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Objective: To explore the relationship between serum phosphate, arterial stiffness and left ventricular mass (LVM) in patients with early-stage chronic kidney disease (CKD)., Design: A cross-sectional observational study., Setting: Single centre., Patients: 208 patients with stage 2 to stage 4 non-diabetic CKD., Interventions: Arterial stiffness was determined through measurement of aortic pulse wave velocity (PWV). Cardiac magnetic resonance was used to determine LVM., Main Outcome Measure: Relationship between serum phosphate, aortic PWV and LVM., Results: Mean age was 54 ± 13 years, mean glomerular filtration rate was 50 ± 15 ml/min/1.73 m(2), mean serum phosphate was 1.11 ± 0.21 mmol/l and mean PWV was 8.6 ± 2.1 m/s. When the cohort was divided into quartiles according to serum phosphate, LVM increased across quartiles (p=0.04), with no significant differences in age, kidney function, blood pressure or PWV. Serum phosphate correlated with LVM (r=0.173; p=0.01), but PWV did not (p=0.2). In a regression model containing gender, serum phosphate, office systolic blood pressure, albumin/creatinine ratio and haemoglobin, 30% of the variation in LVM was explained (p<0.0005), with serum phosphate accounting for 5% of the variance., Conclusion: Serum phosphate is independently associated with LVM in patients with CKD. Interventional studies are required to determine whether this association is causative and whether reducing phosphate exposure reduces LVM in this population.

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.

Background: The rate of decline in kidney function is a powerful predictor of cardiovascular risk in patients with chronic kidney disease (CKD). Serum phosphate and increased arterial stiffness are associated with elevated cardiovascular risk in CKD and the general population. We sought to determine whether serum phosphate and markers of arterial stiffness predict progression of renal dysfunction in patients with early CKD., Methods: Two hundred and twenty-five patients with Stage II-IV CKD were prospectively followed up at University Hospital Birmingham. Serum phosphate was measured at baseline and arterial stiffness was determined through measurement of aortic pulse wave velocity (PWV) and augmentation index (AIx). Progression of renal dysfunction was defined as the slope of estimated glomerular filtration rate (eGFR) against time. We determined the associations between possible predictors and rate of progression and also examined a combined end point of start of dialysis or ≥ 25% decline in eGFR., Results: Mean baseline eGFR was 43 ± 19 mL/min/1.73 m(2) and serum phosphate 1.22 ± 0.27 mmol/L. Median follow-up was 924 days. Serum phosphate independently predicted a greater decline in eGFR; a 1 mmol/L increment in serum phosphate was associated with a 0.34 mL/min/month steeper decline (P = 0.02). Brachial and aortic systolic pressure independently predicted the rate of renal function decline but aortic PWV and AIx had no significant influence. Forty-one patients (18%) reached the combined end point; serum phosphate was significantly higher in this group (1.32 ± 0.36 versus 1.19 ± 0.24 mmol/L, P = 0.04) and was an independent predictor for the combined end point., Conclusions: Serum phosphate independently predicts decline in renal function in early CKD. Further studies are required to determine the mechanisms involved and to investigate the potential benefits of phosphate lowering on preserving kidney function.

The impact of disordered mineral and bone metabolism following kidney transplantation is not well defined. We studied the association of serum phosphate and calcium concentrations, and surrogate measures of arterial stiffness (augmentation index: AIx and Timing of the reflected wave: Tr), with long-term kidney transplant recipient and allograft survival. Prevalent adult renal transplant patients (n = 270) were prospectively studied over a median 88-month follow-up. Detailed demographic, clinical and laboratory data, in addition to both peripheral and central non-invasive blood pressure measurements, were recorded. Higher serum phosphate and calcium levels were associated with increased all-cause mortality (HR: 1.21; 95% CI 1.09,1.35, p < 0.001 and HR: 1.22; 95% CI 1.01,1.48; p < 0.04, respectively; adjusted Cox model) and death-uncensored graft loss (p < 0.001 and p = 0.03, respectively). In addition, serum calcium and phosphate were associated with death-censored graft loss on univariable analysis (p < 0.001 and p = 0.02, respectively), but did not retain significance on multivariable analysis. AIx and Tr were not associated with mortality or graft loss on multivariable analysis. This is the first report to demonstrate that both higher serum phosphate and calcium levels are associated with increased mortality in kidney transplant recipients. It highlights the need for randomized trials assessing current interventions available for improving disordered mineral-bone metabolism post transplantation., (© 2010 John Wiley & Sons A/S.)

