Search

Introduction: Patients with renal dysfunction are more prone to bleeding when receiving antithrombotic drugs. The aim of the study was to assess the impact of clopidogrel on safety and efficacy in patients with renal dysfunction in non-ST elevation acute coronary syndromes., Methods and Results: Patients in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial were analysed to assess the relationship of chronic kidney disease to cardiovascular outcomes. Renal function was estimated by the glomerular filtration rate computed from the baseline serum creatinine measurements in 12 253 (97.5%) patients enrolled in the trial. Patients were grouped into tertiles of glomerular filtration rate. The primary outcome (cardiovascular death, myocardial infarction, stroke combined) occurred more frequently in the lowest glomerular filtration rate tertile. The bleeding risk was also significantly increased in patients in this tertile, compared with the other two. The beneficial effect of adding clopidogrel to standard treatment in non-ST elevation acute coronary syndrome was observed in all three tertiles of renal function {(lower third relative risk (RR)=0.89 [95% confidence interval (CI) 0.76-1.05]; medium third RR=0.68 (95% CI 0.56-0.84); upper third RR=0.74 (95% CI 0.60-0.93) (P for heterogeneity=0.11)}. Clopidogrel treatment significantly increased the risk of minor bleeding in all tertiles of renal function. The risk of major or life-threatening bleeding increased moderately with the addition of clopidogrel to standard treatment [lower third RR=1.12 (95% CI 0.83-1.51); medium third RR=1.4 (95% CI 0.97-2.02); upper third RR=1.83 (95% CI 1.23-2.73)], but this did not appear to be greatest in those with the lowest renal function., Conclusions: Even mild chronic kidney disease worsens the prognosis in patients with non-ST elevation acute coronary syndromes. Clopidogrel was beneficial and safe in patients with and without chronic kidney disease.

Background: In the Heart Outcomes Prevention Evaluation Study, microalbumin and albumin levels measured by using radioimmunoassay (RIA) and less than the microalbuminuria threshold in baseline urine samples were associated independently with cardiovascular (CV) events. Conventional immunoassays may underestimate albuminuria by not detecting a mildly denatured unfragmented form of albumin, immunounreactive to conventional antibodies., Methods: Microalbuminuria was reanalyzed in baseline samples stored at -70 degrees C for 5,358 North American participants, 1,992 with diabetes mellitus, by using a high-performance liquid chromatography (HPLC) system that also detects immunochemically nonreactive urinary albumin., Results: The HPLC compared with RIA method identified microalbuminuria in 1,585 versus 719 participants, 809 versus 423 patients with diabetes, by using a conventionally accepted albumin-creatinine ratio (ACR) of 29 mg/g or greater (>or=3 mg/mmol) as a cutoff value. HPLC-detected microalbuminuria increased risk for the primary outcome (a composite of myocardial infarction, stroke, and CV death); unadjusted hazard ratio, 1.85 (95% confidence interval, 1.57 to 2.19). Receiver operating characteristic analysis did not differentiate between HPLC- and RIA-detected microalbuminuria as predictors of CV outcomes., Conclusion: The prevalence of microalbuminuria is 2 to 3 times greater with HPLC than RIA using an ACR of 29 mg/g or greater (>or=3 mg/mmol). The optimal cutoff value for detecting CV risk in the entire study population by means of RIA was 9 mg/g (0.9 mg/mmol), and with HPLC, 32 mg/g (3.4 mg/mmol). Results from this study also show different ACR cutoff values for individuals with diabetes: RIA, 13 mg/g or greater (>or=1.4 mg/mmol); HPLC, 44 mg/g or greater (>or=5.2 mg/mmol) and without diabetes: RIA, 7 mg/g or greater (>or=0.7 mg/mmol); HPLC, 29 mg/g or greater (>or=3/1 mg/mmol). Results highlight the importance of method-dependent cutoff values in the prediction of CV events.

Protein antigens administered via the oral route are exposed to a hostile environment in the gastrointestinal tract, consisting of digestive enzymes and a range of pH (1-7.5). Using a delivery system can afford protection to entrapped components against degradation and permit delivery of antigen to the cells responsible for generating local and systemic immune responses. In this comparative study, mice were immunised orally with tetanus toxoid (40 or 200 microg dose/mouse, four doses in total) entrapped in non-ionic surfactant vesicles formulated with bile salts (bilosomes). The higher entrapped dose (BV-TT, 200 microg) induced IgG1 by study week 3 to similar levels to those observed with subcutaneous un-entrapped TT at the lower (<50 microg) dose. However, both bilosome formulations (BV-TT, low, and high doses), though not un-entrapped TT, caused a rise in the numbers of IgA positive plasma cells observed in the small intestine, primarily in the first 15 cm of the small intestine.

It has not been established firmly whether dyslipidemia contributes independently to the progression of kidney disease. Lipid and lipoprotein parameters, including levels of total, HDL, and LDL cholesterol; triglycerides; lipoprotein(a); apolipoprotein A-IV; and the apolipoprotein E and A-IV polymorphisms, were assessed in 177 patients who had mostly mild to moderate renal insufficiency and were followed prospectively for up to 7 yr. Progression of kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure necessitating renal replacement therapy. In univariate analysis, patients who reached a progression end point (n = 65) were significantly older and had higher serum creatinine and proteinuria as well as lower GFR and hemoglobin levels. In addition, baseline apolipoprotein A-IV and triglyceride concentrations were higher and HDL cholesterol levels were lower. Multivariate Cox regression analysis revealed that baseline GFR (hazard ratio 0.714; 95% confidence interval [CI] 0.627 to 0.814 for an increment of 10 ml/min per 1.73 m(2); P < 0.0001) and serum apolipoprotein A-IV concentrations (hazard ratio 1.062; 95% CI 1.018 to 1.108 for an increment of 1 mg/dl; P = 0.006) were significant predictors of disease progression. Patients with apolipoprotein A-IV levels above the median had a significantly faster progression (P < 0.0001), and their mean follow-up time to a progression end point was 53.7 mo (95% CI 47.6 to 59.8) as compared with 70.0 mo (95% CI 64.6 to 75.4) in patients with apolipoprotein A-IV levels below the median. For the apolipoprotein E polymorphism, only the genotype epsilon2/epsilon4 was associated with an increased risk for progression. In summary, this prospective study in patients with nondiabetic primary kidney disease demonstrated that apolipoprotein A-IV concentration is a novel independent predictor of progression.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening syndrome characterized by platelet aggregation causing occlusive microangiopathy. It has been described as a complication in systemic lupus erythematosus (SLE). Recent research indicated that genetic or autoantibody-induced deficiency of the metalloprotease ADAMTS13 plays a key role in the pathogenesis of TTP. Here we report two uncommon cases of TTP as the first presenting symptom of SLE. Both patients were treated with combined plasma exchange and immunosuppressive therapy, and recovered completely. Although TTP and SLE have several clinical findings in common, and both disorders may coexist more frequently than we currently assume, features of one disease should not mislead to reject the alternative disorder.

