David C Wheeler

University College London, Londinium, England, United Kingdom

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Publications (86)618.88 Total impact

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    ABSTRACT: Patients with chronic kidney disease (CKD) are unlikely to gain the same benefit from conventional doses of statins as do patients with cardiovascular disease alone. This study investigated whether inflammation accompanying CKD causes statin resistance.
    06/2014;
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    ABSTRACT: Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.
    Journal of the American Society of Nephrology 05/2014; · 8.99 Impact Factor
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    ABSTRACT: The incidence and prevalence of diabetes mellitus (DM) continue to grow markedly throughout the world, due primarily to the increase in type 2 DM (T2DM). Although improvements in DM and hypertension management have reduced the proportion of diabetic individuals who develop chronic kidney disease (CKD) and progress to end-stage renal disease (ESRD), the sheer increase in people developing DM will have a major impact on dialysis and transplant needs. This KDIGO conference addressed a number of controversial areas in the management of DM patients with CKD, including aspects of screening for CKD with measurements of albuminuria and estimated glomerular filtration rate (eGFR); defining treatment outcomes; glycemic management in both those developing CKD and those with ESRD; hypertension goals and management, including blockers of the renin-angiotensin-aldosterone system; and lipid management.Kidney International advance online publication, 30 April 2014; doi:10.1038/ki.2014.128.
    Kidney International 04/2014; · 8.52 Impact Factor
  • Bertram L Kasiske, David C Wheeler
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    ABSTRACT: Kidney Disease: Improving Global Outcomes (KDIGO) was founded in 2003 to fulfill a need for international cooperation and consolidation in the development and implementation of clinical practice guidelines. KDIGO has experienced a rapid growth in the development of guidelines, producing three guidelines in its first 6 years and another six in the last 3 years. In addition, it has held 12 global conferences on important issues in kidney disease and its treatment. A major effort is under way to support the dissemination and implementation of KDIGO guidelines through various channels, including an Implementation Task Force with official representatives in 86 countries. KDIGO is now under its own management and remains committed to the development of evidence-based guidelines. Future challenges include finding adequate sources of funding and building stronger links with other organizations involved in guideline development and implementation.
    Nephrology Dialysis Transplantation 11/2013; · 3.37 Impact Factor
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    ABSTRACT: The risk of cardiovascular disease is increased by up to 33 to 50× in chronic inflammatory states and convention doses of statins may not provide the same cardiovascular protection as in noninflamed patients. This study investigated whether the increase in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-R)-mediated cholesterol synthesis observed under inflammatory stress was resistant to the action of statins and if so, whether this was because of interference with the sterol regulatory element binding protein cleavage-activating protein pathway. Inflammatory stress was induced by adding cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6) and lipopolysaccharides to vascular smooth muscle cells in vitro and by subcutaneous casein injection in apolipoprotein E/scavenger receptors class A/CD36 triple knockout mice in vivo. Inflammatory stress exacerbated cholesterol ester accumulation and was accompanied in vitro and in vivo by increased HMGCoA-R mRNA and protein expression mediated via activation of the sterol regulatory element binding protein cleavage-activating protein/sterol regulatory element binding protein-2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro. However, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 16 μmol/L inhibited HMGCoA-R activity by 50% in vascular smooth muscle cells, but the same concentration resulted in only 30% of HMGCoA-R activity in vascular smooth muscle cells in the presence of interleukin-1β. Knocking down sterol regulatory element binding protein cleavage-activating protein prevented statin resistance induced by interleukin-1β, and overexpression of sterol regulatory element binding protein cleavage-activating protein induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease aortic lipid accumulation rose from 2 to 10 mg/kg per day in the presence of inflammatory stress. Increased cholesterol synthesis mediated by HMGCoA-R under inflammatory stress may be one of the mechanisms for intracellular lipid accumulation and statin resistance.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2013; · 6.34 Impact Factor
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    ABSTRACT: Context:The clinical course of secondary hyperparathyroidism (sHPT) in patients on hemodialysis is not well described, and the effect of the calcimimetic cinacalcet on disease progression is uncertain.Objective:To describe (a) the clinical course of sHPT in patients treated with phosphate binders and/or vitamin D sterols and (b) the impact of cinacalcet on occurrence of severe unremitting HPT, defined by the persistence of markedly elevated parathyroid hormone (PTH) concentrations together with hypercalcemia or parathyroidectomy (PTX).Design:Randomized, double-blind, placebo-controlled clinical trial.Setting:Global, multicenter.Patients:3883 patients on hemodialysis of 5755 screened with moderate to severe sHPT.Main outcome measures:Parathyroidectomy, severe, unremitting HPT and use of commercial cinacalcet (a protocol violation).Intervention:Cinacalcet (30 to 180 mg daily) or placebo for up to 64 months.Results:In the 1935 patients randomized to placebo, 278 (14%) patients underwent PTX (median PTH 1872 pg/mL within prior 12 weeks of surgery). Age, sex, geographic region, co-morbidity, calcium-containing phosphate binder use, and baseline serum calcium, phosphorus and PTH concentrations were associated with PTX. Commercial cinacalcet was started in 443 (23%) patients (median PTH 1108 pg/mL before treatment began). Severe unremitting HPT developed in 470 (24%) patients. In a multivariable Cox model, the relative hazard (comparing patients randomized to cinacalcet versus placebo) of severe unremitting HPT was 0.31 (95% CI 0.26 to 0.37). The relative hazard differed little when adjusted by baseline clinical characteristics.Conclusions:Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.
