Casey M. Rebholz

Dietary Protein Intake and Blood Pressure: A Meta-Analysis of Randomized Controlled Trials

The authors conducted a meta-analysis of randomized controlled trials to evaluate the association of dietary protein intake with blood pressure. To identify articles published before April 2011, the authors searched electronic databases, conducted a manual bibliography review, and consulted experts in the field. Forty trials (including 3,277 participants in total) met the eligibility criteria and were included. Using a standardized form, 2 investigators independently abstracted data on study design, participant characteristics, and treatment outcomes. Net change estimates were pooled across trials using random-effects models. Compared with carbohydrate, dietary protein intake was associated with significant changes in mean systolic and diastolic blood pressure of -1.76 mm Hg (95% confidence interval (CI): -2.33, -1.20) and -1.15 mm Hg (95% CI: -1.59, -0.71), respectively (both P s < 0.001). Both vegetable protein and animal protein were associated with significant blood pressure changes of -2.27 mm Hg (95% CI: -3.36, -1.18) and -2.54 mm Hg (95% CI: -3.55, -1.53), respectively, for systolic blood pressure (both P s < 0.001) and -1.26 mm Hg (95% CI: -2.26, -0.26) and -0.95 mm Hg (95% CI: -1.72, -0.19), respectively, for diastolic blood pressure (both P s = 0.014). Blood pressure reduction was not significantly different when vegetable protein was compared directly with animal protein. These findings indicate that partially replacing dietary carbohydrate with protein may be important for the prevention and treatment of hypertension.

Effect of soybean protein on novel cardiovascular disease risk factors: a randomized controlled trial.

Background/objectives:Cardiovascular disease (CVD) is the leading cause of death in the United States and the world. Clinical trials have suggested that soybean protein lowers lipids and blood pressure. The effect of soybean protein on novel CVD risk factors has not been well studied. The objective of this study was to examine the effect of soybean protein on biomarkers of inflammation, endothelial dysfunction and adipocytokines.Subjects/methods:The effect of 8 weeks of 40 g of soybean protein supplement (89.3 mg isoflavones), 40 g of milk protein supplement and 40 g of complex carbohydrate placebo was examined in a randomized, placebo-controlled, double-blind, three-phase crossover trial among adults in New Orleans, Louisiana and Jackson, Mississippi. Plasma levels of inflammation biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-α), endothelial dysfunction biomarkers (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, thrombomodulin) and adipocytokines (high-molecular weight adiponectin, leptin, resistin) were measured at baseline and at the end of each intervention using immunoturbidimetric and enzyme-linked immunosorbent assay techniques.Results:Soy protein supplementation resulted in a significant mean net change (95% confidence interval) in plasma E-selectin of −3.93 ng/ml (−7.05 to −0.81 ng/ml; P=0.014) compared with milk protein, and in plasma leptin of −2089.8 pg/ml (−3689.3 to −490.3 pg/ml; P=0.011) compared with carbohydrate. There were no significant changes in any other risk factors.Conclusions:Soy protein supplementation may reduce levels of E-selectin and leptin. Further research is warranted to investigate the mechanisms through which protein may confer protective effects on novel CVD risk factors.

Identification of incident CKD stage 3 in research studies.

BACKGROUND In epidemiologic research, incident chronic kidney disease (CKD) commonly is determined by laboratory tests performed at planned study visits. Given the morbidity and mortality associated with CKD, persons with incident disease may be less likely to attend scheduled visits, affecting observed associations. The objective of this study was to quantify loss to follow-up by CKD status and determine whether supplementation with diagnostic code data improves capture of incident CKD. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS 11,560 participants in the Atherosclerosis Risk in Communities (ARIC) Study underwent continuous surveillance for hospitalizations and death from baseline visit (1996-1999) to follow-up visit (2011-2013). A subset of hospitalizations in Washington County, MD, was used in diagnostic code validation (n=2,540). PREDICTOR Baseline demographics and comorbid conditions. OUTCOMES Incident CKD stage 3 ascertained by follow-up visit (visit-based definition) or hospitalization surveillance (hospitalization-based definition). MEASUREMENTS Visit-based definition: ≥25% decline from baseline estimated glomerular filtration rate to <60 mL/min/1.73 m2 at follow-up visit; hospitalization-based definition: hospitalization CKD diagnostic code. RESULTS Of 11,560 participants, 5,951 attended the follow-up visit and 9,264 were hospitalized. Never-hospitalized participants were younger, more often female, and had fewer comorbid conditions; 73.5% attended the follow-up visit. Incident CKD stage 3 occurred in 1,172 participants by the visit-based definition (251 were never hospitalized) and 1,078 participants by the hospitalization-based definition (237 attended the follow-up study visit). Sensitivity of the hospitalization-based CKD definition was 35.5% (95% CI, 31.6%-39.7%); specificity was 95.7% (95% CI, 94.2%-96.8%). Sensitivity was higher with later time period, older participant age, and baseline prevalent diabetes and CKD. LIMITATIONS A subset of hospitalizations was used for validation; 15-year gap between study visits. CONCLUSIONS The sensitivity of diagnostic code-identified CKD is low and varies by certain factors; however, supplementing a visit-based definition with hospitalization information can increase disease identification during periods of follow-up without study visits.

Dietary Acid Load and Incident Chronic Kidney Disease: Results from the ARIC Study

Background: Higher dietary acid load can result in metabolic acidosis and is associated with faster kidney disease progression in patients with chronic kidney disease (CKD). However, the relationship between dietary acid load and incident CKD has not been evaluated. Methods: We conducted prospective analyses of the Atherosclerosis Risk in Communities study participants without CKD at baseline (1987-1989, n = 15,055). Dietary acid load was estimated using the equation for potential renal acid load by Remer and Manz, incorporating dietary intake data from a food frequency questionnaire. Incident CKD was assessed from baseline through 2010 and defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 accompanied by 25% eGFR decline, CKD-related hospitalization or death or end-stage renal disease identified by linkage to the US Renal Data System registry. Results: In the overall study population, 55% were female, 26% were African-American and mean age at baseline was 54 years. During a median follow-up of 21 years, there were 2,351 (15.6%) incident CKD cases. After adjusting for demographics (age, sex, race-center), established risk factors (diabetes status, hypertension status, overweight/obese status, smoking status, education level, physical activity), caloric intake and baseline eGFR, higher dietary acid load were associated with higher risk of incident CKD (hazard ratio [HR] for quartile 4 vs. 1: 1.13, 95% CI 1.01-1.28, p for trend = 0.02; HR per interquartile range increase: 1.06, 95% CI 1.00-1.11, p = 0.04). Conclusion: Dietary acid load is associated with incident CKD in a population-based sample. These data suggest a potential avenue for CKD risk reduction through diet.

Serum Fibroblast Growth Factor-23 Is Associated with Incident Kidney Disease

Fibroblast growth factor-23 is a bone-derived hormone that increases urinary phosphate excretion and inhibits hydroxylation of 25-hydroxyvitamin D. Recent studies suggest that fibroblast growth factor-23 may be an early biomarker of CKD progression. However, its role in kidney function decline in the general population is unknown. We assessed the relationship between baseline (1990-1992) serum levels of intact fibroblast growth factor-23 and incident ESRD in 13,448 Atherosclerosis Risk in Communities study participants (56.1% women, 74.7% white) followed until December 31, 2010. At baseline, the mean age of participants was 56.9 years and the mean eGFR was 97 ml/min per 1.73 m(2). During a median follow-up of 19 years, 267 participants (2.0%) developed ESRD. After adjustment for demographic characteristics, baseline eGFR, traditional CKD risk factors, and markers of mineral metabolism, the highest fibroblast growth factor-23 quintile (>54.6 pg/ml) compared with the lowest quintile (<32.0 pg/ml) was associated with risk of developing ESRD (hazard ratio, 2.10; 95% confidence interval, 1.31 to 3.36; trend P<0.001). In a large, community-based study comprising a broad range of kidney function, higher baseline fibroblast growth factor-23 levels were associated with increased risk of incident ESRD independent of the baseline level of kidney function and a number of other risk factors.

Mortality from suicide and other external cause injuries in China: A prospective cohort study

BackgroundPremature death from suicide is a leading cause of death worldwide. However, the pattern and risk factors for suicide and other external cause injuries are not well understood. This study investigates mortality from suicide and other injuries and associated risk factors in China.MethodsA prospective cohort study of 169,871 Chinese adults aged 40 years and older was conducted. Mortality due to suicide or other external cause injuries was recorded.ResultsMortality from all external causes was 58.7/100,000 (72.3 in men and 44.4 in women): 14.1/100,000 (14.2 in men and 14.2 in women) for suicide and 44.6/100,000 (58.1 in men and 30.2 in women) for other external cause injuries. Transport accidents (17.2/100,000 overall, 23.4 in men and 10.8 in women), accidental poisoning (7.5/100,000 overall, 10.2 in men and 4.8 in women), and accidental falls (5.7/100,000 overall, 6.5 in men and 5.0 in women) were the three leading causes of death from other external cause injuries in China. In the multivariable analysis, male sex (relative risk [RR] 1.56, 95% confidence interval [CI] 1.03-2.38), age 70 years and older (2.27, 1.29-3.98), living in north China (1.68, 1.20-2.36) and rural residence (2.82, 1.76-4.51) were associated with increased mortality from suicide. Male sex (RR 2.50, 95% CI 1.95-3.20), age 60-69 years (1.93, 1.45-2.58) and 70 years and older (3.58, 2.58-4.97), rural residence (2.29, 1.77-2.96), and having no education (1.56, 1.00-2.43) were associated with increased mortality from other external cause injuries, while overweight (0.60, 0.43-0.83) was associated with decreased risk of mortality from other external cause injuries.ConclusionsExternal cause mortality has become a major public health problem in China. Developing an integrated national program for the prevention of mortality due to external cause injuries in China is warranted.

Association of Dietary Protein Consumption With Incident Silent Cerebral Infarcts and Stroke The Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— The effect of dietary protein on the risk of stroke has shown inconsistent results. We aimed to evaluate the relationship of dietary protein sources with the risk of stroke and silent cerebral infarcts in a large community-based cohort. Methods— We studied 11601 adults (age, 45–64 years at baseline in 1987–1989) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, free of diabetes mellitus and cardiovascular disease. Dietary protein intake was assessed with validated food frequency questionnaires at baseline and after 6 years of follow-up. Incident stroke events were identified through hospital discharge codes and stroke deaths and physician-adjudicated through December 31, 2011. A subset of participants (n=653) underwent brain magnetic resonance imaging in 1993 to 1995 and in 2004 to 2006. Cox proportional hazard models and logistic regression were used for statistical analyses. Results— During a median follow-up of 22.7 years, there were 699 stroke events. In multivariable analyses, total, animal, and vegetable protein consumption was not associated with risk of stroke. Red meat consumption was associated with increased stroke risk, particularly ischemic events. The hazard ratios (95% confidence interval) for risk of ischemic stroke across ascending quintiles of red meat consumption were 1 (ref), 1.13 (0.85–1.49), 1.44 (1.09–1.90), 1.33 (0.99–1.79), and 1.47 (1.06–2.05); Ptrend=0.01. No association of major dietary protein sources with silent cerebral infarcts was detected. Conclusions— This study supports the notion that consumption of red meat may increase the risk of ischemic stroke. No association between dietary protein intake and silent cerebral infarcts was found.

Soluble receptor for advanced glycation end products and the risk for incident heart failure: The Atherosclerosis Risk in Communities Study.

BACKGROUND Experimental studies in animals suggest that circulating soluble receptor for advanced glycation end products (sRAGE) decrease oxidative stress, inflammation, and fibrosis. The association between sRAGE and incident heart failure has not been systematically examined in a prospective study. METHODS We conducted a prospective analysis of a subsample of 1,086 participants from the Atherosclerosis Risk in Communities Study who attended visit 2 (1990-1992) without a history of coronary heart disease, stroke, or heart failure and with measured plasma sRAGE levels. Incident heart failure was defined as death from heart failure or hospitalization due to heart failure during a median of 20 years of follow-up. RESULTS In this sample of a community-based population (mean age 63 years, 60% women, 78% white), there were 126 incident cases of heart failure. Lower levels of sRAGE were significantly associated with an increased risk of heart failure; the adjusted hazard ratios (95% CIs) of heart failure were 1.0 (reference), 1.81 (0.94-3.49), 1.57 (0.80-3.08), and 3.37 (1.75-6.50), for fourth, third, second, and first quartiles, respectively (P for trend = .001). We did not observe significant interactions by diabetes status or by race or obesity status. CONCLUSIONS Lower circulating levels of sRAGE are independently associated with the development of heart failure in a community-based population. Our results add to the growing evidence that sRAGE is a valuable predictor of cardiovascular disease.

Association of plasma levels of soluble receptor for advanced glycation end products and risk of kidney disease: the Atherosclerosis Risk in Communities study

BACKGROUND Advanced glycation end products and their cell-bound receptors are thought to mediate the adverse effects of vascular disease through oxidative stress, inflammation and endothelial dysfunction. We examined the association between the soluble form of receptor for advanced glycation end products (sRAGE) and kidney disease. METHODS In this case-cohort study nested within the Atherosclerosis Risk in Communities (ARIC) study, baseline sRAGE levels were measured in a cohort random sample of participants without kidney disease (n= 1218), and among participants who developed incident chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and ≥25% eGFR decline, n = 151] and end-stage renal disease (ESRD) [entry in the US Renal Data System (USRDS) registry, n = 152]. RESULTS Baseline sRAGE levels were inversely related to baseline eGFR (r = -0.13). After adjusting for age, sex and race, one interquartile range higher log10-transformed sRAGE was associated with development of CKD [odds ratio: 1.39; 95% confidence interval (95% CI) 1.06-1.83; P = 0.02] and ESRD (hazard ratio: 1.97; 95% CI 1.47-2.64; P < 0.001). These associations were not significant after eGFR adjustment. CONCLUSIONS High sRAGE levels are associated with incident CKD and ESRD risk, but not after adjustment for kidney function at baseline. Future studies are needed to investigate specific mechanisms underlying the association of sRAGE with kidney disease risk.

Change in Novel Filtration Markers and Risk of ESRD

BACKGROUND Chronic kidney disease progression is a risk factor for end-stage renal disease (ESRD). A 57% decline in creatinine-based estimated glomerular filtration rate (eGFRcr) is an established surrogate outcome for ESRD in clinical trials, and a 30% decrease recently has been proposed as a surrogate end point. However, it is unclear whether change in novel filtration marker levels provides additional information for ESRD risk to change in eGFRcr. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Atherosclerosis Risk in Communities (ARIC) Study participants from 4 US communities. PREDICTORS Percent change in levels of filtration markers (eGFRcr, cystatin C-based eGFR [eGFRcys], the inverse of β2-microglobulin concentration [1/B2M]) over a 6-year period. OUTCOME Incident ESRD. MEASUREMENTS Cox proportional hazards regression with adjustment for demographics, kidney disease risk factors, and first measurement of eGFRcr. RESULTS During a median follow-up of 13 years, there were 142 incident ESRD cases. In adjusted analysis, declines > 30% in eGFRcr, eGFRcys, and 1/B2M were associated significantly with ESRD compared with stable concentrations of filtration markers (HRs of 19.96 [95% CI, 11.73-33.96], 16.67 [95% CI, 10.27-27.06], and 22.53 [95% CI, 13.20-38.43], respectively). Using the average of declines in the 3 markers, >30% decline conferred higher ESRD risk than that for eGFRcr alone (HR, 31.97 [95% CI, 19.40-52.70; P=0.03] vs eGFRcr). LIMITATIONS Measurement error could influence estimation of change in filtration marker levels. CONCLUSIONS A >30% decline in kidney function assessed using novel filtration markers is associated strongly with ESRD, suggesting the potential utility of measuring change in cystatin C and B2M levels in settings in which improved outcome ascertainment is needed, such as clinical trials.