We review the evidence linking mild renal insufficiency (MRI) with increased cardiovascular risk. MRI is associated with a number of cardiovascular risk factors, including nighttime hypertension, and increased levels of lipoprotein (a), homocysteine, asymmetric dimethyl-arginine, and inflammation and insulin resistance markers and mediators. Epidemiologic evidence associates coronary artery disease and nephrosclerosis, a frequent cause of early renal insufficiency in the elderly. In a middle-aged general population MRI was found in 8% of women and 9% of men, but was not associated with cardiovascular disease. Nonetheless, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the sub-group with MRI: in people at high cardiovascular risk (mostly coronary disease), the HOPE study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with MRI. The combined incidence of cardiovascular death, myocardial infarction and stroke increased with the level of serum creatinine. Several studies have examined the cardiovascular risk associated with MRI in hypertension. In HDFP, as in HOPE, cardiovascular mortality increased with serum creatinine (five-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). The risk associated with renal insufficiency was independent of other classic cardiovascular risk factors. Two trials of hypertensives with low risk (HOT and a small Italian trial) found that cardiovascular outcomes approximately doubled in subjects with MRI. Another study (MRFIT) found that it was not baseline creatinine, but its increase on follow-up that predicted future cardiovascular disease. These observational data suggest that regardless of etiology MRI is a strong predictor of cardiovascular disease and is found in 10% of populations at low cardiovascular risk and in up to 30% of those at high risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in people with MRI are available. Subgroup analyses of the HOPE study indicate that angiotensin-converting enzyme (ACE) inhibition with ramipril is beneficial and does not increase the risk of such side effects as acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since MRI identifies a group at high risk that appears to benefit most from treatment. Moreover, there is evidence that ACE inhibitors improve renal outcomes in renal insufficiency. Prospective studies should test the predictive power of early renal insufficiency for cardiovascular disease and prognosis with various therapeutic options.

Aims/hypothesis: Emerging data suggest that different indices of glycaemia are risk factors for clinical events. The aim of this analysis was to investigate the relationship between fasting plasma glucose or glycated haemoglobin (GHb) levels and incident cardiovascular (CV) outcomes, death, heart failure and overt nephropathy in diabetic and non-diabetic individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study., Materials and Methods: The adjusted 4.5-year risk of CV events (myocardial infarction or stroke or CV death), heart failure, death and overt nephropathy was analysed in relation to baseline and updated GHb levels (in 3,529 diabetic HOPE study participants) and baseline fasting plasma glucose levels (in 1,937 non-diabetic and 1,013 diabetic participants)., Results: In diabetic participants, a 1% absolute rise in the updated GHb predicted future CV events (relative risk [RR]=1.07, 95% CI 1.01-1.13; p=0.014), death (RR=1.12, 95% CI 1.05-1.19; p=0.0004), heart failure (RR=1.20, 95% CI 1.08-1.33; p=0.0008) and overt nephropathy (RR=1.26, 95% CI 1.17-1.36; p<0.0001) after adjusting for age, sex, diabetes duration, blood pressure, WHR, hyperlipidaemia and ramipril. Similarly, a 1 mmol/l rise in fasting plasma glucose was related to an increased risk of CV outcomes (RR=1.09, 95% CI 1.05-1.13; p<0.0001), death (RR=1.06, 95% CI 1.01-1.12; p=0.017), heart failure (RR=1.16, 95% CI 1.06-1.13; p=0.0007) and overt nephropathy (RR=1.34, 95% CI 1.23-1.45; p<0.0001) in the group composed of diabetic and non-diabetic individuals. The significant relationship between fasting plasma glucose and CV outcomes persisted after adjustment for diabetes status (RR=1.06, 95% CI 1.00-1.12; p=0.043)., Conclusions/interpretation: There is an independent progressive relationship between indices of glycaemia and incident CV events, renal disease and death. Clinical trials of glucose lowering to prevent these outcomes in diabetic and non-diabetic individuals are indicated.

Background: Statins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus. However, the benefit of statins in such patients receiving hemodialysis, who are at high risk for cardiovascular disease and death, has not been examined., Methods: We conducted a multicenter, randomized, double-blind, prospective study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were randomly assigned to receive 20 mg of atorvastatin per day or matching placebo. The primary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. Secondary end points included death from all causes and all cardiac and cerebrovascular events combined., Results: After four weeks of treatment, the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin, and among those receiving placebo it was reduced by 1.3 percent. During a median follow-up period of four years, 469 patients (37 percent) reached the primary end point, of whom 226 were assigned to atorvastatin and 243 to placebo (relative risk, 0.92; 95 percent confidence interval, 0.77 to 1.10; P=0.37). Atorvastatin had no significant effect on the individual components of the primary end point, except that the relative risk of fatal stroke among those receiving the drug was 2.03 (95 percent confidence interval, 1.05 to 3.93; P=0.04). Atorvastatin reduced the rate of all cardiac events combined (relative risk, 0.82; 95 percent confidence interval, 0.68 to 0.99; P=0.03, nominally significant) but not all cerebrovascular events combined (relative risk, 1.12; 95 percent confidence interval, 0.81 to 1.55; P=0.49) or total mortality (relative risk, 0.93; 95 percent confidence interval, 0.79 to 1.08; P=0.33)., Conclusions: Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis.

Background: Both hyper- and hypokalemia increase cardiovascular risk. Modest hyperkalemia is common with angiotensin-converting enzyme inhibition. We studied post-hoc the association of an initial, on-treatment serum potassium measurement with subsequent cardiovascular outcomes over 4.5 years in 9297 individuals at high cardiovascular risk, randomized to an ACE inhibitor or to placebo., Methods: Post-hoc analysis of cardiovascular outcomes, as related to serum potassium levels, in the HOPE (Heart Outcomes and Prevention Evaluation) study which compared ramipril to placebo, and included 692 patients with a serum potassium level >5.0 mM and 137 with a serum potassium level <3.5 mM, defined as hyper- and hypokalemia, respectively. Serum potassium was measured 1 month after start of randomized treatment., Results: With hyperkalemia, the primary event rate was unchanged compared to normokalemia (15.5 vs 15.7%, p > 0.4, respectively), with hypokalemia, the primary event rate was higher (22.6% vs 15.5%, respectively, p = 0.023). The hazard ratio for the primary outcome associated with this initial hypokalemia was 1.44 (1.00-2.06) on multivariate analysis. The combined primary outcome (myocardial infarction, cardiovascular death, stroke) was not different throughout deciles of serum potassium but the lowest and highest deciles included many with normokalemia. Randomized treatment was withheld because of hyperkalemia in 8 and 6 people allocated to ramipril and placebo, respectively. The benefit of ramipril on cardiovascular outcomes was independent of serum potassium, but ramipril reduced hypokalemia in the entire cohort (1.15 vs 1.86% with placebo, p = 0.005), particularly in those participants on diuretics (3.8% vs 6.5%, p = 0.07)., Conclusions: In patients at high cardiovascular risk, modest hypokalemia predicts a less favorable outcome while modest hyperkalemia does not. Ramipril reduces hypokalemia and decreases risk.