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.

Chronic kidney disease is a proinflammatory state associated with increased arterial stiffness. We hypothesized that chronic kidney disease patients on long-term immunosuppression would have lower arterial stiffness and require treatment with less antihypertensive medication compared with non-immunosuppressed patients. A total of 254 patients (97 on immunosuppression) with chronic kidney disease were recruited from specialist renal clinics. Brachial blood pressure, central aortic pressure and waveform and pulse wave velocity were measured. Age, peripheral blood pressure and pulse wave velocity increased with worsening renal function but were not different between immunosuppressed and non-immunosuppressed patients. Central systolic (P < 0.001) and pulse pressure (P = 0.003) and the number of antihypertensive medications (P < 0.001) increased with worsening renal function and were higher in non-immunosuppressed patients (P = 0.02, P = 0.004 and P < 0.001, respectively). Age, mean arterial pressure, number of antihypertensive medications and a diagnosis of diabetes were found to be independent predictors of pulse wave velocity (R(2) = 0.375; P < 0.001). In a subgroup of 30 patient pairs without diabetes mellitus and cardiovascular disease and with a proven renal diagnosis, carefully matched for age, gender, renal function and systolic pressure, the prescribed antihypertensive medication remained lower in the immunosuppressed patients compared with non-immunosuppressed patients (P = 0.04). Pulse wave velocity was lower in the immunosuppressed group (7.5 ± 1.8 vs. 8.8 ± 1.9 m s(-1); P = 0.02). This study suggests that immunosuppression might be a method of reducing blood pressure and arterial stiffness in patients with chronic kidney disease.

Patients with early chronic kidney disease (CKD) have an increased risk for cardiovascular disease. Aldosterone levels are elevated and might impair ventricular function through adverse myocardial and vascular proinflammatory and fibrotic effects. In the Chronic Renal Impairment in Birmingham II (CRIB II) study, it was hypothesized that mineralocorticoid receptor blockade with spironolactone in addition to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers would improve left ventricular (LV) function and markers of inflammation, ventricular stretch, and collagen turnover in early CKD. A total of 112 patients with early CKD were randomized to spironolactone 25 mg/day or placebo for 40 weeks. Ventricular function was assessed by echocardiography and cardiac magnetic resonance imaging tagging. High-sensitivity C-reactive protein, N-terminal-pro-B-type natriuretic peptide, and aminoterminal propeptide of type III procollagen were measured. Spironolactone improved LV long-axis systolic function (Sm 8.2 ± 1.4 vs 7.7 ± 1.3 cm/s, p <0.05), torsion (7.77 ± 1.61° vs 6.77 ± 1.48°, p <0.05), and myocardial deformation (strain rate -1.14 ± 0.24 vs -1.09 ± 0.20 s(-1), p <0.05) compared to placebo, without a change in the ejection fraction. Markers of LV relaxation (E/e' ratio 7.2 ± 2.3 vs 8.5 ± 2.3, p <0.05) and suction (M-mode propagation velocity 56 ± 12 vs 50 ± 12 cm/s, p <0.05) were also improved. Spironolactone reduced N-terminal-pro-B-type natriuretic peptide (24.8 pmol/L [range 0.4 to 122.4] vs 39.4 pmol/L [range 10.8 to 102.4], p <0.01) and attenuated an increase in aminoterminal propeptide of type III procollagen observed with placebo. In conclusion, spironolactone improves markers of regional LV systolic and diastolic function in early CKD., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.)

Chronic kidney disease is associated with elevated cardiovascular risk, and heart failure and arrhythmias are the biggest causes of cardiovascular death in this population. Increased arterial stiffness is a hallmark of chronic kidney disease and is associated with adverse alterations in cardiac structure and function that may predispose to an increased risk of cardiovascular death. These changes are already apparent in early kidney disease, which is highly prevalent in the developed world. The mechanisms underlying increased arterial stiffness in chronic kidney disease are undoubtedly complex, but an understanding is paramount to enable the development of novel therapeutic strategies to prevent or reverse this pathophysiology and therefore reduce the cardiovascular disease burden in this high-risk cohort.

