Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study).

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression. STUDY DESIGN: Prospective, multicenter, open-label randomized controlled trial. SETTING AND PARTICIPANTS: One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73 m2 without previous cardiovascular events. INTERVENTION: Aspirin treatment (100 mg/day) (n = 50) or usual therapy (n = 61). Mean follow-up time was 64.8 ± 16.4 months. OUTCOMES: The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥ 50% decrease in eGFR, or renal replacement therapy), and bleeding episodes. RESULTS: During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146-1.076), p = 0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p = 0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077-0.955; p = 0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered. LIMITATIONS: Small sample size and open-label trial. CONCLUSIONS: Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.

The effect of some medications given to CKD patients on vitamin D levels.

BACKGROUND: Vitamin D deficiency and polypharmacy is a common problem over chronic kidney disease (CKD) population. OBJECTIVES: To assess the clinical and analytical characteristics of CKD patients with 25-OH-D3 deficiency (<15 ng/mL), including the possible role of associated drugs. METHODS: A single center observational review of 137 incident patients referred to our outpatient clinic with different stages of CKD and 25-OH-D3<15ng/mL (male gender 53.3%, mean age 70.8 [±16.1] years, mean GFR (MDRD-4) 43.6 [±25.5] ml/min/1.73 m²). 25-OH-D3 levels were collected in spring. Clinical and biochemical data and associated medications were recorded. RESULTS: Mean 25-OH-D3 levels were 8.23 [±4.03] ng/ml. Eighty-eight patients (64.7%) had 3 or more concomitant drugs. Only 7 patients (5.1%) were not receiving any medication. Patients were divided in three groups according the therapies into none (n=26), RAS inhibitors or allopurinol (n=81), and RAS inhibitors plus allopurinol (n=30); with the aim to study the influence of statin therapy. Patients under renin angiotensin (RAS) inhibitors or Allopurinol treatment presented significantly higher 25-OH-D3 levels (p=0.001 and p=0.01 respectively), however patients with Statins treatment had lower 25-OH-D3 level (p=0.039). Personal history of diabetes, cardiovascular events or other therapies did not modify 25-OH-D3 levels, adjusted by age and eGFR. CONCLUSIONS: CKD patients with vitamin D deficiency who received RAS inhibitors or Allopurinol treatment had higher 25-OH-D3 levels, however those with statins treatment had lower vitamin D levels. Randomized controlled trials are required to confirm these findings.

25 (OH) vitamin D levels and renal disease progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system.

BACKGROUND AND OBJECTIVES: Experimental studies show that 25 (OH) vitamin D is a suppressor of renin biosynthesis and that vitamin D deficiency has been associated with CKD progression. Patients with type II diabetes and CKD have an exceptionally high rate of severe 25 (OH) vitamin D deficiency; however, it is not known whether this deficiency is a risk factor for progression of diabetic nephropathy. This study aimed to investigate whether there is an association of 25 (OH) vitamin D deficiency with disease progression in type II diabetic nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 25 (OH) vitamin D levels were measured at baseline and 4 and 12 months in 103 patients included in a multicenter randomized controlled trial to compare the efficacy of combining an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker with the efficacy of each drug in monotherapy to slow progression of established diabetic nephropathy during 2006-2011. The primary composite endpoint was a >50% increase in baseline serum creatinine, ESRD, or death. All study participants were included in the analysis. RESULTS: Fifty-three patients (51.5%) had 25 (OH) vitamin D deficiency (<15 ng/ml). After a median follow-up of 32 months, the endpoint was reached by 23 patients with deficiency (43.4%) and 8 patients without (16%). Multivariate Cox regression analysis adjusted for urinary protein/creatinine ratio, estimated GFR, and baseline aldosterone showed that 25 (OH) vitamin D deficiency was associated with the primary endpoint (hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67; P=0.04). CONCLUSIONS: These results show that 25 (OH) vitamin D deficiency is independently associated with a higher risk of the composite outcome in patients with type II diabetic nephropathy.

Effect of dual blockade of the renin-angiotensin system on the progression of type 2 diabetic nephropathy: a randomized trial.