    The Journal of clinical endocrinology and metabolism 10/2013; · 6.50 Impact Factor
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    ABSTRACT: The amount of irreversible injury on renal allograft biopsy predicts function, but little is known about the early evolution of this damage. In a single-center cohort, we examined the relationship between donor-, recipient-, and transplantation-associated factors and change in a morphometric index of chronic damage (ICD) between protocol biopsies performed at implantation and at 2-3 months. We then investigated whether early delta ICD predicted subsequent biochemical outcomes. We found little evidence to support differences between the study group, who had undergone serial biopsies, and a contemporaneous control group, who had not. In allografts with serial biopsies (n = 162), there was an increase in ICD between implantation (median: 2%, IQR:0-8) and 2-3 months post-transplant (median 8% IQR:4-15; p < 0.0001). Donation from younger or live donors was independently associated with smaller early post-transplant increases in ICD. There was no evidence for a difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD after three months did not predict allograft function at one yr. These findings suggest that graft damage develops shortly after transplantation and reflects donor factors, but does not predict future biochemical outcomes.
    Clinical Transplantation 10/2013; · 1.63 Impact Factor
  • Richard Haynes, David C Wheeler
    Nature Reviews Nephrology 07/2013; · 7.94 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD)-mineral and bone disorder is associated with diverse metabolic and endocrine disturbances that ultimately may contribute to further loss of kidney function, bone demineralization, and fatal or nonfatal cardiovascular events. Recent insights into the pathophysiology of the events that unfold during the development of this disorder suggest that disturbances in phosphate metabolism are pivotal. The consequences of abnormal phosphate homeostasis are evident at estimated glomerular filtration rates <70 mL/min/1.73 m(2), long before serum phosphate levels increase. Healthy individuals with blood phosphate levels in the top quartile of the normal range have an increased risk of developing CKD, reaching end-stage renal disease, and experiencing cardiovascular events. Substantial public health consequences may be related to increased dietary phosphorus exposure from additives that contain phosphate in the food supply and from modest increases in serum phosphate levels; however, it remains to be established whether interventions aimed at these targets can impact on the development of adverse clinical outcomes. Current approaches involving dietary intervention and intestinal phosphate binders are based on principles and assumptions that need to be examined more rigorously. Compelling animal, observational, and clinical data indicate that interventions directed at lowering phosphate exposure and serum phosphate levels should be subject to rigorous clinical trials that use appropriate placebo comparators and focus on key clinical outcomes, such as cardiovascular events, progression of CKD, fractures, quality of life, and mortality.
    American Journal of Kidney Diseases 06/2013; · 5.29 Impact Factor
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    ABSTRACT: BACKGROUND: Arterial calcification (AC) is a major health problem associated with extreme morbidity and a shortened survival. It is currently without any effective treatment. ATP and the purinergic system in general are now emerging as being important in the pathogenesis of AC and potentially provide a new focus for novel therapies. METHODS: This review systematically analyses and discusses the current literature examining the relevance of the purinergic system to AC. Particular emphasis is given to the enzymes associated with ATP metabolism and their role in maintaining a balance between promotion and inhibition of arterial mineralization. Points of controversy are highlighted, and areas for future research are suggested. CONCLUSION: The potential roles of ATP and the purinergic system in AC are beginning to be elucidated. While further work is necessary, current knowledge suggests that several components of the purinergic system could be targeted to develop new treatments for AC.
    European Journal of Clinical Investigation 01/2013; · 3.37 Impact Factor
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    ABSTRACT: Mortality in patients with end-stage renal disease (ESRD) remains unacceptably high. Emerging techniques and advances in dialysis technology have the potential to improve clinical outcomes in the ESRD population. This report summarizes the deliberations and recommendations of a conference sponsored by Kidney Disease: Improving Global Outcomes to address the following questions: (1) what is the appropriate frequency and duration of hemodialysis; (2) how should we optimize water quality and dialysate composition; and (3) what technical innovations in blood purification and bioengineering can result in better clinical outcomes? The conference report will augment our current understanding of clinical practice in blood purification and will pose several high-priority research questions.Kidney International advance online publication, 16 January 2013; doi:10.1038/ki.2012.450.
    Kidney International 01/2013; · 8.52 Impact Factor
  • Bertram L Kasiske, David C Wheeler