Chronic kidney disease is associated with elevated cardiovascular risk, and heart failure and arrhythmias are the biggest causes of cardiovascular death in this population. Increased arterial stiffness is a hallmark of chronic kidney disease and is associated with adverse alterations in cardiac structure and function that may predispose to an increased risk of cardiovascular death. These changes are already apparent in early kidney disease, which is highly prevalent in the developed world. The mechanisms underlying increased arterial stiffness in chronic kidney disease are undoubtedly complex, but an understanding is paramount to enable the development of novel therapeutic strategies to prevent or reverse this pathophysiology and therefore reduce the cardiovascular disease burden in this high-risk cohort.

The existence of the renin-angiotensin-aldosterone system was first postulated over 100 years ago. Following the identification of all the major components, came the discovery of their potential pathogenicity in cardiovascular and renal disease. The introduction of drugs that inhibit the synthesis or actions of this system has prompted a number of trials that have largely shaped how cardiovascular and renal disease is managed today. The continued discovery of yet more components of this system promises to further our understanding of its influence on disease processes and herald the development of more highly selective drugs, ensuring that the renin-angiotensin-aldosterone system will continue to be a key area of interest for many years to come.

Objective: To explore the risk of cardiovascular disease in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAVs) and to assess contributing risk factors., Methods: In a retrospective matched-pair cohort study, 113 of 131 patients with AAVs from a vasculitis clinic registry were matched 1:1 for renal function, age at diagnosis, sex, smoking status, and previous history of a cardiovascular disease to patients with noninflammatory chronic kidney disease (CKD). Cardiovascular events were defined as acute coronary syndrome, new-onset angina, symptomatic peripheral vascular disease, stroke, and transient ischemic attack., Results: Median followup times were 3.4 years for the AAV patients and 4.2 years for the CKD patients. More cardiovascular events occurred in the AAV group (23 of 113) than in the CKD group (16 of 113). Cox regression survival analysis showed a significantly increased risk of a cardiovascular event for AAV patients, with a hazard ratio (HR) of 2.23 (95% confidence interval [95% CI] 1.1-4.4) (P = 0.017). Within the cohort of AAV patients, the most strongly predictive factors were previous history of cardiovascular disease (HR 4 [95% CI 1.7-9.8]), history of dialysis dependency (HR 4.3 [95% CI 1.5-12.1]), ever having smoked (HR 3.9 [95% CI 1.5-10]), age at diagnosis (HR 1.038 [95% CI 1.006-1.072]), estimated glomerular filtration rate at remission (HR 0.977 [95% CI 0.957-0.998]), and serum cholesterol concentration at presentation (HR 0.637 [95% CI 0.441-0.92])., Conclusion: In this retrospective study, patients with AAVs appear at greater risk of cardiovascular disease, with increased risk in those with a previous history of cardiovascular disease, dialysis dependency, poor renal function at remission, or a history of smoking. Measures to reduce the risk of cardiovascular disease should be integral to the management of systemic vasculitis.

Objectives: We sought to determine whether the addition of spironolactone to angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) improves left ventricular mass and arterial stiffness in early-stage chronic kidney disease (CKD)., Background: Chronic kidney disease is associated with a high risk of cardiovascular disease and a high prevalence of left ventricular hypertrophy and arterial stiffness that confer an adverse prognosis. It is believed that these abnormalities are in part a result of activation of the renin-angiotensin-aldosterone system., Methods: After an active run-in phase with spironolactone 25 mg once daily, 112 patients with stage 2 and 3 CKD with good blood pressure control (mean daytime ambulatory blood pressure <130/85 mm Hg) on established treatment with ACE inhibitors or ARBs were randomized to continue spironolactone or to receive a matching placebo. Left ventricular mass (cardiac magnetic resonance) and arterial stiffness (pulse wave velocity/analysis, aortic distensibility) were measured before run in and after 40 weeks of treatment., Results: Compared with placebo, the use of spironolactone resulted in significant improvements in left ventricular mass (-14 +/- 13 g vs. +3 +/- 11 g, p < 0.01), pulse wave velocity (-0.8 +/- 1.0 m/s vs. -0.1 +/- 0.9 m/s, p < 0.01), augmentation index (-5.2 +/- 6.1% vs. -1.4 +/- 5.9%, p < 0.05), and aortic distensibility (0.69 +/- 0.86 x 10(-3) mm Hg vs. 0.04 +/- 1.04 x 10(-3) mm Hg, p < 0.01)., Conclusions: The use of spironolactone reduces left ventricular mass and improves arterial stiffness in early-stage CKD. These effects suggest that aldosterone exerts adverse cardiovascular effects in CKD and that spironolactone is worthy of further study as a treatment that could reduce adverse cardiovascular events. (Is Spironolactone Safe and Effective in the Treatment of Cardiovascular Disease in Mild Chronic Renal Failure; NCT00291720).

