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.

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.

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.

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.