The Cardioprotective Effects of the Angiotensin-Converting Enzyme Inhibitor Perindopril in Patients With Stable Coronary Artery Disease Are Not Modified by Mild to Moderate Renal Insufficiency: ...Insights From the EUROPA Trial Jasper J. Brugts, Eric Boersma, Michel Chonchol, Jaap W. Deckers, Michel Bertrand, Willem J. Remme, Roberto Ferrari, Kim Fox, Maarten L. Simoons, on behalf of the EUROPA Investigators In light of the growing interest in tailored therapy and recent remarks of the PEACE (Prevention of Events With ACE Inhibition) trial on heterogeneity in the treatment effect of trandolapril in relation to renal function, identification of specific patients who benefit more from angiotensin-converting enzyme inhibition therapy is important. The level of renal function is a potential target for this purpose. We examined whether the treatment effect of perindopril is modified by renal function in 12,056 patients with stable coronary artery disease. The treatment effect of perindopril was consistent and not modified by mild to moderate renal insufficiency. Renal function does not identify specific patients more likely to benefit from angiotensin-converting enzyme inhibition.
Background Data regarding the effect of a solitary kidney during pregnancy have come from studies of living kidney donors. We evaluated the risk for adverse pregnancy outcomes in women with a single ...kidney from renal agenesis. Study Design Matched cohort study. Setting & Participants Using data from 7,079 childbirths from an integrated health care delivery system from 1996 through 2015, we identified births from women with renal agenesis. Only first pregnancies and singleton births were included. After excluding those with diabetes and kidney disease, 200 women with renal agenesis were matched 1:4 by age (within 2 years), race, and history of hypertension to women with 2 kidneys. Predictor Renal agenesis defined by International Classification of Diseases, Ninth Revision ( ICD-9 ) codes prior to pregnancy. Outcomes The primary outcome was adverse maternal outcomes, including preterm delivery, delivery by cesarean section, preeclampsia/eclampsia, and hospital length of stay. Adverse neonatal end points were considered as a secondary outcome and included low birth weight (<2,500 g) and infant death/transfer to acute inpatient facility. Results Mean gestational age at delivery was 37.9 ± 2.1 weeks for women with renal agenesis compared to 38.6 ± 1.8 weeks for women with 2 kidneys. Compared with women with 2 kidneys, those with renal agenesis had increased risk for preterm delivery (OR, 2.88; 95% CI, 1.86-4.45), delivery by cesarean section (OR, 2.11; 95% CI, 1.49-2.99), preeclampsia/eclampsia (OR, 2.41; 95% CI, 1.23-4.72), and length of stay longer than 3 days (OR, 1.81; 95% CI, 1.18-2.78). Renal agenesis was not significantly associated with increased risk for infant death/transfer to acute facility (OR, 2.60; 95% CI, 0.57-11.89) or low birth weight after accounting for preterm delivery (OR, 2.11; 95% CI, 0.76-5.88). Limitations Renal agenesis was identified by ICD-9 code, not by imaging of the abdomen. Conclusion Women with unilateral renal agenesis have a higher risk for adverse outcomes in pregnancy.
Abstract Background Recent systematic reviews have cast doubt on the association between vitamin D and cardiovascular disease. No prior studies have investigated the association between ...25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25OH2 D), or intact parathyroid hormone and cardiovascular mortality in a temperate climate. Methods A total of 1073 community-dwelling older adults were evaluated in 1997-1999; serum levels of 25(OH)D (mean 42 ng/mL), 1,25(OH)2 D (median 29 pg/mL), and intact parathyroid hormone (median 46 pg/mL) were measured; mean estimated glomerular filtration rate was 74 mL/min/1.73 m2 . Participants were followed up to 10.4 (mean 6.4) years with 111 cardiovascular deaths. Results In unadjusted Cox proportional hazards models, higher levels of 1,25(OH)2 D were protective against cardiovascular mortality, whereas higher levels of intact parathyroid hormone predicted increased risk of cardiovascular death. After adjusting for age alone or multiple covariates, there was no significant association between 25(OH)D, 1,25(OH)2 D, or intact parathyroid hormone and cardiovascular mortality; results did not differ by an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 or < 60 mL/min/1.73 m2. Conclusion In this prospective study of Caucasian, middle-income, community-dwelling older adults living in sunny southern California, serum levels of 25(OH)D, 1,25(OH)2 D, and intact parathyroid hormone were not independently associated with cardiovascular mortality.