    American Journal of Kidney Diseases 12/2012; · 5.29 Impact Factor
  • New England Journal of Medicine 11/2012; · 51.66 Impact Factor
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    ABSTRACT: OBJECTIVE: Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure. METHODS AND RESULTS: In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052). CONCLUSIONS: Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure.
    Arteriosclerosis Thrombosis and Vascular Biology 09/2012; · 6.34 Impact Factor
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    ABSTRACT: Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.
    Journal of the American Society of Nephrology 07/2012; 23(8):1407-15. · 8.99 Impact Factor
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    ABSTRACT: Secondary hyperparathyroidism (sHPT) and other abnormalities associated with chronic kidney disease-mineral bone disorder can contribute to dystrophic (including vascular) calcification. Dietary modification and variety of medications can be used to attenuate the severity of sHPT. However, it is unknown whether any of these approaches can reduce the high risks of death and cardiovascular disease in patients with end-stage renal disease. The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial was designed to test the hypothesis that treatment with the calcimimetic agent cinacalcet compared with placebo (on a background of conventional therapy including phosphate binders +/- vitamin D sterols) reduces time to death or non-fatal cardiovascular events (specifically myocardial infarction, unstable angina, heart failure and peripheral arterial disease events) among patients on hemodialysis with sHPT. This report describes baseline characteristics of enrolled subjects with a focus on regional variation. There were 3883 subjects randomized from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations. The burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363-1694 pg/mL). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed activated vitamin D derivatives. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions. EVOLVE enrolled 3883 subjects on hemodialysis with moderate to severe sHPT. Inclusion of subjects from multiple global regions with varying degrees of disease severity will enhance the external validity of the trial results.
    Nephrology Dialysis Transplantation 04/2012; 27(7):2872-9. · 3.37 Impact Factor
  • David C Wheeler, Ben Caplin
    Journal of the American Society of Nephrology 04/2012; 23(5):770-3. · 8.99 Impact Factor
  • Dorothea Nitsch, David C Wheeler
    American Journal of Kidney Diseases 03/2012; 60(3):347-9. · 5.29 Impact Factor
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    ABSTRACT: Associations between inflammation and ESRD and death in chronic kidney disease are well established. However, the potential role of the adaptive immune system is uncertain. We aimed to prospectively study the relevance of the adaptive immune system to ESRD and mortality by measuring monoclonal and polyclonal excesses of highly sensitive serum free light chains (sFLCs). Three hundred sixty-four patients selected from a nephrology outpatient clinic had kappa and lambda sFLCs concentrations and serum immunofixation electrophoresis measured. Cox regression was used to assess the relevance of monoclonal and polyclonal excess of sFLCs to the incidence of ESRD and death (mean follow-up for death 6.0 years). After adjustment for baseline eGFR, there was no significant association between monoclonal excess of sFLCs and risk of ESRD or mortality. Baseline log κ and log λ concentrations were positively associated with ESRD risk, but these associations seemed to be due to correlations with eGFR (per 1 SD higher concentration: adjusted hazard ratio 1.05 [95% confidence interval 0.88 to 1.26] and 0.99 [0.83 to 1.19], respectively). For mortality, after adjustment for eGFR plus markers of cardiac damage, there was weak evidence of an association with λ, but not κ, sFLC concentration (fully adjusted hazard ratio 1.33 [95% confidence interval 1.05 to 1.67] per 1 SD higher concentration). Associations between monoclonal and polyclonal excess of sFLCs and risk of ESRD are explained by the correlation between these measures and renal function. We found only weak evidence of an association between polyclonal excess of λ sFLC concentration and mortality.
    Clinical Journal of the American Society of Nephrology 12/2011; 6(12):2829-37. · 5.07 Impact Factor
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    ABSTRACT: Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74-0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76-1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60-0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68-0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10,000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13). Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.
    The Lancet 06/2011; 377(9784):2181-92. · 39.06 Impact Factor

Publication Stats

3k Citations
618.88 Total Impact Points

Institutions

  • 2001–2014
    • University College London
      • Centre for Nephrology
      Londinium, England, United Kingdom
  • 2013
    • University of Toronto
      Toronto, Ontario, Canada
  • 2012–2013
    • Hennepin County Medical Center
      Minneapolis, Minnesota, United States
    • London School of Hygiene and Tropical Medicine
      • Faculty of Epidemiology and Population Health
      Londinium, England, United Kingdom
  • 2005–2013
    • University of Oxford
      • Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)
      Oxford, ENG, United Kingdom
  • 2010
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 2007
    • Universitair Ziekenhuis Ghent
      Gand, Flanders, Belgium
  • 2003
    • University Hospitals Birmingham NHS Foundation Trust
      • Department of Nephrology
      Birmingham, ENG, United Kingdom
  • 2000–2001
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 1999–2001
    • University of Birmingham
      • Group of Medical Science and Education
      Birmingham, ENG, United Kingdom
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia