjects with moderate CKD but low CV risk, LGE was present in approximately a third of patients. LGE was not associated with adverse CV outcomes. Further studies in high risk CKD cohorts are required to assess the role of LGE with multiplicative risk factors.
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- 2019
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11. Arterial stiffness in chronic kidney disease: a modifiable cardiovascular risk factor?
- Author
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Pickup L, Radhakrishnan A, Townend JN, and Ferro CJ
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- Blood Pressure physiology, Humans, Risk Factors, Cardiovascular Diseases etiology, Renal Insufficiency, Chronic complications, Vascular Stiffness physiology
- Abstract
Purpose of Review: There is an inverse, graded relationship between worsening chronic kidney disease (CKD) and increasing cardiovascular risk independent of traditional cardiovascular risk factors. Increasing arterial stiffness is a powerful predictor of cardiovascular outcomes in CKD. Developing novel therapeutic strategies to reverse this process is an attractive concept. This review presents the results of a literature survey of the last 18 months to establish if arterial stiffness can be considered a reversible cardiovascular risk factor in patients with CKD., Recent Findings: Multiple potential therapeutic approaches to reduce arterial stiffness have been proposed and tested. However, arterial stiffness and blood pressure (BP) have a very close bidirectional relationship. Any change in BP will have an effect on arterial stiffness and vice versa. At present, there is no robust evidence to support the notion that arterial stiffness can be considered reversible other than as a direct consequence of reduction in BP., Summary: For now, arterial stiffness should be considered an indirectly modifiable cardiovascular risk factor through optimal control of BP. Measures of arterial stiffness should be regarded as research and risk stratification tools rather than a therapeutic target in itself.
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- 2019
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12. Early effects of kidney transplantation on the heart - A cardiac magnetic resonance multi-parametric study.
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Hayer MK, Radhakrishnan A, Price AM, Baig S, Liu B, Ferro CJ, Captur G, Townend JN, Moon JC, Edwards NC, and Steeds RP
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- Adult, Female, Fibrosis, Humans, Male, Postoperative Period, Treatment Outcome, Uremia complications, Cardiomyopathies diagnostic imaging, Cardiomyopathies etiology, Cardiomyopathies pathology, Kidney Transplantation methods, Magnetic Resonance Imaging, Cine methods, Myocardium pathology, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic physiopathology, Renal Insufficiency, Chronic surgery
- Abstract
Increased native myocardial T1 times in chronic kidney disease (CKD) may be due to diffuse interstitial myocardial fibrosis (DIF) or due to interstitial edema/inflammation. Concerns relating to nephrogenic systemic fibrosis with gadolinium-based contrast agents (GBCA) limit their use in end-stage kidney disease (ESKD) to measure extracellular volume (ECV) and characterise myocardial fibrosis. This study aimed to examine stability of myocardial T1 and T2 times before, and within 2 months after kidney transplantation; a time frame when volume status normalises but myocardial remodelling is unlikely to have occurred, and to compare these with ECV using GBCA after transplantation. Twenty-four patients with ESKD underwent serial cardiovascular magnetic resonance imaging, including T1 and T2 mapping. GBCA was administered on follow-up provided eGFR was >30 ml/min/1.73 m
2 . Eighteen age- and sex-matched controls were studied at one timepoint. ECV (ECV 28 ± 2% vs. 24 ± 2%, p = 0.001) and T2 times were higher in ESKD compared to controls. After transplantation, septal T1 times increased (MOLLI 985 ms ± 25 vs. 1002 ms ± 30, p = 0.014; ShMOLLI 974 ms ± 39 vs. 992 ms ± 33, p = 0.113), LV volumes reduced (LVEDvol indexed 79 ± 24 vs. 63 ± 20 ml/m2 , p = 0.005) but LV mass was unchanged (LV mass index 89 g/m2 ± 38 to 83 g/m2 ± 23, p = 0.141). T2 times did not change after transplantation. Both ECV and myocardial T1 times are elevated in ESKD, supporting the theory that elevated T1 times are due to DIF, although a contribution from myocardial edema cannot be fully excluded. The lack of any fall in T1 or T2 times after transplantation suggests that myocardial T1 times are a stable measure of DIF in CKD., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2019
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13. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.
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Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, Boesby L, Edwards NC, Ferro CJ, Townend JN, van den Meiracker AH, Saklayen MG, Oveisi S, Jardine AG, Delles C, Preiss DJ, and Mark PB
- Subjects
- Angiotensin Receptor Antagonists therapeutic use, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Blood Pressure drug effects, Disease Progression, Glomerular Filtration Rate drug effects, Humans, Mineralocorticoid Receptor Antagonists adverse effects, Patient Dropouts statistics & numerical data, Proteinuria etiology, Proteinuria urine, Randomized Controlled Trials as Topic, Renal Insufficiency, Chronic complications, Risk Assessment, Hyperkalemia chemically induced, Mineralocorticoid Receptor Antagonists therapeutic use, Proteinuria drug therapy, Renal Insufficiency, Chronic drug therapy
- Abstract
Background: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease., Methods: We conducted a meta-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966-2014), EMBASE (1947-2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators. We included randomised controlled trials, and the first period of randomised cross over trials lasting ≥4 weeks in adults., Results: Nineteen trials (21 study groups, 1 646 patients) were included. In random effects meta-analysis, addition of mineralocorticoid receptor antagonists to renin angiotensin system inhibition resulted in a reduction from baseline in systolic blood pressure (-5.7 [-9.0, -2.3] mmHg), diastolic blood pressure (-1.7 [-3.4, -0.1] mmHg) and glomerular filtration rate (-3.2 [-5.4, -1.0] mL/min/1.73 m(2)). Mineralocorticoid receptor antagonism reduced weighted mean protein/albumin excretion by 38.7 % but with a threefold higher relative risk of withdrawing from the trial due to hyperkalaemia (3.21, [1.19, 8.71]). Death, cardiovascular events and hard renal end points were not reported in sufficient numbers to analyse., Conclusions: Mineralocorticoid receptor antagonism reduces blood pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit.