Background Low vitamin D concentrations are prevalent in patients with chronic kidney disease (CKD). We investigated the relationship between plasma 25-hydroxyvitamin D (25OHD) or ...1,25-dihydroxyvitamin D (1,25OH2 D) concentrations with death, cardiovascular events, and dialysis therapy initiation in patients with advanced CKD. Study Design The HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and long-term dialysis therapy initiation in patients with advanced CKD (stages 4 and 5 not yet on dialysis therapy). 25(OH)D and 1,25(OH)2 D were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (<15, 15-22, and >22 pg/mL), respectively. Cox proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes. Setting & Participants 1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers. Predictors 25(OH)D and 1,25(OH)2 D concentrations. Outcomes Death, cardiovascular events, and time to initiation of long-term dialysis therapy. Results After a median follow-up of 2.9 years, 41% (n = 453) died, whereas 56% (n = 615) initiated dialysis therapy. Mean 25(OH)D and 1,25(OH)2 D concentrations were 21 ± 10 ng/mL and 20 ± 11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)2 D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of long-term dialysis therapy (HR, 1.78; 95% CI, 1.40-2.26) compared with the highest tertile. The association with death and initiation of dialysis therapy was moderately attenuated after adjustment for plasma fibroblast growth factor 23 (FGF-23) concentrations (HRs of lower tertiles of 1.20 95% CI, 0.91-1.58 and 1.56 95% CI, 1.23-1.99, respectively, compared with highest tertile). There was no association between 25(OH)D concentrations and outcomes. Limitations Participants were mostly men. Conclusions Low plasma 1,25(OH)2 D concentrations are associated with death and initiation of long-term dialysis therapy in patients with advanced CKD. FGF-23 level may attentuate this relationship.
Background Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25OHD3 ). Effects of low GFR on vitamin D catabolism are less ...well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25OH2 D3 ), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs. Study Design Cross-sectional study. Setting & Participants 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N = 1,193), Multi-Ethnic Study of Atherosclerosis (N = 6,470), Cardiovascular Health Study (N = 932), Seattle Kidney Study (N = 289), and Hemodialysis Study (N = 712). Predictor eGFR. Outcome Circulating 24,25(OH)2 D3 concentration. Measurements GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry. Results Circulating 24,25(OH)2 D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2 D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2 D3 per 10 ng/mL of 25(OH)D3 for eGFRs ≥ 90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2 D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2 D3 with 25(OH)D3. Limitations Lack of direct pharmacokinetic measurements of vitamin D catabolism. Conclusions Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2 D3 concentration.
Background Chronic kidney disease (CKD) is associated with an increased risk of incident cardiovascular disease (CVD); however, the role of statins for the primary prevention of acute cardiovascular ...events in patients with CKD and the effect of statins on kidney function loss in persons without prevalent CVD have not been studied. Study Design Post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study. Setting & Participants Multicenter, randomized, double-blind, placebo-controlled trial of 5,608 men and 997 women without CVD randomly assigned to treatment with lovastatin or placebo. Intervention Placebo or lovastatin, 20 mg/d. Outcomes & Measurements First major acute cardiovascular event in participants with mild CKD and kidney function loss in persons with or without CKD. Estimated glomerular filtration rate was calculated using the 4-variable Modification of Diet in Renal Disease Study equation. Results At baseline, mean estimated glomerular filtration rate in participants with CKD (n = 304) was 53.0 ± 6.0 mL/min/1.73 m2 . After an average follow-up of 5.3 ± 0.8 years, the incidence of a fatal and nonfatal CVD event was lower in participants with CKD receiving lovastatin than in those receiving placebo (adjusted relative risk RR, 0.31; 95% CI, 0.13-0.72; P = 0.01). Tests for interaction suggested that the benefit of lovastatin was independent of the presence of CKD. Lovastatin did not reduce the annualized mean decrease in estimated glomerular filtration rate (−1.3 ± 0.07 vs −1.4 ± 0.07 mL/min/1.73 m2 /y, respectively; P = 0.1) or the frequency of a ≥ 25% decrease in kidney function (adjusted RR, 1.10; 95% CI, 0.96-1.28; P = 0.2) or incident CKD (adjusted RR, 1.04; 95% CI, 0.86-1.27; P = 0.6). Limitations Unable to determine the cause and duration of kidney disease, and information regarding proteinuria was not available. Conclusions Lovastatin is effective for the primary prevention of CVD in patients with CKD, but is not effective in decreasing kidney function loss in persons with no CVD.