Background: Increased body mass index (BMI) and abdominal adiposity increase the risk of cardiovascular disease (CVD) in persons free of these diseases, but their independent prognostic impact in persons with CVD has not been well defined., Methods: BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were measured in 6620 men and 2182 women with a mean age of 66 and stable CVD without congestive heart failure (CHF) participating in the Heart Outcomes Prevention Evaluation (HOPE) study. The main outcomes were CVD death, myocardial infarction, stroke, hospitalization for CHF, and all-cause mortality., Results: During the 4.5-year follow-up, 658 had a CVD death, 1018 a myocardial infarction, 364 a stroke, 297 a CHF event, and 1034 died. When compared with the first tertile, the third tertile of BMI increased the adjusted relative risk (RR) of myocardial infarction by 20% (P < .02). Patients in the third tertile of WC had an increased adjusted RR of 23% for myocardial infarction (P < .01), 38% for heart failure (P < .03), and 17% for total mortality (P < .05). For WHR, there was an increased adjusted RR of 24% for CVD death (P < .03), 20% for myocardial infarction (P < .01), and 32% for total mortality (P < .001)., Conclusions: Obesity, particularly abdominal adiposity, worsens the prognosis of patients with CVD; weight reduction program should be integrated in the active management of these patients.

Background: Microalbuminuria predicts elevated cardiovascular risk in those with and without diabetes. In diabetes, microalbuminuria also heralds overt diabetic nephropathy. The predictive value of albuminuria below the microalbuminuria cutoff, and the development of overt nephropathy in nondiabetics with microalbuminuria, have not been well studied. We review findings of the HOPE Study., Methods: The HOPE Study database includes data on first morning urine albumin/creatinine ratio (ACR) in 9043 participants at baseline, and in 7674 participants at baseline and at last follow-up. Inclusion criteria were known vascular disease or diabetes, plus one other cardiovascular risk factor; exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (> 1+), and serum-creatinine > 2.3 mg/dL (200 micromol/L). Microalbuminuria was defined as an ACR > or = 2 mg/mmol., Results: Microalbuminuria at baseline approximately doubled the relative risk (RR) of the primary outcome (myocardial infarction, stroke, or CV death). For every 1 mg/mmol rise of ACR, even below the level of microalbuminuria, the adjusted hazard of the primary outcome increased by about 15%. Baseline microalbuminuria predicted subsequent clinical proteinuria, RR 17.5, similarly in participants without and with diabetes. New microalbuminuria developed in 1542 participants, and clinical proteinuria in 317., Conclusion: Albuminuria is a continuous risk factor for CV events even below the level of microalbuminuria. Microalbuminuria predicts clinical proteinuria in nondiabetics.

Background: Several interventional trials have shown a lower success rate for coronary angioplasty and lower long-term event-free survival in patients with renal insufficiency, and data are conflicting about restenosis after coronary angioplasty., Methods: This study included 4,131 consecutive patients with coronary artery disease treated with coronary angioplasty (23%) or stenting (77%). Renal insufficiency is defined as a creatinine clearance (CrCl) less than 60 mL/min (<1.0 mL/s). Of 4,131 patients, 1,412 patients (34.2%) had renal insufficiency and 2,719 patients (65.8%) did not have renal insufficiency. The primary end point of the study is clinical restenosis, defined as the need for target-lesion revascularization., Results: There was no difference in clinical restenosis rates between groups after 1 year (18.8% versus 18.4%; P = 0.75). The incidence of angiographic restenosis at the 6-month angiography was 32.7% in the group with renal insufficiency and 29.7% in the group without renal insufficiency ( P = 0.10). The composite end point of death and myocardial infarction was observed more frequently in patients with than without renal insufficiency (8.3% versus 3.2%; P < 0.001). Renal insufficiency was not independently associated with clinical restenosis (for 10-mL/min [0.167-mL/s]) decrease in CrCl, adjusted odds ratio, 1.03; 95% confidence interval [CI], 0.98 to 1.08; P = 0.198), but remained as an independent predictor for death or myocardial infarction (for 10-mL/min [0.167-mL/s] decrease in CrCl, hazard ratio, 1.29; 95% CI, 1.18 to 1.42; P < 0.001)., Conclusion: Patients with renal insufficiency do not show an increased incidence of restenosis after coronary revascularization.

We discuss the evidence supporting the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), or the combination of both in children with chronic renal disease. Several large-scale, prospective, randomized studies with clinical end points have been performed in adult patients, but studies in children are relatively scarce. In adult patients with chronic renal diseases, ACEI clearly delay the progression of chronic non-diabetic renal diseases, and nephropathy in patients with type 1 diabetes. The benefits of ACEI are most apparent in glomerular diseases with marked proteinuria but extend also to kidney diseases with lower proteinuria. This notion is also supported by several smaller or retrospective trials in children. Therefore, ACEI should be given to children with chronic renal diseases, particularly if high blood pressure and/or proteinuria are present. In adults, large-scale trials have documented that ARB exert similar effects as ACEI but tend to exert fewer undesired side effects. Data on ARB in children with chronic renal disease are still very scarce, but these substances offer an alternative for patients who cannot tolerate ACEI due to unwarranted side effects. Combination therapy with ARB plus ACEI may be more effective than either drug class alone. However, we will need the results of further long-term prospective clinical studies, as well as a better understanding of the role of the AT(2) receptor, before combination therapy can be widely recommended. A trial of ARB plus ACEI is justified in selected patients if blood pressure and/or proteinuria cannot adequately be lowered by ACEI or ARB alone.

Vaccine antigens administered by the oral route are often degraded by gastric secretions during gastrointestinal transit. This necessitates larger and more frequent doses of antigen for vaccination. A delivery system, which overcomes this, is a lipid vesicle containing bile salts (bilosome), which prevents antigen degradation and enhances mucosal penetration. The effect of bilosome formulation modification on vaccine transit efficacy across the mucosa was determined. Specific antibody levels were assessed by end-point titre ELISA and the subclasses determined. Significant IgG1 titres were induced when the protein loading was doubled from 15 to 30 microg (P=0.009) and was equivalent to antigen administration by the subcutaneous route. No IgG2a was induced, indicating the generation of a TH2 response. Significant mucosal IgA levels were also observed with this treatment group (P=0.05).