- Published
- 2016
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14. Caveolin-1 single-nucleotide polymorphism and arterial stiffness in non-dialysis chronic kidney disease.
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Chand S, Edwards NC, Chue CD, Jesky M, Stringer S, Simmonds MJ, Duff CE, Cockwell P, Harper L, Steeds RP, Townend JN, Ferro CJ, and Borrows R
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- Adult, Aged, Arteriosclerosis diagnosis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Pulse Wave Analysis, Vascular Stiffness genetics, Arteriosclerosis genetics, Caveolin 1 genetics, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic genetics
- Abstract
Background: Arteriosclerosis is an independent predictor of increased cardiovascular mortality in chronic kidney disease (CKD). Histologically it is characterized by hypertrophy and fibrosis of the arterial media wall leading to increased arterial stiffness and end-organ damage. Caveolin-1 acts as an intracellular signalling pathway chaperone in human fibrotic and vascular diseases. The purpose of this study was to assess the association between caveolin-1 (CAV1) single-nucleotide polymorphism (SNP) rs4730751 and arterial stiffness as measured by arterial pulse wave velocity (PWV) in an early-stage CKD cohort and in a cohort with more severe CKD., Methods: Two prospectively maintained patient cohorts with non-dialysis CKD were studied: 144 patients in the Chronic Renal Impairment in Birmingham (CRIB) cohort and 147 patients in the Renal Impairment in Secondary Care (RIISC) cohort, with matched exclusion criteria and DNA sampling availability. At entry to each cohort database, each patient's initial arterial PWV was measured, as well as their anthropomorphic and biochemical data. CAV1 rs4730751 SNP genotyping was performed using Taqman technology., Results: The CAV1 rs4730751 SNP CC genotype was associated with lower arterial PWV in both CRIB early stage CKD patients [8.1 versus 8.6 m/s; coefficient -0.780 (-1.412, -0.149); P = 0.016] and RIISC more advanced stage CKD patients [8.7 versus 9.4 m/s; coefficient -0.695 (-1.288, -0.102); P = 0.022]; these relationships held following adjustment for other important confounders., Conclusions: This replicated study suggests potential utility of the studied CAV1 SNP as a genetic biomarker in CKD and a role for CAV1 in the development of arteriosclerosis in this setting. Further studies are warranted to further explore the basic science driving these clinical observations., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2016
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15. Results and lessons from the Spironolactone To Prevent Cardiovascular Events in Early Stage Chronic Kidney Disease (STOP-CKD) randomised controlled trial.
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Ng KP, Jain P, Gill PS, Heer G, Townend JN, Freemantle N, Greenfield S, McManus RJ, and Ferro CJ
- Subjects
- Aged, Cardiovascular Diseases complications, Double-Blind Method, England, Feasibility Studies, Female, Humans, Male, Mineralocorticoid Receptor Antagonists pharmacology, Prospective Studies, Treatment Outcome, Cardiovascular Diseases prevention & control, Renal Insufficiency, Chronic complications, Spironolactone therapeutic use
- Abstract
Objectives: To determine whether low-dose spironolactone can safely lower arterial stiffness in patients with chronic kidney disease stage 3 in the primary care setting., Design: A multicentre, prospective, randomised, placebo-controlled, double-blinded study., Setting: 11 primary care centres in South Birmingham, England., Participants: Adult patients with stage 3 chronic kidney disease. Main exclusion criteria were diagnosis of diabetes mellitus, chronic heart failure, atrial fibrillation, severe hypertension, systolic blood pressure < 120 mm Hg or baseline serum potassium ≥ 5 mmol/L., Intervention: Eligible participants were randomised to receive either spironolactone 25 mg once daily, or matching placebo for an intended period of 40 weeks., Outcome Measures: The primary end point was the change in arterial stiffness as measured by pulse wave velocity. Secondary outcome measures included the rate of hyperkalaemia, deterioration of renal function, barriers to participation and expected recruitment rates to a potential future hard end point study., Results: From the 11 practices serving a population of 112,462, there were 1598 (1.4%) patients identified as being eligible and were invited to participate. Of these, 134 (8.4%) attended the screening visit of which only 16 (1.0%) were eligible for randomisation. The main reasons for exclusion were low systolic blood pressure (<120 mm Hg: 40 patients) and high estimated glomerular filtration rate (≥ 60 mL/min/1.73 m(2): 38 patients). The trial was considered unfeasible and was terminated early., Conclusions: We highlight some of the challenges in undertaking research in primary care including patient participation in trials. This study not only challenged our preconceptions, but also provided important learning for future research in this large and important group of patients., Trial Registration Number: ISRCTN80658312., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
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16. Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials.