Background: Abnormal left ventricular (LV) deformation is an independent predictor of poor cardiovascular outcome in end-stage renal disease. Studies in early-stage chronic kidney disease (CKD) have not been performed despite the known graded inverse relationship between glomerular filtration rate and adverse cardiovascular events., Methods: Forty patients with CKD stage 2 or 3 and no history of cardiovascular disease or diabetes and 30 healthy controls underwent Doppler myocardial imaging for longitudinal deformation (strain/strain rate)., Results: There were no differences in LV ejection fraction or systolic tissue Doppler velocities between patients with CKD and controls. In CKD, mean global strain (-15% +/- 4% vs -17% +/- 3%, P <.01) and mean global strain rate were reduced compared with controls (-0.88 +/- 0.16 vs -1.06 +/- 0.31, P <.05). Peak systolic strain was reduced in the basal lateral (-13.9% +/- 0.9% vs -17.9% +/- 1.02%, P <.01), basal septal (-17.1% +/- 0.8% vs -19.4% +/- 0.77%, P <.05), and mid-septal (-16.4% +/- 0.78% vs -18.9% +/- 0.88%, P <.05) walls with more basal postsystolic shortening (P <.01). Peak systolic strain rate was reduced in the basal lateral, mid-lateral, and mid-septal segments (P <.05)., Conclusion: Conventional measures of systolic function are preserved in early-stage CKD, but systolic deformation is abnormal, consistent with an adverse cardiovascular prognosis.

Background: Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD., Methods: Seven patients with CKD (mean arterial pressure 103 mmHg; mean plasma creatinine 3.5 mg/dl) received three 15 min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750 mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs., Results: Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100 mg: 7.4 +/- 1.9 mmHg, 750 mg: 8.4 +/- 2.3 mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5).m(-2), 750 mg: 829 +/- 141 dyne.s.cm(-5).m(-2), P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100 mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750 mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged., Conclusions: These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.

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., (Copyright 2002 by the National Kidney Foundation, Inc.)

The importance of endothelin-1 (ET-1) in the pathophysiology of essential hypertension is unclear. We therefore compared the effects of endothelin ET(A) receptor blockade and the stimulation of ET(A) and ET(B) receptors, and their interaction with the sympathetic nervous system, in the forearm resistance vessels of patients with essential hypertension and healthy control subjects. A total of 27 untreated patients with essential hypertension (blood pressure >160/100 mmHg) and 25 normotensive (blood pressure <140/90 mmHg) age- and sex-matched control subjects participated in these studies. A total of 10 patients and 10 controls took part in each phase. Locally active doses of study drugs were infused into the non-dominant brachial artery, while forearm blood flow was measured by venous occlusion plethysmography. A 60 min infusion of BQ-123 (an ET(A) receptor antagonist; 100 nmol/min) significantly increased forearm blood flow by 40+/-8% in hypertensive patients and by 35+/-5% in controls, with no difference between groups (P=0.49). Forearm vasoconstriction to ET-1 (an ET(A) and ET(B) receptor agonist; 5 pmol/min) for 90 min was significantly blunted in hypertensive patients (21+/-4%) compared with control subjects (37+/-3%; P=0.0001). Forearm vasoconstriction to sarafotoxin S6c (an ET(B) receptor agonist; 10 pmol/min) for 90 min was similar in hypertensive patients (44+/-5%) and control subjects (48+/-4%; P=0.95). Sympathetically mediated vasoconstriction produced by lower-body negative pressure was not different in hypertensive patients compared with controls, and was not affected by infusion of ET-1 or sarafotoxin S6c. There were no differences in the observed increase in forearm blood flow with a control vasodilator (sodium nitroprusside) or the observed decrease in forearm blood flow with a control vasoconstrictor (noradrenaline) between hypertensive patients and control subjects. BQ-123 produced a significant increase in forearm blood flow in hypertensive patients, consistent with the anti-hypertensive actions of this agent. In conclusion, forearm vasoconstriction to ET-1, but not to sarafotoxin S6c, was reduced in patients with essential hypertension, consistent with possible down-regulation of the ET(A) receptor in this condition.

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.

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.