Several studies demonstrated the prognostic importance of renal failure and peripheral artery disease in patients undergoing coronary artery bypass grafting (CABG), but data regarding the prognostic ...value of renal artery disease in this context are scarce. We aimed to study the prevalence and prognostic value of renal artery disease in patients undergoing CABG. We assessed by duplex ultrasound the renal arteries of 429 consecutive patients who underwent CABG, of whom 401 had satisfactory imaging quality to detect >60% renal artery stenosis (RAS) and/or an elevated resistive index (ERI >0.80). Of the 401 subjects included (age 68 ± 10 years, 83% men), 40 (10%) had RAS and 35 (9%) had ERI. Nine patients (2.2%) had both conditions. Patients were followed up for 12.4 ± 7.0 months. The primary outcome was composite, including 30-day death, stroke, and/or myocardial infarction. In a multivariate model adjusted for age, gender, cardiovascular (CV) risk factors, renal function, chronic obstructive pulmonary disease, the use of off-pump CABG, CV co-morbidities, and drugs, the presence of ERI was strongly associated with the occurrence of the composite outcome (odds ratio 4.3, 95% confidence interval 1.7 to 9.9, p = 0.0006). Similarly, ERI, not RAS, was significantly associated with the 30-day acute kidney disease and the midterm mortality, as well as fatal and nonfatal CV events. In conclusion, regardless of renal function and other factors, the renal resistive index is a strong predictor of CV and renal events after CABG. Renal duplex ultrasound can identify a subgroup of patients at high risk of CABG.
Background Secondary hyperparathyroidism is observed in patients with early chronic kidney disease (CKD). This study investigated the safety and efficacy of cinacalcet for secondary ...hyperparathyroidism in participants with CKD not receiving dialysis. Study Design Double-blind, randomized, 32-week, phase 3 study. Setting & Participants 404 participants with stage 3 or 4 CKD from 73 centers in 9 countries. Interventions Cinacalcet:placebo (3:1 ratio). Outcomes & Measurements Proportion of participants with a mean decrease of 30% or greater in intact parathyroid hormone (iPTH) level, proportion with iPTH level of 70 or less or 110 or less pg/mL (stage 3 and 4 CKD, respectively), and mean percentage of iPTH change from baseline, all during the efficacy-assessment phase. Results A greater proportion of cinacalcet than placebo participants achieved a 30% or greater decrease in iPTH level (74% versus 28%; P < 0.001), corresponding to a 43.1% decrease in iPTH level from baseline (cinacalcet) compared with a 1.1% increase (placebo). At week 32, serum calcium levels were 8.9 ± 0.8 mg/dL (−8.9%; cinacalcet) and 9.9 ± 0.6 mg/dL (+0.8%; placebo), phosphorus levels were 4.5 ± 1.0 mg/dL (+21.4%) and 4.0 ± 0.7 mg/dL (+6.8%), and calcium-phosphorus product values were 40.1 ± 8.3 mg2 /dL2 (+18.9%) and 38.9 ± 6.9 mg2 /dL2 (+17.1%), respectively. During the study course, 62% (cinacalcet) and 1% (placebo) of participants experienced 2 consecutive serum calcium concentrations less than 8.4 mg/dL. They generally were asymptomatic and without significant clinical consequences. Treatment generally was well tolerated, and most adverse events were mild to moderate in severity. Limitations The study was not designed to assess the effects of cinacalcet on vascular calcification, bone histomorphometric parameters, or other clinical outcomes. It is not known whether the observed differences in changes in iPTH levels are clinically more important than observed differences in changes in serum calcium or phosphorus levels or dosages of vitamin D sterols and phosphate binders. Conclusions These data show that cinacalcet treatment in patients with CKD not receiving dialysis can decrease plasma iPTH levels, but with frequent (albeit generally asymptomatic) serum calcium levels less than 8.4 mg/dL and increases in serum phosphorus levels.