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Ng KP, Arnold J, Sharif A, Gill P, Townend JN, and Ferro CJ
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- Blood Pressure drug effects, Cardiovascular Diseases blood, Cardiovascular Diseases mortality, Cardiovascular Diseases physiopathology, Carotid Intima-Media Thickness, Creatinine blood, Diastole drug effects, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Glomerular Filtration Rate, Heart Ventricles drug effects, Heart Ventricles pathology, Heart Ventricles physiopathology, Humans, Hyperkalemia blood, Hyperkalemia complications, Mineralocorticoid Receptor Antagonists adverse effects, Mineralocorticoid Receptor Antagonists pharmacology, Organ Size drug effects, Oxidative Stress drug effects, Potassium blood, Publication Bias, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic physiopathology, Stroke Volume drug effects, Systole drug effects, Vascular Stiffness drug effects, Cardiovascular Diseases drug therapy, Mineralocorticoid Receptor Antagonists therapeutic use, Randomized Controlled Trials as Topic, Renal Insufficiency, Chronic drug therapy
- Abstract
Introduction: The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear., Methods: MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials., Results: Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (-5.24, 95% confidence interval (CI) -8.65, -1.82 mmHg; p=0.003 and -1.96, 95% CI -3.22, -0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials., Conclusions: The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established., (© The Author(s) 2015.)
- Published
- 2015
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17. Acute Care QUAliTy in chronic Kidney disease (ACQUATIK): a prospective cohort study exploring outcomes of patients with chronic kidney disease.
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Arnold JJ, Hayer M, Sharif A, Begaj I, Tabriez M, Bagnall D, Ray D, Hoye C, Nazir M, Dutton M, Fifer L, Kirkham K, Sims D, Townend JN, Gill PS, Dasgupta I, Cockwell P, and Ferro CJ
- Subjects
- Adolescent, Adult, Cardiovascular Diseases etiology, Comorbidity, Female, Humans, Kidney, Kidney Failure, Chronic complications, Kidney Failure, Chronic therapy, Male, Patient Selection, Primary Health Care, Prospective Studies, Renal Insufficiency, Chronic complications, Research Design, Risk, Cardiovascular Diseases therapy, Outcome Assessment, Health Care, Patient Readmission, Renal Insufficiency, Chronic therapy
- Abstract
Introduction: Chronic kidney disease (CKD) is common and carries a high risk of morbidity, including hospital admissions and readmissions and mortality. This is largely attributed to an increased risk of cardiovascular disease. Patients with CKD are less likely to receive evidence-based treatments for cardiovascular disease. However, these treatments are based on trials which generally exclude patients with CKD. It is therefore unclear whether this patient group derives the same benefits without an increased risk of adverse effects., Methods and Analysis: The Acute Care QUAliTy in chronic Kidney disease (ACQUATIK) study is a prospective, observational, multicentre cohort study. Over 4000 patients will be recruited with an enrolment period of 2 years and a follow-up period of 2-4 years. Patients under follow-up by a renal team will be excluded. Data will be obtained from patient and hospital records during the index admission. Preadmission data will be extracted from general practice records based on the Quality and Outcomes Framework. Diagnosis, comorbidities and procedure data pertaining to the index and subsequent admissions will be extracted from the Hospital Episode Statistics database and long-term mortality data will be tracked using the Office of National Statistics. This information will allow us to examine a complete patient journey through primary and secondary care, providing unequalled levels of information on treatment and outcomes of patients with CKD. The combined data set will be used to compare outcomes and treatments among patients with CKD versus patients without CKD. The primary end point is hospital readmission rates. The relationship between age, sex, ethnicity, socioeconomic status and concurrent comorbidities will be analysed to determine their influence on outcomes and treatments., Ethics and Dissemination: The ACQUATIK study has been approved by the NRES Committee West Midlands-South Birmingham-Reference 13/WM/0317. The results from ACQUATIK will be submitted for publication in peer-reviewed journals and presented at primary and secondary care conferences., Trial Registration Number: ISRCTN37237454., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
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- 2015
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18. Diffuse interstitial fibrosis and myocardial dysfunction in early chronic kidney disease.