BACKGROUND: Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers has been shown to lessen the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy. STUDY DESIGN: A multicenter open-label randomized controlled trial to compare the efficacy of combining the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker irbesartan with that of each drug in monotherapy (at both high and equipotent doses) in slowing the progression of type 2 diabetic nephropathy. SETTING & POPULATION: 133 patients with type 2 diabetic nephropathy (age, 66 ± 8 years; 76% men) from 17 centers in Spain. INTERVENTION: Patients were randomly assigned (1:1:2) to lisinopril (n = 35), irbesartan (n = 28), or the combination of both (n = 70). OUTCOMES: The primary composite outcome was a >50% increase in baseline serum creatinine level, end-stage renal disease, or death. RESULTS: Baseline values for mean estimated glomerular filtration rate and blood pressure were 49 ± 21 mL/min/1.73 m(2) and 153 ± 19/81 ± 11 mm Hg. Mean geometric baseline proteinuria was protein excretion of 1.32 (95% CI, 1.10-1.62) g/g creatinine. After a median follow-up of 32 months, 21 (30%) patients in the combination group, 10 (29%) in the lisinopril group, and 8 (29%) in the irbesartan group reached the primary outcome. HRs were 0.96 (95% CI, 0.44-2.05; P = 0.9) and 0.90 (95% CI, 0.39-2.02; P = 0.8) for the combination versus the lisinopril and irbesartan groups, respectively. There were no significant differences in proteinuria reduction or blood pressure control between groups. The number of adverse events, including hyperkalemia, was similar in all 3 groups. LIMITATIONS: The study was not double blind. The sample size studied was small. CONCLUSIONS: We were unable to show a benefit of the combination of lisinopril and irbesartan compared to either agent alone at optimal high doses on the risk of progression of type 2 diabetic nephropathy.

Utility of bioimpedance spectroscopy (BIS) in the management of refractory hypertension in patients with chronic kidney disease (CKD).

BACKGROUND: Expansion of extracellular volume (ECV) is a frequent cause of resistant hypertension (RHT) in patients with chronic kidney disease (CKD). The aim of this exploratory study was that of applying bioimpedance spectroscopy (BIS) for the identification of CKD patients with RHT and expansion of ECV, while trying to control blood pressure (BP) using an intensification of diuretic treatment. METHODS: We included 50 patients with RHT and CKD who underwent BIS. In order to control BP, diuretic treatment was intensified in those patients with expansion of the ECV. In all other cases, another antihypertensive drug was added. RESULTS: The mean age was 68.2 ± 10.4 years, 68% were male and 58% were diabetic. The mean estimated glomerular filtration rate (eGFR) was 50.7 ± 22.4 mL/min/1.72 m(2). Baseline systolic BP was 167.2 ± 8.6 mmHg and diastolic BP was 84.8 ± 9.5 mmHg. The mean number of antihypertensive drugs received was 3.8 ± 0.9. Expansion of ECV was recorded in 30 (60%) patients and was more frequent in diabetics and in patients with more albuminuria. At 6 months of follow-up, a decline of 21.4 ± 7.1 mmHg was observed in systolic BP in the patients with expansion of ECV, compared with a decrease of 9.4 ± 3.4 mmHg in the normal ECV group (P < 0.01). We did not find differences in the decrease in diastolic BP between the groups. Nine patients (30%) with ECV expansion who increased diuretic therapy reached the target blood pressure (BP) of <140/90 mmHg, when compared with only two patients (10%) who had normal ECV and in whom other antihypertensive drug was added. A total decrease in body water of 1.9 ± 1.1 L was observed in patients with ECV expansion who intensified diuretic treatment at the expense of a decline in ECV of 1.1 ± 1 L. eGFR remained stable in both groups (47.1 ± 21.1 versus 54.1 ± 25.2 mL/min/1.73 m(2); P = 0.37). CONCLUSIONS: An increase in ECV as measured by BIS frequently occurs in RHT in patients with CKD. Diabetic and severe proteinuric patients are more exposed to expansion of ECV. BIS is a potentially useful method for identifying and treating patients with RHT and expansion of ECV. The hypothesis generated by this exploratory study needs to be tested in a randomized clinical trial.

Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.

BACKGROUND AND OBJECTIVES: Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. RESULTS: Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. CONCLUSIONS: Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.

Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease.

