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Biomedical subjects

Charles R V Tomson

Publications and source records attributed to Charles R V Tomson.

16 recordsLinked to original sources
PubMed2006

The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD.

BACKGROUND: Evaluating the effects of decreasing low-density lipoprotein (LDL) cholesterol levels requires large randomized trials. In preparation for such a trial, we assessed the biochemical efficacy, safety, and tolerability of adding ezetimibe, 10 mg/d, to simvastatin, 20 mg/d, as initial therapy for such patients. METHODS: Two hundred three patients (152 predialysis patients with creatinine levels > or = 1.7 mg/dL [> or = 150 micromol/L], 18 patients on peritoneal dialysis therapy, and 33 patients on hemodialysis therapy) were randomly assigned to the administration of simvastatin, 20 mg/d, plus ezetimibe, 10 mg/d; or simvastatin, 20 mg, plus placebo ezetimibe daily. RESULTS: After 6 months, allocation to simvastatin monotherapy was associated with a 31-mg/dL (0.8-mmol/L) decrease in nonfasting LDL cholesterol levels compared with baseline. Allocation to simvastatin plus ezetimibe produced an additional 18-mg/dL (0.47-mmol/L) decrease in LDL cholesterol level, representing an incremental 21% reduction over that achieved with simvastatin monotherapy (P < 0.0001). There were no statistically significant effects of the addition of ezetimibe to simvastatin on triglyceride or high-density lipoprotein cholesterol levels. Ezetimibe was not associated with an excess risk of abnormal liver function test results or of elevated creatine kinase levels and did not impair absorption of fat-soluble vitamins. There were no serious adverse events caused by study treatment. CONCLUSION: This 6-month study shows that the addition of ezetimibe to simvastatin, 20 mg/d, as initial therapy for patients with chronic kidney disease was well tolerated and produced an additional 21% decrease in LDL cholesterol levels. The clinical efficacy and safety of combination therapy in this population are now being assessed in a large randomized trial.

Anticholesteremic Agents↗
PubMed2005

First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular disease, but the efficacy and safety of simvastatin and aspirin are unknown in this patient group. METHODS: Patients were randomly assigned in a 2 x 2 factorial design to the administration of: (1) 20 mg of simvastatin daily versus matching placebo, and (2) 100 mg of modified-release aspirin daily versus matching placebo. RESULTS: Overall, 448 patients with chronic kidney disease were randomly assigned (242 predialysis patients with a creatinine level > or = 1.7 mg/dL [> or =150 micromol/L], 73 patients on dialysis therapy, and 133 patients with a functioning transplant). Compliance with study treatments was 80% at 12 months. Allocation to treatment with 100 mg of aspirin daily was not associated with an excess of major bleeds (aspirin, 4 of 225 patients [2%] versus placebo, 6 of 223 patients [3%]; P = not significant [NS]), although there was a 3-fold excess of minor bleeds (34 of 225 [15%] versus 12 of 223 patients [5%]; P = 0.001). Among those with predialysis renal failure or a functioning transplant at baseline, aspirin did not increase the number of patients who progressed to dialysis therapy (7 of 187 [4%] versus 6 of 188 patients [3%]; P = NS) or experienced a greater than 20% increase in creatinine level (63 of 187 patients [34%] versus 56 of 188 patients [30%]; P = NS). After 12 months of follow-up, allocation to 20 mg of simvastatin daily reduced nonfasting total cholesterol levels by 18% (simvastatin, 163 mg/dL [4.22 mmol/L] versus placebo, 196 mg/dL [5.08 mmol/L]; P < 0.0001), directly measured low-density lipoprotein cholesterol levels by 24% (89 mg/dL [2.31 mmol/L] versus 114 mg/dL [2.96 mmol/L]; P < 0.0001), and triglyceride levels by 13% (166 mg/dL [1.87 mmol/L] versus 186 mg/dL [2.10 mmol/L]; P < 0.01), but there was no significant effect on high-density lipoprotein cholesterol levels (2% increase; P = NS). Allocation to simvastatin therapy was not associated with excess risk for abnormal liver function test results or elevated creatine kinase levels. CONCLUSION: During a 1-year treatment period, simvastatin, 20 mg/d, produced a sustained reduction of approximately one quarter in low-density lipoprotein cholesterol levels, with no evidence of toxicity, and aspirin, 100 mg/d, did not substantially increase the risk for a major bleeding episode. Much larger trials are now needed to assess whether these treatments can prevent vascular events.

Adult↗
PubMed2005

Estimating kidney function in adults using formulae.

With increasing emphasis on the earlier detection and management of chronic kidney disease (CKD), estimation of the glomerular filtration rate (GFR) has assumed greater importance. It is accepted that use of serum creatinine concentration alone as a marker of kidney function is inadequate; in particular, it has a poor sensitivity for detecting CKD. International recommendations favour the reporting of creatinine-based estimates of GFR using formulae which also take into account age, gender and other variables that affect the relationship between serum creatinine and GFR: in particular, the four-variable formula derived from the Modification of Diet in Renal Disease study (4-v MDRD) is increasingly being used. We have reviewed the literature supporting the use of this formula compared with the well-established Cockcroft and Gault formula. Overall, evidence supports the use of the 4-v MDRD formula as an improved estimate of GFR in people with moderate/advanced CKD. Neither formula performs well in people with normal and mildly reduced kidney function. However, there remain significant problems with this approach and areas where further research is required. In particular, the widespread adoption of estimated GFR reporting has refocused attention on the limitations of creatinine measurement and highlighted clinical situations in which the formulae are inadequate.

Adult↗
PubMed2004

Retransplantation in Alport post-transplant anti-GBM disease.

BACKGROUND: Post transplant anti-glomerular basement membrane (GBM) disease affects up to 5% of patients with Alport's syndrome. Defects in the COL4A5 gene are responsible for most cases, and alpha 5(IV)NC1 is the usual target for alloantibodies. Gene deletions are more commonly associated with this complication than are point mutations. The disease is severe in renal allografts and nearly always results in graft loss. METHODS: Three cases of retransplantation in Alport's syndrome are described here in detail. All cases were started on immunosuppressive therapy early in the course of their disease and one patient (case 2) received pre-emptive anti-T-cell therapy (Campath IH). Anti-GBM antibodies in these cases were investigated by standard anti-GBM enzyme-linked immunosorbent assay (ELISA), by indirect immunofluorescence, and by Western blotting using collagenase-digested human GBM and recombinant type IV collagen NC1 domains made in insect cells. RESULTS: All cases showed early antibody and complement fixation to human GBM. Target alloantibodies were to alpha 5(IV)NC1 domain predominantly. Cases two and three gave negative results on standard ELISA for anti-GBM antibodies. Pathologic examination revealed crescentic glomerulonephritis, which was rapid in onset in case 1, blunted and less aggressive in case 3, and case 2 developed segmental necrosis without crescent formation. Neutrophilic infiltrates were an early feature in all 3 cases. All cases are compared with a review of all retransplanted cases in the literature. CONCLUSION: Alport anti-GBM disease is a severe disease in retransplanted patients. Anti-T-cell therapy seemed to modify the pathologic findings but did not prevent graft loss. Longer term plasma exchange and mycophenolate mofetil may attenuate the illness, but in these cases did not prevent graft loss. Western blotting detected alloantibodies to alpha 5(IV) NC1 domain and is more sensitive and specific for this disease than standard ELISAs.

Adolescent↗
PubMed2004

Hemoperitoneum in a patient with ANCA-associated polyangiitis syndrome.

Antineutrophil cytoplasmic antibody-associated vasculitides often cause small-vessel vasculitis, usually involving the kidney. Involvement of other organ systems and medium to large arteries is recognized, but free-vessel rupture is rare. A case of a man with classic renal involvement caused by microscopic polyangiitis associated with multiple episodes of hemoperitoneum secondary to splanchnic vasculitis is described. Although his renal vasculitis responded to conventional immunosuppressive treatment, relentless progression of splanchnic vasculitis ultimately proved fatal.

Aged↗
PubMed2003

Ambulatory blood pressure measurement in kidney transplantation: an overview.

Adequate control of hypertension is among the most important aims of medical management of the kidney transplant recipient, with the aim of reducing the risk of premature cardiovascular disease and preserving graft function. Antihypertensive therapy should be adjusted according to the best available estimates of usual resting blood pressure. If clinic measurements are used, care should be taken to ensure that these measurements are taken under optimal conditions. Home blood pressure monitoring is a useful adjunct in many patients. Ambulatory blood pressure monitoring gives valuable additional data; mean ambulatory blood pressure correlates better with markers of target organ damage such as left ventricular hypertrophy. However, current treatment thresholds and targets are based on clinic measurements. Ambulatory blood pressure monitoring is certainly a useful adjunct to clinic and home blood pressure measurement, but its role in routine clinical practice in the transplant clinic remains to be defined.