Background Anemia is a risk factor for adverse cardiovascular disease outcomes. However, there is limited information concerning the association of hemoglobin concentration and new onset of ...clinically recognized coronary artery disease (CAD). Methods An historical cohort study was conducted with patients from Veterans Affairs medical centers. Baseline hemoglobin determinations were evaluated with respect to CAD using data from records of 25 622 subjects with no known heart disease. Coronary artery disease was identified from a new diagnosis based on the International Classification of Diseases, Ninth Edition , coding or a new prescription for nitroglycerin. Models were adjusted for age, sex, body mass index, smoking, systolic blood pressure, diastolic blood pressure, fasting glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine clearance, and use of statin or β-blocker. Results Among the cohort, 5297 (20.7%) subjects developed CAD over 73 895 person-years of follow-up. Compared with control hemoglobin levels of 15.0 to 17.0 g/dL, the multivariable-adjusted risk of CAD increased with lower hemoglobin levels: an adjusted hazard ratio (HR) of 1.47 and 95% confidence interval (CI) of 1.18 to 1.84 for hemoglobin levels of 9.0 to 11.0 g/dL; an HR of 1.34 and 95% CI of 1.20 to 1.49 for 11.0 to 13.0 g/dL; and an HR of 1.07 and 95% CI of 1.01 to 1.13 for 13.0 to 15.0 g/dL. Hemoglobin levels ≥17.0 g/dL were also associated with increased risk for CAD (adjusted HR 1.22, 95% CI 1.08-1.37). Conclusions Hemoglobin levels ≥17 or <15 g/dL are independently associated with increase risk for new cardiac events.
Higher levels of serum phosphorus that remain within the reference range are associated with increased risk of cardiovascular disease (CVD). However, the mechanisms by which higher serum phosphorus ...concentrations may contribute to the development of CVD remain unclear. Cross-sectional association between serum phosphorus levels and arterial stiffness as estimated by an ankle brachial pressure index (ABPI) >1.3 was examined in 581 participants in the Third National Health and Nutrition Examination Survey. Logistic regression analysis was performed to evaluate whether higher serum phosphorus levels were associated with high ABPI, independently of several potential confounders. Of 581 participants, 38% and 10% had a serum phosphorus levels >3.5 and >4.0 mg/dl, respectively. An ABPI >1.3 was present in 7.3% of participants. Higher quartiles of serum phosphorus levels were associated with a greater prevalence of high ABPI: 5.4%, 3.7%, 7.8%, and 12.9% for quartiles 1 (<3.1 mg/dl), 2 (3.1 to 3.4 mg/dl), 3 (3.4 to 3.7 mg/dl), and 4 (3.7 to 5.0 mg/dl), respectively. There was a strong, positive association between the highest quartile of serum phosphorus (3.7 to 5.0 mg/dl) and high ABPI compared to the reference group (3.1 to 3.4 mg/dl) after adjustment for demographics, traditional CVD risk factors, kidney function, C-reactive protein, serum calcium, and 25-hydroxyvitamin D levels (adjusted odds ratio 4.78, 95% confidence interval 1.73 to 13.2, p = 0.003). In conclusion, serum phosphorus levels, even within the reference range, are independently associated with high ABPI, a marker of arterial stiffness, in the US adult population.
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