Background: A controlled trial reported cardiovascular benefits of vitamin E in terminal renal insufficiency. There are no data for renal insufficiency before the stage of terminal renal failure. We evaluated effects of vitamin E supplementation on cardiovascular and renal outcomes in 993 people with a serum creatinine > or =1.4 to 2.3 mg/dL., Methods: Post-hoc analysis of a randomized trial that compared treatment with natural source vitamin E (400 IU/day) to placebo in 9541 people, 993 of which had renal insufficiency. Participants had either known cardiovascular disease or diabetes and at least one additional coronary risk factor. Exclusion criteria included a serum creatinine > 2.3 mg/dL and dipstick-positive proteinuria. The primary study outcome after an average of 4.5 years was the composite of myocardial infarction, stroke, or cardiovascular death. Secondary outcomes included revascularizations, total mortality, and clinical proteinuria., Results: In renal insufficiency, vitamin E supplementation had a neutral effect on the primary study outcome, on each component of the composite primary outcome, and on all secondary outcomes. Two hundred twenty-four primary outcomes, 23% of the vitamin E group and 22.1% of the placebo group, relative risk 1.03 (95% CI, 0.79-1.34; P= 0.82), were observed, and 585 secondary outcomes, including death in 17% and 18.8% of the vitamin E and placebo groups, respectively (RR 0.88, 95% CI, 0.66-1.18; P= 0.40). There was no effect of vitamin E on progression of proteinuria., Conclusion: In people with mild-to-moderate renal insufficiency at high cardiovascular risk, vitamin E at a dose of 400 IU/day had no apparent effect on cardiovascular outcomes.

This review focuses on the association between mild renal insufficiency (stage 2 and 3 of chronic kidney disease) and cardiovascular disease and discusses therapeutic options. Although the association of chronic renal insufficiency and cardiovascular risk was first shown in patients with end-stage renal disease, even minor renal dysfunction is now established as an independent risk for atherosclerotic cardiovascular disease. The association has been established in patients with a high cardiovascular risk but also in the general population. Treatment with angiotensin-converting enzyme inhibitors and statins can reduce cardiovascular morbidity and mortality in patients with renal insufficiency. Coronary revascularization improves the prognosis in patients with minor renal dysfunction, but there is still an underutilization of coronary revascularization procedures in people with renal insufficiency. The use of coronary stenting has now reduced the incidence of restenosis in these patients, and there is hope that the development of new devices will improve the prognosis in patients with renal insufficiency as well. Nevertheless, people with cardiovascular disease and renal insufficiency die significantly more often than people without renal insufficiency independent of prior successful treatment. Further investigations should focus on the causes of and possible preventive interventions for the staggering cardiovascular risk in the ever-increasing number of people with minor renal dysfunction.

Objective: To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria., Design: Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years., Setting: Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries., Participants: 4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion > or = 20 mg/l in two consecutive samples), and serum creatinine < or = 150 micromol/l., Main Outcome Measures: The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure., Results: Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study., Conclusions: Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.

A modified GnRH peptide (CHWSYGLRPG-NH2) was conjugated to tetanus toxoid and formulated with different adjuvants (non-ionic surfactant vesicles, aluminium hydroxide, Quil A, PLGA (poly(lactide-co-glycolide)/triacetin), and Quil A/PLGA). A comparison of the anti-fertility efficacy of the formulations was made by examining specific antibody levels, antibody subclasses, endocrine ablation and gonadal atrophy. The production of IgG2b antibody provided the best correlation for castration. PLGA was considered the most effective adjuvant as it produced a consistent anti-fertility response in all the treated animals.

Patients with type 2 diabetes on dialysis are at a substantially increased risk of cardiovascular and cerebrovascular diseases. Dyslipidemia characterized by moderately elevated low-density lipoprotein cholesterol and high triglycerides and low high-density lipoprotein cholesterol levels is common in this population. We hypothesized that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors would reduce vascular morbidity and mortality in this patient group. The 'Deutsche Diabetes Dialyse Studie' (4D study) is a prospective, randomized, double-blind study involving 178 dialysis centers throughout Germany. Between March 1998 and October 2002, 1,255 patients were randomized to either atorvastatin 20 mg or placebo; 677 men and 578 women, aged 30-83 years, have been enrolled. The study will be terminated as soon as the predefined number of 424 patients with primary combined end points (i.e., cardiovascular death, nonfatal myocardial infarction, or fatal/nonfatal stroke) will have occurred. The total cohort had the following characteristics at baseline: the mean age was 65.7 years, 54% were men, 89% had a history of hypertension, 21% had coronary artery disease, 17.8% had a history of stroke or a transient ischemic attack, and 45% suffered from peripheral arterial disease. The mean time interval between the diagnosis of diabetes and the onset of dialysis was 17.4 years. On average, the patients were on hemodialysis for 8.3 months. Mean lipid and lipoprotein levels were: total cholesterol 219 +/- 43 mg/dl, low-density lipoprotein cholesterol 126 +/- 30 mg/dl, high-density lipoprotein cholesterol 36 +/- 13 mg/dl, and triglycerides 264 +/- 167 mg/dl. The results of the study will provide important information on the efficacy and safety of atorvastatin to support its use in patients with an impaired renal function who are at a high risk of vascular morbidity and mortality., (Copyright 2004 S. Karger AG, Basel)

Background: In patients with type 2 diabetes with overt nephropathy, the risk for progressive renal failure is high. This risk is less well established for those with type 2 diabetes and microalbuminuria or normalbuminuria. We studied changes in serum creatinine levels during 3.5 to 5.5 years in a large cohort of people with diabetes at high cardiovascular risk with microalbuminuria or normalbuminuria., Methods: Retrospective analysis of serum creatinine levels at baseline and yearly thereafter was performed in the Microalbuminuria and Renal Outcomes in the Heart Outcomes and Prevention Evaluation study comparing ramipril's effects with placebo during 4.5 years in 3,577 participants with diabetes, including 1,139 participants with microalbuminuria and 333 participants with renal insufficiency. Participants with dipstick-positive proteinuria (>1+) or serum creatinine levels greater than 2.3 mg/dL (200 micromol/L) were excluded., Results: Serum creatinine levels did not increase significantly during the study if all participants with diabetes are considered or for subgroups with microalbuminuria and/or renal insufficiency at baseline. However, slopes of serum creatinine over time showed a significant trend for increasing values. There were no differences between the placebo and ramipril-treated groups. A serum creatinine level of 1.4 mg/dL (125 micromol/L) or greater newly developed in 474 of 3,238 people (243 patients, placebo; 231 patients, ramipril; P = 0.5033). A doubling of baseline serum creatinine level or end-stage renal disease developed in 8 of 333 participants with renal insufficiency at baseline., Conclusion: In people with type 2 diabetes, but without overt nephropathy, who are at high risk for cardiovascular disease, progression of renal insufficiency is slow on the basis of changes in creatinine levels. On the basis of reaching threshold levels of renal function, progression rates are clinically meaningful, especially considering population life expectancy.

Purpose: Variation in the effects of selective estrogen receptor modulators (SERMs) on the estrous cycle and reproductive organs during aging could play an important role in the observed heterogeneity of tamoxifen chemoprevention efficacy against breast cancer., Methods: Of the 1,022 female Sprague Dawley rats enrolled in a long-term tamoxifen chemoprevention study, 87 were randomly chosen from four groups (irradiated, irradiated and tamoxifen treated, tamoxifen treated, and control). Vaginal smears were evaluated for determination of cycle stage, and vaginal pathologic changes. Correlation with the histologic features of reproductive tissues in 43 animals was made., Results: More tamoxifen-treated (21.9%; 7/32) rats had irregular cycling than did control (9%; 3/23) rats. Ovarian granulosa cell hyperplasia was present in 50% (3/6) of tamoxifen-treated rats, and 20% (2/10) of control rats. Endometrial-type cells (ETCs) were present only in tamoxifen-treated (tamoxifen alone 6.25% [2/32]) and tamoxifen/ radiation-treated (28.6% [4/14]) rats., Conclusion: The modified Papanicolaou stain used here provided excellent morphologic detail for evaluating the estrous cycle in rodents. Tamoxifen altered vaginal cytologic and ovarian histologic features during aging. Results indicated that tamoxifen had direct and indirect effects on the reproductive tract, causing disturbance of the estrous cycle, shedding of ETCs, and promoting granulosa cell hyperplasia. Understanding of the heterogeneous response to tamoxifen chemoprevention during aging in rodents may provide important insights into the basis for tamoxifen chemoprevention failures in humans.

We reviewed the evidence linking mild renal insufficiency (MRI) to an increased cardiovascular risk. A number of cardiovascular risk factors become prevalent with MRI, including night-time hypertension, increase in lipoprotein(a), in homocysteine, in asymmetric dimethyl-arginine (ADMA), markers and mediators of inflammation, and insulin resistance. Also, an epidemiologic association between coronary artery disease and nephrosclerosis, a frequent cause of mild renal insufficiency in the elderly, is documented. In the middle-aged, general population MRI, found in 8% of women and 9% of men, was not associated with cardiovascular disease. However, in a representative sample of middle-aged British men, the risk of stroke was 60% higher for the subgroup of people with MRI; in people at high cardiovascular risk (mostly coronary disease), the HOPE study found a 2-fold (unadjusted), or 1.4-fold (adjusted), higher incidence of cardiovascular outcomes with MRI. The incidence of primary outcome increased with the level of serum creatinine. Several studies determined the cardiovascular risk associated with MRI in hypertension. In HDFP, as in HOPE, cardiovascular mortality increased with higher serum creatinine (five-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). The risk associated with renal insufficiency was independent from other classic cardiovascular risk factors. In hypertensives with low risk, the HOT, and a small Italian trial found about a doubling in cardiovascular outcomes in MRI. However, in MRFIT, increase in follow-up creatinine predicted future cardiovascular disease, not baseline creatinine. These observational data suggest that MRI, independent of etiology, is a strong predictor of cardiovascular disease, present in 10% of a population at low risk, and up to 30% at high cardiovascular risk. No prospective therapeutic trials, aimed at reducing the cardiovascular burden in people with MRI, are available. Subgroup analyses of the HOPE study indicate that ACE inhibition with ramipril is beneficial without an increased risk for side effects like acute renal failure or hyperkalemia. Thus, the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since this identifies a group at high risk that appears to benefit most from treatment. In addition, there is evidence that ACE inhibitors improve renal outcomes in renal insufficiency. Prospective studies should test the predictive power of MRI for cardiovascular disease and therapeutic options.

In people with diabetes, renal disease tends to progress from microalbuminuria to clinical proteinuria to renal insufficiency. Little evidence has been published for the nondiabetic population. This study retrospectively analyzed changes of proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation) study, which compared ramipril's effects to placebo in 9297 participants, including 3577 with diabetes and 1956 with microalbuminuria. This report is restricted to 7674 participants with albuminuria data at baseline and at follow-up. Inclusion criteria were known vascular disease or diabetes plus one other cardiovascular risk factor, exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (>1+), and serum creatinine >2.3 mg/dl (200 microM). Baseline microalbuminuria predicted subsequent clinical proteinuria for the study participants overall (adjusted odds ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859 participants; 1542 developed new microalbuminuria, and 317 participants developed clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87; 95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at high risk for cardiovascular disease are also at risk for a progressive rise in albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic and in diabetic people. Ramipril prevents or delays the progression of albuminuria.

Background: Darbepoetin alfa is a glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine whether darbepoetin alfa is as effective and well tolerated as rHuEPO for treating renal anemia in dialysis patients when administered at a reduced dose frequency., Methods: A total of 522 European and Australian hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2 ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving rHuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and darbepoetin alfa were titrated to maintain hemoglobin close to the patient's baseline level for up to 52 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period at weeks 25 to 32 of treatment., Results: The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (-0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was 0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. At the end of the evaluation period, >/=95% of patients had their hemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected., Conclusions: Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a reduced dose frequency.

Objectives: Experimental and observational studies suggest that vitamin E may reduce the risk of cardiovascular (CV) events and of microvascular complications in people with diabetes. However, data from randomized clinical trials are limited. Therefore, we evaluated the effects of vitamin E supplementation on major CV outcomes and on the development of nephropathy in people with diabetes., Research Design and Methods: The Heart Outcomes Prevention Evaluation (HOPE) trial is a randomized clinical trial with a 2 x 2 factorial design, which evaluated the effects of vitamin E and of ramipril in patients at high risk for CV events. Patients were eligible for the study if they were 55 years or older and if they had CV disease or diabetes with at least one additional coronary risk factor. The study was designed to recruit a large number of people with diabetes, and the analyses of the effects of vitamin E in this group were preplanned. Patients were randomly allocated to daily treatment with 400 IU vitamin E and with 10 mg ramipril or their respective placebos and were followed for an average of 4.5 years. The primary study outcome was the composite of myocardial infarction, stroke, or CV death. Secondary outcomes included total mortality, hospitalizations for heart failure, hospitalizations for unstable angina, revascularizations, and overt nephropathy., Results: There were 3,654 people with diabetes. Vitamin E had a neutral effect on the primary study outcome (relative risk = 1.03, 95% CI 0.88-1.21; P = 0.70), on each component of the composite primary outcome, and on all predefined secondary outcomes., Conclusions: The daily administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and elderly people with diabetes and CV disease and/or additional coronary risk factor(s) has no effect on CV outcomes or nephropathy.