Patients with chronic kidney disease (CKD) show a high cardiovascular morbidity and mortality. This seems to be consequence of the cardiovascular risk factor clustering in CKD patients. Non traditional risk factors such as oxidative stress and inflammation are also far more prevalent in this population than in normal subjects. Renal disease is associated with a graded increase in oxidative stress markers even in early CKD. This could be consequence of an increase in reactive oxygen species as well as a decrease in antioxidant defence. This oxidative stress can accelerate renal injury progression. Inflammatory markers such as C reactive protein and cytokines increase with renal function deterioration suggesting that CKD is a low-grade inflammatory process. In fact, inflammation facilitates renal function deterioration. Several factors can be involved in triggering the inflammatory process including oxidative stress. Statin administration is accompanied by risk reduction in all major vascular events in patients with CKD that are considered high-risk patients. These beneficial effects seem to be consequence of not only their hypolipidemic effect but especially their pleitropic actions that involve modulation of oxidative stress and inflammation.

Serum fibrinogen levels are an independent predictor of mortality in patients with chronic kidney disease (CKD) stages 3 and 4.

Patients with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown. Several studies in hemodialysis patients have demonstrated that inflammatory markers are potent predictors of mortality, however there are scarce data about stable patients with moderate chronic kidney disease. 128 outpatients with estimated glomerular filtration of less than 60 ml/min per 1.73 m(2) were included in the study. Medical records about cardiovascular factors were recorded. Analytical parameters and inflammation markers were determined in baseline period. Participants were initially recruited from January 2002 to May 2002. The average length of follow-up in this longitudinal study was 5.5 years. Mortality and non-fatal cardiovascular events were the end points. Median follow-up was 67.8 months, all cause of mortality was 22.7%/(n=29) and non-fatal cardiovascular events were 39.1% (n=50). In multivariate analysis adjusting for demographic, cardiovascular and kidney disease factors, age hazard ratio (HR): 1.01, interval confidence (IC): 1.00-1.10), previous congestive heart failure (HR: 3.50, IC: 1.10-11.17) and both high CRP (HR: 3.48, IC: 1.53-7.59) and serum fibrinogen (HR: 1.45, IC: 1.04-1.50) were independent predictors of all-cause of mortality. Age (HR: 1.06, IC: 1.01-1.11), high CRP (HR: 2.80, IC: 1.60-4.90), cardiac troponin T (HR: 1.21, IC: 1.04-1.40) and previous coronary disease (HR: 2.67, IC: 1.28-5.54) but not serum fibrinogen were independent predictors of non-fatal cardiovascular events. Both high CRP and high serum fibrinogen levels and previous congestive heart failure measured in CKD stages 3 and 4, are independent risk factors for all-cause of mortality. High CRP but not high serum fibrinogen is a risk factor for non-fatal cardiovascular events. These results suggest that high CRP and high serum fibrinogen provide prognostic information in CKD patients.

Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins.

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.

Oxidative stress in uremia: the role of anemia correction.

Patients with chronic kidney disease (CKD) are prone to develop cardiovascular disorders. Numerous reports have shown the association between uremia and oxidative stress, which increases patients' risk for cumulative injury to multiple organs. Anemia is a common and disabling feature of CKD and seems to be a main cause of oxidative stress; correction of anemia represents an effective approach to reduce oxidative stress and, consequently, cardiovascular risk. There is increasing evidence that correction of anemia with erythropoiesis-stimulating agents could protect from oxidative stress in patients with CKD and ESRD. However, iron deficiency frequently complicates anemia in patients with CKD, and ferrous iron cation is a co-factor that is needed for hydroxyl radical production, which can promote cytotoxicity and tissue injury. This has raised a justifiable concern that prescription of intravenous iron may exacerbate oxidative stress and, hence, endothelial dysfunction, inflammation, and progression of cardiovascular disease, which are widely known consequences of CKD. Correction of anemia represents an effective approach to reduce oxidative stress and, consequently, cardiovascular risk. Iron deficiency is a common cause of resistance to erythropoiesis-stimulating agents, and the overall risk-benefit ratio favors use of intravenous iron to treat iron deficiency in patients with CKD. Consecutive or combined treatment with intravenous iron and erythropoiesis-stimulating agents clearly is beneficial for patients with CKD and iron deficiency, and anemia and could contribute to prevent the risk for cardiovascular events in these patients.

Insulin resistance, inflammatory biomarkers, and adipokines in patients with chronic kidney disease: effects of angiotensin II blockade.