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Edwards NC, Moody WE, Yuan M, Hayer MK, Ferro CJ, Townend JN, and Steeds RP
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- Aged, Case-Control Studies, Cross-Sectional Studies, Female, Fibrosis, Glomerular Filtration Rate, Humans, Hypertension complications, Magnetic Resonance Imaging, Male, Middle Aged, Cardiomyopathies diagnosis, Cardiomyopathies epidemiology, Heart Ventricles pathology, Hypertension pathology, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic pathology
- Abstract
Early-stage chronic kidney disease (CKD) is an under-recognized highly prevalent cardiovascular (CV) risk factor. Despite a clustering of conventional atherosclerotic risk factors, it is hypothesized that nonatherosclerotic processes, including left ventricular (LV) hypertrophy and fibrosis, account for a significant excess of CV risk. This cross-sectional observational study of 129 age- (mean age 57±10 years) and gender-matched subjects examined: nondiabetic CKD stages 2 to 4 (mean glomerular filtration rate 50±22 ml/min/1.73 m2) with no history of CV disease, subjects who are hypertensive with normal renal function, and healthy controls. Cardiac magnetic resonance imaging was performed for assessment of LV volumes and systolic function (myocardial deformation). Diffuse myocardial fibrosis was assessed using T1 mapping for native myocardial T1 times before contrast and myocardial extracellular volume (ECV) after gadolinium administration in combination with standard late gadolinium enhancement techniques for detection of coarse fibrosis. Patients with CKD had increased native T1 times (986±37 ms) and ECV (0.28±0.04) compared with controls (955±30 ms, 0.25±0.03) and subjects who are hypertensive (956±31 ms, 0.25±0.02, p<0.05). Both T1 times and ECV were correlated with impaired systolic function as assessed by global longitudinal systolic strain (r=-0.22, p<0.05, and r=-0.43, p<0.01, respectively). There were no differences in LV volumes, ejection fraction, or LV mass. T1 times and ECV did not correlate with conventional CV risk factors. In conclusion, diffuse myocardial fibrosis is increased in early CKD and is associated with abnormal global longitudinal strain, an early feature of uremic cardiomyopathy and a key indicator of adverse CV prognosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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19. Impact of renal function on survival after transcatheter aortic valve implantation (TAVI): an analysis of the UK TAVI registry.
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Ferro CJ, Chue CD, de Belder MA, Moat N, Wendler O, Trivedi U, Ludman P, and Townend JN
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- Aged, Aged, 80 and over, Female, Humans, Kidney Function Tests, Male, Prospective Studies, Registries, Survival Rate, United Kingdom, Aortic Valve Stenosis complications, Aortic Valve Stenosis surgery, Postoperative Complications mortality, Renal Insufficiency, Chronic complications, Transcatheter Aortic Valve Replacement
- Abstract
Objective: To determine the nature of the association between renal dysfunction and outcomes following transcatheter aortic valve implantation (TAVI) in all cases performed in the UK between 2007 and 2012., Methods: The UK TAVI registry was established to report outcomes on all TAVI procedures performed within the UK. Data were collected prospectively on 3980 patients from 1 January 2007 until 31 December 2012., Results: In total, 205 patients (5.5%) died during their admission. Moderate to advanced chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m(2)) was significantly associated with increased mortality, even after adjustment for risk factors (OR 1.45, 95% CI 1.03 to 2.05; p=0.04). For every 10 mL/min/1.73 m(2) decrease in eGFR, in-hospital mortality increased by 8.2% (95% CI 1.1% to 14.7%; p=0.03). In total 1119 patients (30.2%) died during the follow-up period (median 543 days). Moderate to advanced CKD (eGFR <45 mL/min/1.73 m(2)) was significantly associated with increased mortality, even after adjustment for risk factors (OR 1.36, 95% CI 1.17 to 1.58; p<0.001). For every 10 mL/min/1.73 m(2) decrease in eGFR, cumulative mortality increased by 4.4% (95% CI 1.2% to 7.5%; p=0.007). Preoperative kidney function and the need for preoperative dialysis treatment discriminated between patients who died and survived. However, predictive power was poor with none of the c-statistics being >0.6., Conclusions: Pre-procedural renal dysfunction is associated, in a graded fashion independently of dialysis status, with worse outcomes, including mortality in patients undergoing TAVI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
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- 2015
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20. Endothelial nitric oxide synthase single nucleotide polymorphism and left ventricular function in early chronic kidney disease.
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Chand S, Chue CD, Edwards NC, Hodson J, Simmonds MJ, Hamilton A, Gough SC, Harper L, Steeds RP, Townend JN, Ferro CJ, and Borrows R
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- Aged, C-Reactive Protein metabolism, Cholesterol blood, Echocardiography, Doppler, Color, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nitric Oxide Synthase Type III metabolism, Radiography, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic diagnostic imaging, Renal Insufficiency, Chronic physiopathology, Nitric Oxide Synthase Type III genetics, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic genetics, Ventricular Function, Left
- Abstract
Background: Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated., Methods: 140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively., Results: The median estimated glomerular filtration rate (eGFR) was 50 mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively)., Conclusions: eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.
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- 2015
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21. Defining the natural history of uremic cardiomyopathy in chronic kidney disease: the role of cardiovascular magnetic resonance.
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Edwards NC, Moody WE, Chue CD, Ferro CJ, Townend JN, and Steeds RP
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- Cardiomyopathies diagnosis, Cardiovascular Diseases etiology, Fibrosis etiology, Gadolinium, Humans, Odds Ratio, Risk Factors, Cardiomyopathies etiology, Magnetic Resonance Imaging, Renal Insufficiency, Chronic complications
- Abstract
Chronic kidney disease (CKD) is an under-recognized, highly prevalent cardiovascular (CV) risk factor affecting 1 in 7 adults. Large epidemiological studies have clearly established a graded association between the severity of CKD and CV event rates. Although patients with end-stage renal disease who are undergoing dialysis are at greatest CV risk, the disease process is evident in the early stages of CKD with glomerular filtration rates as high as 75 ml/min/1.73 m(2). Indeed, these patients are at least 6 times more likely to die of CV disease than to reach end-stage CKD. Thus, the major impact of CKD on the population and the healthcare budget is not that of providing renal replacement therapy but the cost of death and disability from premature CV disease. Although end-stage CKD is characterized by a clustering of conventional atherosclerotic risk factors, it has little association with CV event rates. This is reflected in disproportionate levels of sudden cardiac death, heart failure, and stroke, rather than myocardial infarction. Thus it appears that nonatherosclerotic processes, including left ventricular hypertrophy and fibrosis, account for most of the excess CV risk. Over the past decade, the use of cardiac magnetic resonance in CKD has brought about an improved understanding of the adverse CV changes collectively known as uremic cardiomyopathy. The unique ability of cardiac magnetic resonance to provide a comprehensive noninvasive examination of cardiac structure and function, arterial function, myocardial tissue characterization (T1 mapping and inversion recovery imaging), and myocardial metabolic function (spectroscopy) is ideally suited to characterize the phenotype of CV disease in CKD and to provide insight into the mechanisms leading to uremic cardiomyopathy. Concerns relating to an association between gadolinium contrast agents and nephrogenic systemic fibrosis in dialysis recipients have led to the use of lower doses and lower-risk gadolinium agents that appear to minimize this risk., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
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- 2014
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22. Central blood pressure in chronic kidney disease: latest evidence and clinical relevance.