Patients with end-stage renal disease die from cardiovascular disease at a much younger age than people in the general population do. Here, we review the evidence linking early renal insufficiency (ERI) to an increased cardiovascular risk. A number of cardiovascular risk factors become prevalent with ERI, including night-time hypertension, increase in serum levels of lipoprotein (a), homocysteine and asymmetric dimethyl-arginine, and insulin resistance. Also, an epidemiologic association between coronary artery disease (CAD) and nephrosclerosis, a frequent cause of ERI in the elderly, is documented. In the middle-aged, general population ERI, found in 8% of women and 9% of men, was not associated with cardiovascular disease. However, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the subgroup of individuals with ERI. In people at high cardiovascular risk (mostly CAD), the Heart Outcomes Prevention Evaluation (HOPE) study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with ERI. The incidence of primary outcome increased with the level of serum creatinine. At least four studies have determined the cardiovascular risk associated with ERI in hypertension. In Hypertension Detection and Follow-up Program, as in HOPE, cardiovascular mortality increased with higher serum creatinine levels (5-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). In patients with hypertension with low risk, the Hypertension Optimal Treatment and a small Italian trial found about a doubling in cardiovascular outcomes in ERI. However, in the Multiple Risk Factor Intervention Trial, not baseline serum creatinine level, but its increase on follow-up predicted future cardiovascular disease. These observational data suggest that ERI, independent of etiology, is a strong predictor of cardiovascular disease, present in 10% of a population at low, and up to 30% at high, cardiovascular risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in individuals with ERI are available. Subgroup analyses of the HOPE study indicate that ACE inhibition with ramipril is beneficial without an increased risk of adverse effects like acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since this identifies a group at high risk who appears to benefit most from treatment. In addition, there is evidence that ACE inhibitors improve renal outcomes in renal insufficiency. Prospective studies should test the predictive power of ERI for cardiovascular disease and therapeutic options.

Conflicting data have been reported concerning the independent association between proteinuria and plasma total homocysteine (tHcy) levels, particularly among chronic renal disease (CRD) patients with a normal range serum creatinine. Studies of this potential relationship have been limited by failure to assess true GFR, failure to assess proteinuria in a quantitative manner, or arbitrary restriction of the range of proteinuria examined. We examined the potential independent relationship between plasma tHcy levels and a wide range of quantitatively determined proteinuria (i.e., 0.000-8.340 g/day), among 109 CRD patients with a normal range serum creatinine (range; 0.8-1.5 mg/dl; median=1.2 mg/dl). Glomerular filtration rate (GFR) was directly assessed by iohexol clearance, and plasma status of folate, pyridoxal 5'-phosphate, and B12, along with serum albumin, were also determined. Linear modeling with ANCOVA revealed that proteinuria was not independently associated with tHcy levels (partial R=0.127; P=0.201), after adjustment for potential confounding by GFR (partial R=0.408; P<0.001), age, sex, plasma B-vitamin status, and serum albumin. Moreover, descending across quartiles (Q) [from Q4 to Q1] of GFR, ANCOVA-adjusted (i.e., for age, sex, and folate status) geometric mean tHcy levels (micromol/l) were significantly increased: tHcy Q4 GFR=9.6; tHcy Q3 GFR=10.5; tHcy Q2 GFR=11.9; tHcy Q4 GFR=14.5; P<0.001 for overall Q difference. We conclude that across a broad spectrum of quantitatively determined proteinuria, after adjustment for true GFR, in particular, there is no independent relationship between proteinuria and tHcy levels among CRD patients with a normal range serum creatinine.

Background: Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect., Methods and Results: Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg. kg(-1). d(-1) or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects., Conclusions: Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.

Context: Microalbuminuria is a risk factor for cardiovascular (CV) events. The relationship between the degree of albuminuria and CV risk is unclear., Objectives: To estimate the risk of CV events in high-risk individuals with diabetes mellitus (DM) and without DM who have microalbuminuria and to determine whether levels of albuminuria below the microalbuminuria threshold increase CV risk., Design: The Heart Outcomes Prevention Evaluation study, a cohort study conducted between 1994 and 1999 with a median 4.5 years of follow-up., Setting: Community and academic practices in North and South America and Europe., Participants: Individuals aged 55 years or more with a history of CV disease (n = 5545) or DM and at least 1 CV risk factor (n = 3498) and a baseline urine albumin/creatinine ratio (ACR) measurement., Main Outcome Measures: Cardiovascular events (myocardial infarction, stroke, or CV death); all-cause death; and hospitalization for congestive heart failure., Results: Microalbuminuria was detected in 1140 (32.6%) of those with DM and 823 (14.8%) of those without DM at baseline. Microalbuminuria increased the adjusted relative risk (RR) of major CV events (RR, 1.83; 95% confidence interval [CI], 1.64-2.05), all-cause death (RR, 2.09; 95% CI, 1.84-2.38), and hospitalization for congestive heart failure (RR, 3.23; 95% CI, 2.54-4.10). Similar RRs were seen for participants with or without DM, even after adjusting for other CV risk factors (eg, the adjusted RR of the primary aggregate end point was 1.97 [95% CI, 1.68-2.31] in those with DM and 1.61 [95% CI, 1.36-1.90] in those without DM). Compared with the lowest quartile of ACR (<0.22 mg/mmol), the RRs of the primary aggregate end point in the second quartile (ie, ACR range, 0.22-0.57 mg/mmol) was 1.11 (95% CI, 0.95-1.30); third quartile, 1.38 (95% CI, 1.19-1.60; ACR range, 0.58-1.62 mg/mmol); and fourth quartile, 1.97 (95% CI, 1.73-2.25; ACR range, >1.62 mg/mmol) (P for trend <.001, even after excluding those with microalbuminuria). For every 0.4-mg/mmol increase in ACR level, the adjusted hazard of major CV events increased by 5.9% (95% CI, 4.9%-7.0%)., Conclusions: Our results indicate that any degree of albuminuria is a risk factor for CV events in individuals with or without DM; the risk increases with the ACR, starting well below the microalbuminuria cutoff. Screening for albuminuria identifies people at high risk for CV events.

Renal transplant recipients (RTR) are considered representative of patients with chronic renal insufficiency (CRI) in general with respect to both reduced, progressively declining renal function, and increased risk for cardiovascular disease (CVD). In accord with this argument, we hypothesized that total (t) plasma concentrations of the putatively atherothrombotic amino acid homocysteine (Hcy) would be equivalent in RTR and CRI patients with comparable renal function. We determined plasma tHcy, folate, pyridoxal 5'-phosphate, and B12 concentrations, in addition to serum creatinine and albumin concentrations, in 86 chronic, stable RTR, and 238 patients with CRI. Within comparable ranges of serum creatinine (i.e. RTR=0.6-4.2 mg/dl; CRI=0.7-4.1 mg/dl), tHcy concentrations did not differ between the two groups (RTR=15.0 micromol/l; CRI=14.9 micromol/l, P=0.899). ANCOVA revealed that renal function, gauged as a simple creatinine measurement, was the major independent determinant of plasma tHcy concentrations, accounting for approximately 80-90% of the total variability in tHcy predicted by the full model (i.e. full model R(2)) containing, in addition to creatinine, the seven other potential explanatory variables. If controlled trials confirm that tHcy-lowering treatment reduces CVD events rates in RTR, these results should be applicable to CRI patients in general.

Background: The cardiovascular risk associated with early renal insufficiency is unknown. Clinicians are often reluctant to use angiotensin-converting enzyme inhibitors in patients with renal insufficiency., Objective: To determine whether mild renal insufficiency increases cardiovascular risk and whether ramipril decreases that risk., Design: Post hoc analysis., Setting: The Heart Outcomes and Prevention Evaluation (HOPE) study, a randomized, double-blind, multinational trial involving 267 study centers., Patients: 980 patients with mild renal insufficiency (serum creatinine concentration >/= 124 micromol/L [>/=1.4 mg/dL]) and 8307 patients with normal renal function (serum creatinine concentration < 124 micromol/L [<1.4 mg/dL]) Patients with a baseline serum creatinine concentration greater than 200 micromol/L (2.3 mg/dL) were excluded., Measurements: The primary outcome measure was incidence of cardiovascular death, myocardial infarction, or stroke., Results: Cumulative incidence of the primary outcome was higher in patients with renal insufficiency than in those without (22.2% vs. 15.1%; P < 0.001) and increased with serum creatinine concentration. Patients with renal insufficiency had a substantially increased risk for cardiovascular death (11.4% vs. 6.6%) and total mortality (17.8% vs. 10.6%) (P < 0.001 for both comparisons). The effect of renal insufficiency on the primary outcome (adjusted hazard ratio, 1.40 [95% CI, 1.16 to 1.69]) was independent of known cardiovascular risks and treatment. Ramipril reduced the incidence of the primary outcome in patients with and those without renal insufficiency (hazard ratio, 0.80 vs. 0.79; P > 0.2 for the difference)., Conclusions: In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects.

Lemierre's syndrome, a systemic anaerobic infection caused by Fusobacterium necrophorum, is characterized by an acute oropharyngeal infection, septic thrombophlebitis of the internal jugular veins, sepsis, and multiple metastatic infections. It commonly leads to pulmonary parenchymal abscesses and occasionally to septic arthritis, osteomyelitis, or liver or spleen abscesses. Reported here is a case of spondylitis and pulmonary and gluteal abscesses that occurred as part of a classic presentation of Lemierre's syndrome. Treatment with imipenem and clindamycin was successful.

Background: We investigated whether monocyte chemoattractant protein-1 (MCP-1) is expressed in hypertensive nephrosclerosis, and tested the effect of angiotensin II type 1 receptor blockade on MCP-1 expression and macrophage (MPhi) infiltration., Methods: Rats with two-kidney, one-clip (2K1C) hypertension with and without treatment with the angiotensin II type 1 receptor antagonist valsartan (3 mg/kg/day) were studied. In these animals as well as in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), hypertensive mRen-2 transgenic rats (TGR), and respective control strains, MCP-1 expression in the kidney was investigated by Northern and Western blots and by immunohistochemistry. Glomerular and interstitial MPhis were counted., Results: In the nonclipped kidney of 2K1C rats, MCP-1 expression was elevated at 14 and 28 days when significant MPhi infiltration was present. MCP-1 was localized to glomerular endothelial and epithelial cells, interstitial and tubular cells, MPhis, and vascular smooth muscle cells. A similar pattern of MCP-1 staining was present in TGR kidneys, whereas MCP-1 expression was not increased in SHR and SHR-SP. Valsartan reduced but did not normalize blood pressure, blocked the induction of MCP-1 protein in 2K1C kidneys, and decreased interstitial MPhi infiltration significantly., Conclusion: MCP-1 expression is increased in angiotensin II-dependent models of hypertensive nephrosclerosis and is temporally and spatially related to MPhi infiltration. The angiotensin II type 1 receptor mediates the induction of MCP-1.

Objective: To describe the characteristics of diabetic and nondiabetic participants in the Heart Outcomes Prevention Evaluation (HOPE) Study who are at high risk of developing cardiovascular (CV) disease and who have microalbuminuria (MA), and to identify the key determinants of MA in these two groups., Research Design and Methods: Albuminuria was measured in 97% of patients enrolled in the HOPE Study as part of the MICRO-HOPE (MA, CV, and Renal Outcomes in HOPE) substudy. Baseline clinical characteristics of diabetic and nondiabetic participants with MA were recorded, and the univariate and multivariate relationship between these characteristics and the presence of MA was estimated for both groups., Results: Baseline urinary albumin determinations were available in 3,574 (97.8%) diabetic participants and 5,708 (97.0%) nondiabetic participants. MA was detected in 1,151 (32.2%) diabetic participants and 837 (14.7%) nondiabetic participants. Age, waist-to-hip ratio, diabetes, smoking, hypertension, vascular disease, and left ventricular hypertrophy were independent determinants of MA in all participants. In diabetic participants, the odds of MA increased 16% for every 10.4 years of diabetes duration, and increased 8% for every 0.9% increase in glycated hemoglobin (assuming a GHb assay with an upper limit of 6% in the nondiabetic range)., Conclusions: MA is independently associated with several risk factors for CV and renal disease in both diabetic and nondiabetic individuals at high risk for CV disease.

There is a clear relationship between anaemia and cardiovascular risk in chronic renal failure (CRF) patients. Left ventricular hypertrophy (LVH) is present in about three-quarters of patients starting dialysis, and is a strong predictor of mortality. Anaemia contributes to the development of LVH, mainly via increased cardiac output. In some patients, anaemia results in an increase in LV mass, while in others it also results in LV end-diastolic volume dilatation. These changes increase the risk of arrhythmias, myocardial infarction and myocardial fibrosis. The lower the haemoglobin, the more likely it is that LVH and heart failure will develop. Furthermore, a haemoglobin of < 11 g/dl is associated with increased morbidity and mortality. Partial correction of anaemia with epoetin leads to a partial, but not complete, reversal of LVH. One large prospective study (Lombardy Registry) found that epoetin treatment was accompanied by a 30% reduction in crude relative risk of mortality. A progressive reduction in the relative risk of general and cardiovascular mortality was found with increasing haematocrit, with and without adjustment for co-morbid conditions. Mean hospitalizations also decreased with increasing haematocrit. The long-term effects of normalized haematocrit/haemoglobin values in uraemic patients have not yet been evaluated exhaustively in prospective, randomized, multicentre studies. Epoetin treatment has been shown to induce lasting improvements in patients' sense of well-being, reduce fatigue, increase appetite and work capacity, and improve exercise tolerance, libido and work performance. Further studies are needed to demonstrate whether greater haemoglobin concentrations are associated with greater improvements in quality of life during epoetin treatment.

A protective effect of angiotensin-converting enzyme (ACE) inhibitors has been shown in patients with diabetic nephropathy but has not been clearly established in nondiabetic renal disease. A multicenter European study was designed to determine whether the ACE inhibitor benazepril was safe and effective in protecting residual renal function in patients with various renal diseases and mild to moderate renal failure. The trial involved 583 patients from 49 centers in Italy, France, and Germany. The patients were randomized to receive benazepril or placebo plus other antihypertensive agents, the target being a diastolic blood pressure of less than 90 mm Hg. Thirty-one patients in the benazepril group and 57 patients in the placebo group reached the end point [the time elapsed from entry to (a) doubling of serum creatinine (SCr) concentrations and (b) start of renal replacement therapy; p < 0.001 at 3 years]. The associated reduction in the relative risk of reaching the end point was 53% in benazepril-treated patients, with actuarial renal survival probability significantly better at 3 years. The best survival of renal function was observed in patients with chronic glomerular diseases and proteinuria greater than 1.0 g/24 h. Benazepril is effective in slowing the rate of progression and improving the survival of renal function in patients with renal diseases of various origins. This protective effect is associated with a clinically relevant decrease in both blood pressure and proteinuria.

Angiotensin (Ang) II type 1 (AT1) receptor antagonists are orally active drugs that specifically block the subtype 1 of Ang receptors. In contrast to AT1 receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors block the actions of Ang II incompletely. Furthermore, the bradykinin-potentiating effects of ACE inhibitors may contribute to the mechanism of action of ACE inhibitors. Data in experimental animals suggest that AT1 receptor antagonists decrease the glomerular filtration rate (GFR) to a lesser degree than ACE inhibitors. The greater effect of ACE inhibitors in decreasing glomerular pressure was attenuated with a bradykinin antagonist. In rat models of renal damage with proteinuria, acute reduction of proteinuria was seen with ACE inhibitors but not with AT1 receptor antagonists, whereas long-term reductions of proteinuria were of similar magnitude with both agents. Renal histology after several months revealed that AT1 receptor antagonists and ACE inhibitors were equally renoprotective in various renal damage models. AT1 receptor antagonists, like ACE inhibitors, exhibit a natriuretic effect equal to moderate doses of a thiazide diuretic. In patients with severe volume depletion, use of AT1 receptor antagonists may lead to acute renal failure. Valsartan was tested in a double-blind trial in patients with moderate to severe renal failure and led to a substantial decrease in diastolic and systolic blood pressure, whereas there was no difference from placebo for changes in GFR. Urine protein increased with placebo and decreased with valsartan. The data indicate that valsartan in renal failure patients is effective in lowering blood pressure while leaving renal excretory function unaltered. Whether there is a renoprotective effect can only be shown in long-term trials, which are under way.

1. Angiotensin (Ang) II modulates cardiovascular baroreflexes; whether or not the peptide influences chemosensitive cardiovascular reflexes is not known. We tested the hypothesis that Ang II modulates the reflex control of sympathetic nerve activity exerted by 5-hydroxytryptamine 3 (5HT3) cardiopulmonary receptors. 2. The 5HT3 receptor agonist phenylbiguanide (PBG), infused intravenously for 15 min, elicited a sustained reflex decrease of renal sympathetic nerve activity (RSNA) but only transient (<3 min) changes of arterial blood pressure (BP) and heart rate (HR) in methohexital-anaesthesized rats. 3. Infusion of Ang II at a dose that did not affect baseline BP, HR and RSNA enhanced the PBG-evoked reflex decrease of RSNA (-54+/-5% in Ang II treated versus -33+/-6% in control rats after 15 min PBG, P<0.05, n = 6 each) in methohexital-anaesthetized rats. 4. The angiotensin converting enzyme (ACE) inhibitor lisinopril blunted the reflex responses to PBG in anaesthetized as well as conscious animals. The effect of the ACE inhibitor was abolished by concomitant infusion of Ang II. 5. The reflex response to stimulation of cardiopulmonary 5HT3 afferents was also impaired by the Ang II type 1 receptor (AT1) blocker ZD7155 but not by the type 2 (AT2) blocker PD 123319. 6. Infusion of a volume load to stimulate cardiopulmonary baroreceptors induced a gradual decrease of RSNA which was impaired by exogenous Ang II (RSNA -26+/-6% in Ang II treated versus -47+/-6% in control rats after volume load, P<0.05, n = 6 each) but unaffected by ACE inhibition. 7. The reflex control of RSNA by cardiopulmonary 5HT3 receptors is enhanced by Ang II via AT1 receptors. Thus, Ang II facilitates a chemosensitive cardiovascular reflex, in contrast to its inhibitory influences on mechanosensitive reflexes.

A prospective, randomized, double-blind trial recently demonstrated that treating patients with chronic renal insufficiency with benazepril significantly decelerates the rate of progression of the disease. We tested the hypothesis that preventative treatment with the angiotensin converting enzyme (ACE) inhibitor benazepril in patients with chronic renal insufficiency is cost-effective. A Markov chain model was used that considered regular treatment, hemodialysis, continuous ambulant peritoneal dialysis, transplantation, rejection and death. Clinical trial data were used to estimate the effects of benazepril treatment and to estimate the duration until renal replacement therapy was needed. Epidemiologic parameters were derived on the basis of Dutch registries of renal diseases, costs are estimated by updating former estimates, literature review and expert opinion. We found that preventative treatment with benazepril decreased the percentage of patients who died or developed end-stage renal disease. Total costs per patient are expected to decrease in three years with more than $4,000 US per patient. Extrapolated to ten years, the savings are estimated at $23,500 US per patient. Benazepril treatment is not only an effective treatment in patients with chronic renal failure. By increasing the years spent without dialysis, it is also a cost-effective treatment.