Patients with chronic kidney disease (CKD) present a high prevalence of insulin resistance (IR). Some studies suggest that angiotensin II may influence some cellular pathways that contribute to the pathogenesis of IR and stimulate the release of proinflammatory cytokines. Fifty-two patients who had stages 3 and 4 CKD and no diabetes were administered an angiotensin receptor blocker (ARB), olmesartan (40 mg), for 16 wk. Before and after ARB treatment, metabolic and inflammatory parameters and adipokines were measured. IR was calculated by Homeostasis Model Assessment (HOMA) index. Baseline data were compared with data that were obtained from 25 healthy control individuals of similar age and normal renal function. Compared with control subjects, patients with CKD presented significantly higher BP and waist circumference, higher triglycerides and lower HDL levels, higher insulin levels, and higher mean HOMA index (6.0 +/- 2.7 versus 2.9 +/- 2.2 muU/ml x mmol/L; P < 0.001). In addition, patients with CKD had increased levels of high-sensitivity C-reactive protein, TNF-alpha, and IL-6. In patients with CKD, leptin was positively correlated to abdominal obesity, insulin levels, and IL-6, and adiponectin was inversely correlated to abdominal obesity and insulin levels. Olmesartan treatment resulted in a significant decrease of BP, urinary protein excretion, plasma glucose (99 +/- 16 versus 92 +/- 14 mg/dl; P < 0.05), insulin (23.1 +/- 8.8 versus 19.9 +/- 9; P < 0.05), HOMA index (6.0 +/- 2.7 versus 4.7 +/- 2.8; P < 0.05), and glycated hemoglobin (5.33 +/- 0.58 versus 4.85 +/- 0.81%; P < 0.01). At the same time, there was a significant reduction of high-sensitivity C-reactive protein levels, from 4.45 mg/L (2.45 to 9.00) to 3.55 mg/L (1.80 to 5.40; P < 0.05) and fibrinogen (412 +/- 100 versus 370 +/- 105 mg/dl; P < 0.05). There were no significant differences in adipokine levels after olmesartan treatment. These data demonstrate that patients with CKD have a high prevalence of IR, metabolic syndrome, and chronic inflammation and that the administration of the ARB olmesartan improves IR and inflammation markers in these patients. Plasma adipokine levels that are related to several metabolic risk factors in patients with CKD were not modified by ARB therapy.

Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease.

Although substantial evidence suggests that treatment of dyslipidemia with statins reduces mortality and morbidity that are associated with cardiovascular disease, only a few studies have examined the efficacy of statins on inflammatory and fibrinolytic status in patients with chronic kidney disease (CKD). A 6-mo, prospective, randomized study was designed to assess the efficacy of atorvastatin in reducing circulating inflammatory and fibrinolytic parameters in patients with CKD. Sixty-six patients with CKD (stages 2, 3, and 4) and LDL cholesterol levels > or =100 mg/dl were randomly assigned (2:1) to receive 20 mg/d atorvastatin (n = 44) or nonatorvastatin therapy (n = 22). Lipid profile, renal function, fibrinolytic balance (tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1), and inflammatory markers (C-reactive protein [CRP], IL-1 beta, IL-6, and TNF-alpha) were measured before and 6 mo after atorvastatin was added to the treatment. Twenty-five age-matched individuals with normal renal function (estimated GFR >90 ml/min) were used as healthy control subjects. Patients with CKD had higher CRP, IL-1 beta, TNF-alpha, and IL-6 levels than age-matched population with normal renal function. t-PA concentration was higher in patients with CKD (P = 0.000). Plasminogen activator inhibitor-1 values were comparable in all patients. Total cholesterol and LDL cholesterol were significantly reduced only in patients who received atorvastatin. In addition to the hypolipidemic effect, atorvastatin treatment significantly reduced inflammatory parameters: CRP (median 4.1 to 2.9; P = 0.015), TNF-alpha (6.0 +/- 2.7 to 4.7 +/- 2.4; P = 0.046), and IL-1 beta levels (1.9 +/- 0.7 to 1.2 +/- 0.7; P = 0.001). These parameters remained unchanged in patients who were not treated with atorvastatin. Fibrinolytic parameters were not modified by atorvastatin treatment. Patients with CKD showed higher levels of inflammatory parameters and t-PA levels than age-matched healthy control subjects. Atorvastatin treatment, in addition to its beneficial effect on cholesterol levels, improved the inflammatory state of these patients without modifying fibrinolytic balance.