Blood Pressure Monitoring, Ambulatory↗
PubMed2002

Reproducibility of derived central arterial waveforms in patients with chronic renal failure.

Arterial stiffness potently predicts mortality in dialysis patients. Pulse-wave analysis permits the non-invasive assessment of indices of arterial stiffness and the central pressure waveform by applanation tonometry. The aim of this study was to assess the reproducibility of pulse-wave analysis in patients with chronic renal failure. A total of 188 subjects (23 healthy controls, along with 71 pre-dialysis, 67 dialysis and 27 transplant patients) took part. Duplicate measurements were recorded of brachial blood pressure using the semi-automated Omron 705 device and of the radial artery pressure waveform using applanation tonometry. The central pressure aortic waveform was then obtained by application of a transfer function incorporated into the SphygmoCor software. Central aortic mean blood pressure (MBP), indices of arterial stiffness [augmentation index (AIx) and time to reflection (TR)] and the subendocardial viability ratio (SEVR) were analysed for intra-observer, inter-observer and long-term reproducibility using Bland-Altman plots. The mean (+/-S.D.) intra-observer difference was 0+/-4% for AIx, 0+/-20 ms for TR, 0+/-3 mmHg for aortic MBP and 0+/-18% for the SEVR. Inter-observer mean differences were 0+/-3% for AIx, 1+/-7 ms for TR, 1+/-4 mmHg for aortic MBP and 1+/-9% for the SEVR. For the long-term study, the mean differences were -1+/-9% for AIx, -2+/-13 mmHg for aortic MBP, -2+/-12 ms for TR and 1+/-29% for the SEVR. Pulse-wave analysis showed excellent reproducibility in all the studies, and is therefore suitable for use in all patients with chronic renal failure. Further prospective and interventional studies are now required to assess whether AIx and TR are important prognostic indices of cardiovascular events, and therefore relevant surrogate indices of arterial stiffness in this susceptible population.

Adult↗
PubMed2002

Human uremic plasma increases microvascular permeability to water and proteins in vivo.

BACKGROUND: The risk of cardiovascular disease is significantly higher in patients with long-term uremia than in otherwise healthy adults. This is true even before patients proceed to dialysis, but the reason why cardiovascular risk is increased is unknown. Transvascular transport of lipids and other macromolecules in both large vessels and the microcirculation has been implicated in generation of cardiovascular disease. METHODS: To determine whether patients with long-term uremia have circulating factors that promote increased vascular permeability, we measured the effect of perfusing microvessels with uremic plasma in a non-mammalian model of vascular permeability measurement. RESULTS: Perfusion of frog mesenteric microvessels with dialyzed normal plasma did not result in an increase in either hydraulic conductivity (Lp, permeability of the vessel wall to water) or oncotic reflection coefficient (sigma, permeability to macromolecules, particularly proteins). Perfusion with dialyzed uremic plasma resulted in a very significant increase in vascular permeability to both water (Lp increased 8.8-fold from 4.1 to 36.4 x 10(-7) cm x s(-1) cm H2O(-1)) and proteins (sigma reduced from 0.93 to 0.53). CONCLUSIONS: These results suggest that one or more circulating macromolecules in uremic plasma are able to increase transvascular solute and fluid flux, and may underlie the increased cardiovascular risk found in these patients.

Animals↗
PubMed2002

Central aortic pressure augmentation in stable renal transplant recipients.