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Yuan M, Moody WE, and Townend JN
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- Blood Pressure drug effects, Blood Pressure Determination methods, Cardiovascular Diseases complications, Glomerular Filtration Rate, Humans, Renal Insufficiency, Chronic complications, Risk Factors, Blood Pressure physiology, Cardiovascular Diseases physiopathology, Renal Insufficiency, Chronic physiopathology
- Abstract
Chronic kidney disease (CKD) has been consistently associated with cardiovascular disease; there is an inverse graded relationship between glomerular filtration rate and cardiovascular risk. Early-moderate CKD receives increasing recognition for its role as an independent risk factor as evidenced by its recent inclusion in the Joint British Societies' consensus recommendations for the prevention of cardiovascular disease. Data from both imaging and epidemiological studies suggest arterial stiffening and structural left ventricular disease (hypertrophy and fibrosis) are the key pathogenic mediators of cardiovascular disease in CKD. This review discusses the rationale for measuring central blood pressure in patients with CKD and whether it could provide incremental prognostic value beyond that of peripheral blood pressure.
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- 2014
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23. Effects of age and chronic kidney disease on regional aortic distensibility: a cardiovascular magnetic resonance study.
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Chue CD, Edwards NC, Ferro CJ, Townend JN, and Steeds RP
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- Adult, Aged, Case-Control Studies, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic physiopathology, Aging pathology, Aorta, Thoracic pathology, Magnetic Resonance Imaging, Cine, Renal Insufficiency, Chronic diagnosis, Vascular Stiffness physiology
- Abstract
Background: Chronic kidney disease (CKD) is associated with increased arterial stiffness, an independent predictor of adverse cardiovascular outcome. Effects of CKD on regional aortic stiffness are unknown. This study aimed to determine the effects of CKD and ageing on regional thoracic aortic distensibility using cardiac magnetic resonance (CMR) imaging., Methods: This was a cross-sectional case control study comparing patients with stage II-IV non-diabetic CKD recruited from a university hospital with healthy controls. Aortic distensibility was measured in triplicate using CMR (1.5 T) at ascending, proximal descending and distal descending thoracic aortic levels and calculated using previously validated formulae., Results: 189 patients and 40 controls were recruited. Distensibility was reduced at all three thoracic aortic levels in CKD patients compared to controls (2.8 vs. 4.1 × 10(-3) mmHg(-1); P < 0.0005 for ascending aorta). The cohort was divided into tertiles of age and glomerular filtration rate (GFR); distensibility decreased with increasing age (P < 0.0005) and decreasing GFR (P < 0.02). In univariate analyses age (r = -0.688, P < 0.0005), systolic blood pressure (r = -0.183, P = 0.006) and GFR (r = 0.172, P = 0.009) all correlated with ascending aortic distensibility. In a multivariate regression model age and GFR were independent predictors of aortic distensibility at all three levels with 50% of the variation in ascending aortic distensibility explained (P < 0.0005)., Conclusions: Patients with early stage chronic kidney disease have reduced distensibility along the entire length of the thoracic aorta. This worsens with ageing and as kidney function declines, emphasizing the importance of early treatment whilst kidney function is still relatively preserved., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
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- 2013
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24. Atrial fibrillation in CKD: balancing the risks and benefits of anticoagulation.
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Ng KP, Edwards NC, Lip GY, Townend JN, and Ferro CJ
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- Aged, Anticoagulants adverse effects, Atrial Fibrillation complications, Humans, Male, Renal Insufficiency, Chronic complications, Risk Assessment, Anticoagulants therapeutic use, Atrial Fibrillation drug therapy, Renal Insufficiency, Chronic drug therapy
- Abstract
Chronic kidney disease (CKD) and atrial fibrillation are common conditions that often coexist and are associated with increased risk of stroke. Despite the wealth of evidence for optimal management of atrial fibrillation in the general population, the role of anticoagulation with warfarin in individuals with CKD with atrial fibrillation is far less well defined. Current recommendations for anticoagulation in patients treated with dialysis and those with an earlier stage of CKD are based on clinical trials in the general atrial fibrillation population that have largely excluded individuals with CKD. Observational studies of anticoagulation in dialysis patients have produced conflicting results, mainly because of increased risk of bleeding. This, together with warfarin's potential adverse effects on ectopic/vascular calcification and progression of CKD, may result in negating the benefits associated with anticoagulation in the general population. With the recent emergence of novel oral anticoagulants, there is an urgent need for a better understanding of the complex inter-relationship among CKD, atrial fibrillation, stroke, and bleeding risk. This knowledge is paramount to optimize the potential benefits of treatment and minimize the potential harms in this very high-risk and growing population., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2013
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25. Cardiovascular effects of sevelamer in stage 3 CKD.
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Chue CD, Townend JN, Moody WE, Zehnder D, Wall NA, Harper L, Edwards NC, Steeds RP, and Ferro CJ
- Subjects
- Aged, Blood Pressure drug effects, Double-Blind Method, Female, Fibroblast Growth Factor-23, Humans, Hypertrophy, Left Ventricular prevention & control, Male, Middle Aged, Polyamines adverse effects, Polyamines therapeutic use, Renal Insufficiency, Chronic physiopathology, Sevelamer, Vascular Stiffness drug effects, Ventricular Function, Left drug effects, Chelating Agents pharmacology, Polyamines pharmacology, Renal Insufficiency, Chronic drug therapy
- Abstract
Serum phosphate independently predicts cardiovascular mortality in the general population and CKD, even when levels are in the normal range. Associations between serum phosphate, arterial stiffness, and left ventricular (LV) mass suggest a possible pathophysiological mechanism, potentially mediated by the phosphaturic hormone fibroblast growth factor-23 (FGF-23). To what extent the phosphate binder sevelamer modulates these effects is not well understood. In this single-center, randomized, double-blind, placebo-controlled trial, we enrolled 120 patients with stage 3 nondiabetic CKD. After a 4-week open-label run-in period, during which time all patients received sevelamer carbonate, we randomly assigned 109 patients to sevelamer (n=55) or placebo (n=54) for an additional 36 weeks. We assessed LV mass and systolic and diastolic function with cardiovascular magnetic resonance imaging and echocardiography, and we assessed arterial stiffness by carotid-femoral pulse wave velocity. The mean age was 55 years, and the mean eGFR was 50 ml/min per 1.73 m(2). After 40 weeks, we found no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity. Only 56% of subjects took ≥ 80% of prescribed therapy; in this compliant subgroup, treatment with sevelamer associated with lower urinary phosphate excretion and serum FGF-23 but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest. In conclusion, this study does not provide evidence that sevelamer carbonate improves LV mass, LV function, or arterial stiffness in stage 3 nondiabetic CKD.
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- 2013
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26. Arterial disease in chronic kidney disease.
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Moody WE, Edwards NC, Chue CD, Ferro CJ, and Townend JN
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- Diagnostic Imaging, Disease Progression, Global Health, Humans, Incidence, Renal Insufficiency, Chronic physiopathology, Risk Factors, Arterial Occlusive Diseases diagnosis, Arterial Occlusive Diseases epidemiology, Arterial Occlusive Diseases etiology, Renal Insufficiency, Chronic complications
- Abstract
End stage renal disease is associated with a very high risk of premature cardiovascular death and morbidity. Early stage chronic kidney disease (CKD) is also associated with an increased frequency of cardiovascular events and is a common but poorly recognised and undertreated risk factor. Cardiovascular disease in CKD can be attributed to two distinct but overlapping pathological processes, namely atherosclerosis and arteriosclerosis. While the risk of athero-thrombotic events such as myocardial infarction is elevated, arteriosclerosis is the predominant pathophysiological process involving fibrosis and thickening of the medial arterial layer. This results in increased arterial stiffness causing left ventricular hypertrophy and fibrosis and the exposure of vulnerable vascular beds such as the brain and kidney to high pressure fluctuations causing small vessel disease. These pathophysiological features are manifest by a high risk of lethal arrhythmia, congestive heart failure, myocardial infarction and stroke. Recent work has highlighted the importance of aldosterone and disordered bone mineral metabolism.
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- 2013
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27. Cytomegalovirus seropositivity is associated with increased arterial stiffness in patients with chronic kidney disease.
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Wall NA, Chue CD, Edwards NC, Pankhurst T, Harper L, Steeds RP, Lauder S, Townend JN, Moss P, and Ferro CJ
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- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Viral blood, Blood Pressure physiology, Cardiovascular Diseases blood, Cardiovascular Diseases etiology, Cardiovascular Diseases virology, Cytomegalovirus immunology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin G blood, Male, Middle Aged, Renal Insufficiency, Chronic blood, Risk Factors, Young Adult, Cytomegalovirus pathogenicity, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic virology, Vascular Stiffness physiology
- Abstract
Background: Patients with chronic kidney disease have an increased cardiovascular risk that is not fully explained by traditional risk factors but appears to be related to increased arterial stiffness. Cytomegalovirus (CMV) infection is associated with increased cardiovascular risk although the mechanisms for this are unknown. We examined whether CMV seropositivity was associated with increased arterial stiffness in patients with chronic kidney disease., Methodology and Principal Findings: In 215 non-diabetic patients with chronic kidney disease, CMV seropositivity was determined using an anti-CMV IgG ELISA. Pulse wave velocity was measured and aortic distensibility assessed in the ascending, proximal descending and distal descending thoracic aorta. Patients seropositive for CMV had a higher pulse wave velocity and lower aortic distensibility at all 3 levels. These differences (except for ascending aortic distensibility) persisted in a subcohort matched for age, gender and renal function, and when the whole cohort was divided into quartiles of age. In multivariable analyses, CMV seropositivity was an independent determinant of pulse wave velocity and proximal and distal descending aortic distensibility., Conclusions: In patients with chronic kidney disease, CMV seropositivity is associated with increased arterial stiffness and decreased distensibility of the proximal descending and distal aorta. These findings suggest that further research is required to examine CMV as a possible cause of arterial disease and increased cardiovascular risk in patients with CKD and may be relevant more widely for CMV seropositive patients with normal renal function.
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- 2013
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28. The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease.
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Edwards NC, Steeds RP, Chue CD, Stewart PM, Ferro CJ, and Townend JN
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- Adult, Aged, Angiotensin II Type 1 Receptor Blockers therapeutic use, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Blood Pressure drug effects, Dose-Response Relationship, Drug, Drug Interactions, Female, Follow-Up Studies, Glomerular Filtration Rate drug effects, Humans, Hyperkalemia chemically induced, Male, Middle Aged, Mineralocorticoid Receptor Antagonists adverse effects, Potassium blood, Regression Analysis, Renal Insufficiency, Chronic blood, Severity of Illness Index, Spironolactone adverse effects, Mineralocorticoid Receptor Antagonists therapeutic use, Renal Insufficiency, Chronic drug therapy, Spironolactone therapeutic use
- Abstract
Aim: Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30-89ml/min/1.73m(2) ) received 25mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed., Results: After 40 weeks of treatment the incidence of serious hyperkalaemia (K(+) ≥6.0mmol/L) was <1%. A potassium 5.5-5.9mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0mmol/L and eGFR ≤45 ml/min/1.73m(2) . Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks., Conclusion: Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)
- Published
- 2012
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29. Aortic calcification and femoral bone density are independently associated with left ventricular mass in patients with chronic kidney disease.
- Author
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Chue CD, Wall NA, Crabtree NJ, Zehnder D, Moody WE, Edwards NC, Steeds RP, Townend JN, and Ferro CJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Calcinosis diagnostic imaging, Female, Humans, Hypertrophy, Left Ventricular pathology, Male, Middle Aged, Radiography, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic pathology, Reproducibility of Results, Young Adult, Aorta, Abdominal pathology, Bone Density, Calcinosis complications, Femur diagnostic imaging, Hypertrophy, Left Ventricular complications, Hypertrophy, Left Ventricular diagnosis, Renal Insufficiency, Chronic complications
- Abstract
Background: Vascular calcification and reduced bone density are prevalent in chronic kidney disease and linked to increased cardiovascular risk. The mechanism is unknown. We assessed the relationship between vascular calcification, femoral bone density and left ventricular mass in patients with stage 3 non-diabetic chronic kidney disease in a cross-sectional observational study., Methodology and Principal Findings: A total of 120 patients were recruited (54% male, mean age 55 ± 14 years, mean glomerular filtration rate 50 ± 13 ml/min/1.73 m(2)). Abdominal aortic calcification was assessed using lateral lumbar spine radiography and was present in 48%. Mean femoral Z-score measured using dual energy x-ray absorptiometry was 0.60 ± 1.06. Cardiovascular magnetic resonance imaging was used to determine left ventricular mass. One patient had left ventricular hypertrophy. Subjects with aortic calcification had higher left ventricular mass compared to those without (56 ± 16 vs. 48 ± 12 g/m(2), P = 0.002), as did patients with femoral Z-scores below zero (56 ± 15 vs. 49 ± 13 g/m(2), P = 0.01). In univariate analysis presence of aortic calcification correlated with left ventricular mass (r = 0.32, P = 0.001); mean femoral Z-score inversely correlated with left ventricular mass (r = -0.28, P = 0.004). In a multivariate regression model that included presence of aortic calcification, mean femoral Z-score, gender and 24-hour systolic blood pressure, 46% of the variability in left ventricular mass was explained (P<0.001)., Conclusions: In patients with stage 3 non-diabetic chronic kidney disease, lower mean femoral Z-score and presence of aortic calcification are independently associated with increased left ventricular mass. Further research exploring the pathophysiology that underlies these relationships is warranted.
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- 2012
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30. Evaluating the effects of sevelamer carbonate on cardiovascular structure and function in chronic renal impairment in Birmingham: the CRIB-PHOS randomised controlled trial.
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Chue CD, Townend JN, Steeds RP, and Ferro CJ
- Subjects
- Blood Flow Velocity drug effects, Cardiovascular Diseases blood, Cardiovascular Diseases physiopathology, Double-Blind Method, Humans, Phosphates blood, Placebos, Pulsatile Flow drug effects, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic physiopathology, Research Design, Sevelamer, Cardiovascular Diseases drug therapy, Chelating Agents therapeutic use, Polyamines therapeutic use, Renal Insufficiency, Chronic drug therapy
- Abstract
Background: Serum phosphate is an independent predictor of cardiovascular morbidity and mortality in patients with chronic kidney disease and the general population. There is accumulating evidence that phosphate promotes arterial stiffening through structural vascular alterations such as medial calcification, which are already apparent in the early stages of chronic kidney disease., Aim: To determine the effects of phosphate binding with sevelamer carbonate on left ventricular mass and function together with arterial stiffness in patients with stage 3 chronic kidney disease., Methods/design: A single-centre, prospective, randomised, double-blind, placebo-controlled trial of 120 subjects with stage 3 chronic kidney disease recruited from University Hospitals Birmingham NHS Foundation Trust. Baseline investigations include transthoracic echocardiography and cardiac magnetic resonance imaging to assess ventricular mass, volumes and function, applanation tonometry to determine pulse wave velocity and pulse wave analysis as surrogate measures of arterial stiffness and dual energy x-ray absorptiometry scanning to determine bone density. During an open-label run in phase, subjects will receive 1600 mg sevelamer carbonate with meals for four weeks. They will then be randomised to either continue sevelamer carbonate or receive an identical placebo (60 subjects per arm) for the remaining 36 weeks. Four-weekly monitoring of serum electrolytes and bone biochemistry will be performed. All baseline investigations will be repeated at the end of the treatment period. The primary endpoint of the study is a reduction in left ventricular mass after 40 weeks of treatment. Secondary endpoints are: i) change in aortic compliance; ii) change in arterial stiffness; iii) change in arterial elastance; iv) change in left ventricular systolic and diastolic elastance; v) change in left ventricular function; and vi) change in bone density., Trial Registration: This trial is registered at ClinicalTrials.gov: NCT00806481 and Current Controlled Trials: ISRCTN35254279.
- Published
- 2011
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31. The effect of spironolactone upon corticosteroid hormone metabolism in patients with early stage chronic kidney disease.
- Author
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Hammer F, Edwards NC, Hughes BA, Steeds RP, Ferro CJ, Townend JN, and Stewart PM
- Subjects
- Adrenal Cortex Hormones urine, Adult, Aged, Aldosterone metabolism, Angiotensin II blood, Blood Pressure drug effects, Female, Humans, Hydrocortisone metabolism, Kidney Failure, Chronic drug therapy, Male, Middle Aged, Mineralocorticoid Receptor Antagonists, Renal Insufficiency, Chronic drug therapy, Renin blood, Tetrahydrocortisol urine, Adrenal Cortex Hormones metabolism, Kidney Failure, Chronic metabolism, Renal Insufficiency, Chronic metabolism, Spironolactone therapeutic use
- Abstract
Context: Aldosterone has emerged as an important mediator of disease progression and mortality in patients with chronic heart and kidney disease (CKD). Despite the increasing use of mineralocorticoid receptor antagonists in these patients, little is known about the effects on corticosteroid hormone secretion and metabolism., Objective: To assess corticosteroid hormone secretion and metabolism in patients with early stage CKD before and after spironolactone (Spiro)., Design: Randomized, double-blind, placebo-controlled interventional study., Setting: Single tertiary referral centre., Patients: A total of 112 patients with stable stage 2/3 CKD., Interventions: Patients were randomized to receive either Spiro 25 mg once daily or placebo for 36 weeks., Main Outcome Measures: Plasma renin activity (PRA), angiotensin II (AngII) and steroid hormones were analysed by standard assays; urinary corticosteroid hormone metabolites (5α+5β-tetrahydro-cortisol (5α+5β-THF), TH-cortisone (THE), 3α5β-TH-aldosterone (TH-Aldo), 5α+5β-TH-deoxycorticosterone (5α+5β-TH-DOC), TH-11-desoxycortisol (THS)) were analysed by gas chromatography/mass spectrometry., Results: Plasma aldosterone concentration (PAC) was inversely correlated with eGFR (r = -0·331, P < 0·001). Urinary 24-h excretion of TH-Aldo was correlated with PAC (r = 0·214, P < 0·05) and diastolic blood pressure (BP) (r = 0·212, P = <0·05), whereas total 24-h urinary cortisol metabolite excretion was correlated with systolic BP (r = 0·316, P < 0·01). In addition, 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 activity (urinary 5α+5β-THF)/THE) ratio) was correlated with PRA (r = 0·277, P < 0·01). Spiro treatment significantly reduced BP (123 ± 11/76 ± 7 vs 119 ± 11/73 ± 8 mmHg, P < 0·01) despite renin-angiotensin-aldosterone system induction, reflected by increased urinary 24-h TH-Aldo excretion (17·6 (12, 86) vs 26 (18, 80) μg/24 h, P < 0·05). By contrast, Spiro had no effect on total urinary cortisol metabolite excretion, 11β-hydroxylase, 11β-HSD type 1 and 2 activity., Conclusions: Aldo and cortisol are positively associated with BP suggesting that adrenal hyperactivity may in part explain the increased cardiovascular risk in patients with early end-stage CKD. Addition of Spiro had no effect on glucocorticoid metabolism or total 24-h corticosteroid production., (© 2010 Blackwell Publishing Ltd.)
- Published
- 2010
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32. Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors at 5 Years.
- Author
-
Price, Anna M., Moody, William E., Stoll, Victoria M., Vijapurapu, Ravi, Hayer, Manvir K., Biasiolli, Luca, Weston, Chris J., Webster, Rachel, Wesolowski, Roman, McGee, Kirsty C., Liu, Boyang, Baig, Shanat, Pickup, Luke C., Radhakrishnan, Ashwin, Law, Jonathan P., Edwards, Nicola C., Steeds, Richard P., Ferro, Charles J., and Townend, Jonathan N.
- Abstract
[Figure: see text]. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
Catalog
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