Dual blockade of the renin-angiotensin system in the progression of renal disease: the need for more clinical trials.

There is clear evidence that pharmacologic blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows the progression of renal disease in diabetic and nondiabetic nephropathies, a beneficial effect that is not related to BP control. Some patients exhibit a significant beneficial response, whereas others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove useful. ARB produces a complete blockade of the RAS. Several studies have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone. A recent study also demonstrated that this more marked antiproteinuric effect is associated with less progression of renal disease in primary nondiabetic nephropathies despite a similar effect on BP. Until now, there has not been any reference to a beneficial effect on progression of the dual blockade in type 2 diabetic nephropathy, which is the most frequent cause of ESRD. A multicenter, prospective, open, active-controlled, and parallel-group trial was designed to compare the effects of an ACE inhibitor versus an ARB or its combination on renal disease progression, proteinuria, and cardiovascular events in type 2 diabetic nephropathy.

Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin <10 g/dL.

BACKGROUND: Left ventricular hypertrophy (LVH) frequently complicates chronic renal insufficiency. Anemia is also common in these patients and may contribute to LVH. METHODS: We conducted an open-label interventional trial to evaluate the effect of recombinant erythropoietin (rhEPO) on left ventricular mass index (LVMI) in anemic patients with renal insufficiency. Adults with creatinine clearance 10 to 30 mL/min (nondiabetics) or 20 to 40 mL/min (diabetics) were recruited, and rhEPO was given to those with anemia (hemoglobin level <10 g/dL). Baseline and 6-month LVMI and LVH (LVMI >130 g/m(2) in men and >100 g/m(2) in women), hemoglobin levels, creatinine clearance, blood pressure, medications, and medical history were obtained. Forty anemic and 61 nonanemic control subjects were enrolled. RESULTS: Overall, the prevalence of LVH was 68.3% (95% CI 58.3-77.2), and entry hemoglobin level was the only significant predictor of baseline LVH (adjusted OR 0.69 per g/dL increase in hemoglobin, 95% CI 0.50-0.94). After 6 months, LVMI decreased in anemic patients receiving rhEPO (142 +/- 56 vs. 157 +/- 56 g/m(2)) (P= 0.007), with an increase in hemoglobin (11.3 +/- 1.9 vs. 9.1 +/- 0.7 g/dL) (P= 0.001). There were no changes in LVMI or hemoglobin level among controls. After adjusting for confounders and change in hemoglobin, receipt of rhEPO was associated with a significant reduction in LVMI (P= 0.01). CONCLUSION: Treatment with rhEPO was not independently associated with significant changes in blood pressure or renal function. LVH is a common finding in chronic renal insufficiency and is associated with lower hemoglobin levels. Treatment with rhEPO may decrease LVH in patients with severe renal insufficiency and anemia.

The reno-protective effect of the dual blockade of the renin angiotensin system (RAS).

Hypertension and proteinuria are risk factors for renal disease progression. There is clear evidence that pharmacological blockade of the RAS with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows down the progression of renal disease in diabetic and non diabetic nephropathies, a beneficial effect not related to blood pressure control. However, not all patients respond similarly to these treatments. Some patients exhibit a significant beneficial response while others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI, which are unable to block completely the formation of AII, some generation of AII is produced via other non ACE pathways. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove to be useful. ARB produces a complete blockade of the RAS and stimulates the vasodilating and non-proliferative actions of AII via the AT-2 receptor. Furthermore, ACE inhibitors but not ARB; inhibit the metabolism of kinins, which increases the level of bradykinin, a potent vasodilator. Recently, several authors have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone in spite of a similar effect on blood pressure. A recent study also has demonstrated that this more marked antiproteinuric effect is associated with a less progression of renal disease in primary, non diabetic nephropathies. Furthermore, at least two studies have shown that, treatment with ARB postpones end-stage renal disease and reduces the rate of decline in renal function in patients with type 2 diabetes and nephropathy, but until now, there is not any clear evidence of a superior beneficial effect of dual blockade versus maximal recommended dose of ARB regarding renal progression in type 2 diabetic nephropathy, which is the most frequent cause of end stage renal disease. Long-term clinical trials are needed and encouraged to further establish the significant role of dual blockade in renal protection particularly in diabetic nephropathy.