BACKGROUND: Premature cardiovascular disease is the leading cause of death in renal transplant recipients and classical risk factors significantly underestimate the risk. The increased effect of arterial wave reflections on central arteries has recently been shown to be an important independent predictor of cardiovascular mortality in chronic hemodialysis patients. The aim of this study was to assess the contribution of several classical and potential non-classical cardiovascular risk factors on aortic pressure augmentation by the reflected arterial wave in stable renal transplant recipients. METHODS: Using the non-invasive technique of pulse wave analysis aortic augmentation was investigated in 250 stable renal transplant recipients. Peripheral pulse waveforms were recorded from the radial artery. Central aortic waveforms were then generated and the aortic augmentation index calculated. RESULTS: In multivariate analysis, female sex (regression coefficient 7.5 +/- 1.7%; P < 0.001), heart rate (-4.8 +/- 0.5% per 10 beats/min; P < 0.001), mean arterial pressure (4.2 +/- 0.6% per 10 mm Hg; P < 0.001), the persistence of an arteriovenous fistula (4.1 +/- 1.3%; P < 0.005), total time on renal replacement therapy (3.8 +/- 0.9% per 10 years; P < 0.001), height (-3.1 +/- 0.8% per 10 cm; P < 0.001), immunosuppression with cyclosporine (2.8 +/- 1.3%; P < 0.005) and age (2.5 +/- 0.5% per 10 years; P < 0.001) were all important correlates of aortic augmentation index. CONCLUSIONS: Our findings suggest, to our knowledge for the first time, that both the presence of a functioning arteriovenous fistula and immunosuppressive treatment with cyclosporine are associated with an increased aortic augmentation index in renal transplant recipients and could, therefore, be potential reversible contributors to the high cardiovascular risk profile in these patients.

Adult↗
PubMed2002

The impact of arteriovenous fistula formation on central hemodynamic pressures in chronic renal failure patients: a prospective study.

BACKGROUND: The presence of an arteriovenous (AV) fistula creates permanently high cardiac output. This may cause an imbalance between available cardiac oxygen supply in response to greater demand and increased arterial stiffness. METHODS: Surrogate markers of subendocardial perfusion (subendocardial viability ratio [SEVR]) and arterial stiffness (augmentation index [AIx]) can be measured noninvasively by using pulse wave analysis on the radial pulse to obtain central pressures. We prospectively followed up nine patients with chronic renal failure (CRF) undergoing creation of an AV fistula for vascular access at regular intervals over 6 months. RESULTS: After surgery, blood pressure and heart rate remained unchanged throughout the study period. AIx stayed the same (baseline versus 6 months, 20% +/- 11% versus 22% +/- 15%), but there was a decrease in SEVR immediately after surgery (-9% +/- 5%; P < 0.05) that persisted for at least 3 months (-14% +/- 7%; P < 0.01). At 6 months, SEVR remained below baseline values in all but one patient (mean SEVR at baseline, 166% +/- 22% versus 6 months, 150% +/- 20%; P < 0.05; -9% +/- 7%). CONCLUSION: Creation of an AV fistula may directly predispose patients with CRF to a risk for myocardial ischemia caused by an adverse imbalance between subendocardial oxygen supply and increased oxygen demand consequent to a greater cardiac output.

Aged↗
PubMed2002

Elevated plasma vascular endothelial growth factor levels in non-diabetic predialysis uraemia.

Chronic renal impairment is associated with increased vascular morbidity and mortality. The pathogenesis of this aggressive vascular pathology is unknown but believed to be multi-factorial in origin. There is accumulating in vivo and in vitro evidence to suggest that the vascular endothelium is dysfunctional in uraemia, including the propensity of endothelial cells to produce VEGF in response to acidosis. There is also preliminary data to suggest abnormally increased endothelial permeability in uraemia. To investigate the potential abnormal circulating levels of VEGF in uraemia, EDTA plasma samples were collected from 20 non-diabetic predialysis patients and matched controls. Free plasma VEGF levels were detected using a commercially available ELISA kit. There were significantly higher plasma levels of VEGF predialysis group (median 351 pg/ml, range 70-636 pg/ml) compared to matched controls (median 125.5 pg/ml, range 22-450 pg/ml), p < 0.002. In conclusion, free plasma VEGF levels are high in chronic renal impairment. We hypothesise that this potent growth and permeability factor may contribute to the endothelial dysfunction of uraemia.

Endothelial Growth Factors↗
PubMedDate not supplied

What can the UK learn from the USA about improving the quality and safety of healthcare?

The US healthcare system provides evidence that spending more on healthcare does not result in better care, but also offers many lessons and surprises on how the quality and safety of healthcare can be improved. The US Institute of Medicine has clearly articulated what needs to be achieved. A series of US agencies, including the Joint Commission on Accreditation of Healthcare Organizations, the Centers for Medicare and Medicaid Services (CMS), other major players, and the Hospital Quality Alliance, routinely collect and report on numerous measures of the quality and safety of inpatient and outpatient healthcare. Most attention to improving care in the UK has focused on vertically integrated, closed healthcare systems, but the US experience provides additional models from the work of Quality Improvement Organizations and of numerous voluntary organisations that sponsor collaborative improvement.

Government Agencies↗