Efficacy of moxonidine in the treatment of hypertension in obese, noncontrolled hypertensive patients.

BACKGROUND: Obesity has become an epidemic problem, contributing to metabolic syndrome, type 2 diabetes, hypertension, and cardiovascular disease. An adequate blood pressure control in this population of obese individuals is extremely difficult to achieve, and in most cases, therapeutic combinations are required. Pharmacologic treatment with moxonidine, a central I(1) imidazole receptor agonist, is a very interesting option because it acts upon the mechanisms implicated in the development of arterial hypertension in these patients. In addition, the drug improves the peripheral insulin resistance often found in obese patents, which contributes to maintain high blood pressure. METHODS: An interventional study has been designed, adding moxonidine to noncontrolled hypertensive, obese subjects in whom a hypocaloric diet was previously recommended. A total of 25 primary care centers participated in the study, with a total of 135 patients recruited. RESULTS: One hundred twelve patients were included in the study; 25 of them had type 2 diabetes. The mean reduction in systolic and diastolic blood pressure after 6 months treatment with moxonidine was 23.0 and 12.9 mm Hg, respectively. The mean systolic and diastolic pressures were 158.5 +/- 10.6 and 95.1 +/- 9 mm Hg, respectively, at baseline, versus 135.5 +/- 11.6 and 82.2 +/- 5.8 mm Hg at the end of the study. Creatinine clearance was significantly decreased in hyperfiltrating obese patients (143.6 +/- 31 vs. 128.2 +/- 27.9, P < 0.0001), without any significant change in patients with normal or slightly decreased renal function (81.9 +/- 18.9 vs. 80.9 +/- 17.5). Only 8 mild adverse reactions in 7 patients were recorded during the study. CONCLUSION: Moxonidine is useful and safe for controlling arterial hypertension in obese patients.

Predictive cardiovascular risk factors in patients with chronic kidney disease (CKD).

BACKGROUND: Traditional cardiovascular risk factors and uremia-related specific factors have been identified in patients with CKD, explaining the highest risk for morbidity and mortality from cardiovascular disease. The aim of this study was to analyze the predictive power of several cardiovascular risk factors and markers in a population of stable patients with moderate CKD. METHODS: One hundred twenty-eight (78 M, 50 F) outpatients with estimated glomerular filtration rate (GFR) <60 mL/min were included in the study. Medical records about cardiovascular factors were recorded. Analytical parameters and cardiac markers were analyzed. The patients were prospectively followed, and the end points were fatal and nonfatal cardiovascular events. RESULTS: After a mean follow-up of 22.3 months, 27 patients had a cardiovascular event. The patients who suffered a cardiovascular event were older (P= 0.002), with more anemia (P= 0.014), higher pulse pressure (P= 0.011), and cTnT levels (P= 0.000). In addition, they had more prevalence of LVH (P= 0.001), diabetes (P= 0.013), previous coronary heart disease (P= 0.008), chronic heart failure (P= 0.000), vascular peripheral disease (P= 0.006), and had also a higher score of 10-year coronary heart disease predicted risk (P= 0.006). Age [hazard ratio (HR) 1.07, P= 0.02], previous coronary artery disease (HR 4.08, P= 0.0012), and cTnT levels (HR 1.64, P= 0.0000) independently predicted cardiovascular events on multivariate Cox analysis. CONCLUSION: In stable patients with CKD, age and previous coronary artery disease were the traditional cardiovascular risk factors more predictive for cardiovascular events. Cardiac troponin T is a powerful marker of cardiovascular events in CKD patients.

Subclinical peripheral arterial disease in patients with chronic kidney disease: prevalence and related risk factors.

BACKGROUND: Atherosclerotic artery disease is a common condition in patients with chronic kidney disease (CKD); however, there are few published data on the prevalence of peripheral arterial disease (PAD) in nondialyzed patients with renal insufficiency. The ankle-brachial index (ABI) is a simple, noninvasive, and reliable method to assess PAD. METHODS AND RESULTS: Prevalence of PAD using ABI was investigated in 102 patients referred for the first time to a nephrology clinic with CKD in stages 3 to 5 of the K/DOQI classification, and with no previous diagnosis of PAD. Patients with ABI <0.9 were considered positive for PAD. A total of 64% of the patients were male. The mean age was 70 +/- 11 (range 58-84) years, and the estimated creatinine clearance (CrCl) was 35 +/- 12 (range 6-59) mL/min(-1). Of the total sample, 26% were diabetics, 10% active smokers, 48% ex-smokers, and 29% had a diagnosis of coronary heart disease (CHD), 15% had been previously diagnosed of stroke, and 17% had signs and symptoms compatible with intermittent claudication, which had passed unnoticed. Thirty-two percent of patients had an ABI <0.9 (mean 0.64 +/- 0.25). Of these patients with PAD, 84% were men (P < 0.005), and only 30% presented a clinical picture compatible with intermittent claudication. Absolute risk of CHD according to the Framingham 1998 score was higher in the PAD group (19.3% +/- 6 vs. 13.1% +/- 8; P= 0.01). Patients with PAD were older (75 +/- 6 vs. 66 +/- 11 years, P= 0.000), and had worse renal function (CrCl 30.8 +/- 12 vs. 37 +/- 10.7 mL.min(-1), P= 0.016) compared to patients without PAD, but no differences were found in cholesterol levels (total, HDL, LDL), calcium, phosphorus, or PTH. In the logistic regression analysis, independent indicators of PAD risk were male sex, age, and lower CrCl. Twelve percent of patients had an ABI > or =1.3, suggestive of parietal arterial calcifications. In these patients, systolic blood pressure and pulse pressure were lower (126 +/- 18 vs. 150 +/- 27, P= 0.005, and 52 +/- 13 vs. 68 +/- 25 mm Hg, P= 0.044), i-PTH levels were higher (228 +/- 267 vs. 117 +/- 63 pg/mL, P= 0.01), and a larger proportion of this group was treated with calcitriol (34% vs. 13%) compared to patients with a normal ABI. CONCLUSION: A high prevalence of PAD, considered as an ABI <0.9, was demonstrated in nondialyzed patients with CKD. This was related with age, male sex, and higher degree of renal insufficiency, while the presence of ABI > or =1.3 was associated with a greater degree of hyperparathyroidism. These data show the need to carry out routine ABI determinations in patients with CKD for early detection of peripheral arterial disease.

Angiotensin II type 1 receptor blockade to control blood pressure in postmenopausal women: influence of hormone replacement therapy.

BACKGROUND: Hypertension is twice as common in postmenopausal than in premenopausal women. This study evaluated the effectiveness of a blockade of the renin-angiotensin-aldosterone system (RAAS) with candesartan cilexetil (CC) to control blood pressure (BP) in hypertensive menopausal women, and the influence of hormone replacement therapy (HRT). METHODS: This was designed as a prospective, open-label and non-comparative study. Included were 618 hypertensive menopausal women grade I/II according to the Sixth Report of the Joint National Committee (VI-JNC), with an average age 52+/-4.7 years (95% CI 52.3-53.0) and with a last menstrual period (LMP) at least one year before. BP was determined by measurement in four visits during six months of follow-up, according to the recommendations of the OMS/SIH. Optimal control of BP was considered as BP <140/90 mm Hg. RESULTS: A statistically significant decrease in systolic (SBP; 19.9+/-11.2) and diastolic (DBP; 11.5+/-7.3) blood pressure mm Hg values was observed (P<0.01). The control of BP increased significantly over time to 61.2% (P<0.01). In multivariate analysis, only age was associated with control of BP (beta= -0.062; P=0.004). Of the women not controlled in the second visit, 12.5 mg of hydrochlorothiazide (HCTZ) were added to 31.5% (N=122), with 80% more BP control achieved in visit 3 than in the non-supplement group (OR=1.8; 95% CI 1.04-3.05; P<0.03). One hundred and three (16.7%) patients were receiving HRT for 2.01+/-2.23 years (95% CI 1.55-2.46). HRT did not affect the control of BP. No severe adverse reactions were reported. CONCLUSIONS: Candesartan cilexetil significantly reduced SBP and DBP and increased control (61.2%) of BP in hypertensive menopausal women. Only age had an inverse association with control of BP. In this study, HRT did not affect the control of BP.