Katherine T. Mills

Effects of Low-Carbohydrate Diets Versus Low-Fat Diets on Metabolic Risk Factors: A Meta-Analysis of Randomized Controlled Clinical Trials

The effects of low-carbohydrate diets (≤45% of energy from carbohydrates) versus low-fat diets (≤30% of energy from fat) on metabolic risk factors were compared in a meta-analysis of randomized controlled trials. Twenty-three trials from multiple countries with a total of 2,788 participants met the predetermined eligibility criteria (from January 1, 1966 to June 20, 2011) and were included in the analyses. Data abstraction was conducted in duplicate by independent investigators. Both low-carbohydrate and low-fat diets lowered weight and improved metabolic risk factors. Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol (2.7 mg/dL; 95% confidence interval: 0.8, 4.6), and low density lipoprotein cholesterol (3.7 mg/dL; 95% confidence interval: 1.0, 6.4), but a greater increase in high density lipoprotein cholesterol (3.3 mg/dL; 95% confidence interval: 1.9, 4.7) and a greater decrease in triglycerides (-14.0 mg/dL; 95% confidence interval: -19.4, -8.7). Reductions in body weight, waist circumference and other metabolic risk factors were not significantly different between the 2 diets. These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors. Low-carbohydrate diets could be recommended to obese persons with abnormal metabolic risk factors for the purpose of weight loss. Studies demonstrating long-term effects of low-carbohydrate diets on cardiovascular events were warranted.

Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries.

Background: Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010. Methods: We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. Results: In 2010, 31.1% (95% confidence interval, 30.0%–32.2%) of the world’s adults had hypertension; 28.5% (27.3%–29.7%) in high-income countries and 31.5% (30.2%–32.9%) in low- and middle-income countries. An estimated 1.39 (1.34–1.44) billion people had hypertension in 2010: 349 (337–361) million in high-income countries and 1.04 (0.99–1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries. Conclusions: Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries.Background: Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010. Methods: We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. Results: In 2010, 31.1% (95% confidence interval, 30.0%–32.2%) of the world’s adults had hypertension; 28.5% (27.3%–29.7%) in high-income countries and 31.5% (30.2%–32.9%) in low- and middle-income countries. An estimated 1.39 (1.34–1.44) billion people had hypertension in 2010: 349 (337–361) million in high-income countries and 1.04 (0.99–1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries. Conclusions: Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries. # Clinical Perspective {#article-title-35}

A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Here we estimated the global prevalence and absolute burden of CKD in 2010 by pooling data from population-based studies. We searched MEDLINE (January 1990 to December 2014), International Society of Nephrology Global Outreach Program funded projects, and bibliographies of retrieved articles and selected 33 studies reporting gender- and age-specific prevalence of CKD in representative population samples. The age standardized global prevalence of CKD stages 1–5 in adults aged 20 and older was 10.4% in men (95% confidence interval 9.3–11.9%) and 11.8% in women (11.2–12.6%). This consisted of 8.6% men (7.3–9.8%) and 9.6% women (7.7–11.1%) in high-income countries, and 10.6% men (9.4–13.1%) and 12.5% women (11.8–14.0%) in low- and middle-income countries. The total number of adults with CKD was 225.7 million (205.7–257.4 million) men and 271.8 million (258.0–293.7 million) women. This consisted of 48.3 million (42.3–53.3 million) men and 61.7 million (50.4–69.9 million) women in high-income countries, and 177.4 million (159.2–215.9 million) men and 210.1 million (200.8–231.7 million) women in low- and middle-income countries. Thus, CKD is an important global-health challenge, especially in low- and middle-income countries. National and international efforts for prevention, detection, and treatment of CKD are needed to reduce its morbidity and mortality worldwide.

Systolic Blood Pressure Reduction and Risk of Cardiovascular Disease and Mortality: A Systematic Review and Network Meta-analysis

Importance Clinical trials have documented that lowering blood pressure reduces cardiovascular disease and premature deaths. However, the optimal target for reduction of systolic blood pressure (SBP) is uncertain. Objective To assess the association of mean achieved SBP levels with the risk of cardiovascular disease and all-cause mortality in adults with hypertension treated with antihypertensive therapy. Data Sources MEDLINE and EMBASE were searched from inception to December 15, 2015, supplemented by manual searches of the bibliographies of retrieved articles. Study Selection Studies included were clinical trials with random allocation to an antihypertensive medication, control, or treatment target. Studies had to have reported a difference in mean achieved SBP of 5 mm Hg or more between comparison groups. Data Extraction and Synthesis Data were extracted from each study independently and in duplicate by at least 2 investigators according to a standardized protocol. Network meta-analysis was used to obtain pooled randomized results comparing the association of each 5–mm Hg SBP category with clinical outcomes after adjusting for baseline risk. Main Outcomes and Measures Cardiovascular disease and all-cause mortality. Results Forty-two trials, including 144 220 patients, met the eligibility criteria. In general, there were linear associations between mean achieved SBP and risk of cardiovascular disease and mortality, with the lowest risk at 120 to 124 mm Hg. Randomized groups with a mean achieved SBP of 120 to 124 mm Hg had a hazard ratio (HR) for major cardiovascular disease of 0.71 (95% CI, 0.60-0.83) compared with randomized groups with a mean achieved SBP of 130 to 134 mm Hg, an HR of 0.58 (95% CI, 0.48-0.72) compared with those with a mean achieved SBP of 140 to 144 mm Hg, an HR of 0.46 (95% CI, 0.34-0.63) compared with those with a mean achieved SBP of 150 to 154 mm Hg, and an HR of 0.36 (95% CI, 0.26-0.51) compared with those with a mean achieved SBP of 160 mm Hg or more. Likewise, randomized groups with a mean achieved SBP of 120 to 124 mm Hg had an HR for all-cause mortality of 0.73 (95% CI, 0.58-0.93) compared with randomized groups with a mean achieved SBP of 130 to 134 mm Hg, an HR of 0.59 (95% CI, 0.45-0.77) compared with those with a mean achieved SBP of 140 to 144 mm Hg, an HR of 0.51 (95% CI, 0.36-0.71) compared with those with a mean achieved SBP of 150 to 154 mm Hg, and an HR of 0.47 (95% CI, 0.32-0.67) compared with those with a mean achieved SBP of 160 mm Hg or more. Conclusions and Relevance This study suggests that reducing SBP to levels below currently recommended targets significantly reduces the risk of cardiovascular disease and all-cause mortality. These findings support more intensive control of SBP among adults with hypertension.

Diabetes mellitus and colorectal cancer prognosis: a meta-analysis.

BACKGROUND: Diabetes mellitus is associated with an increased incidence of colorectal cancer, but the impact of diabetes mellitus on colorectal cancer prognosis is not clear. OBJECTIVE: We conducted a meta-analysis of observational studies to examine the association between preexisting diabetes mellitus and colorectal cancer all-cause mortality, cancer-specific mortality, and recurrence. DATA SOURCES: Medline and Embase were searched through August 22, 2012. STUDY SELECTION: We included studies reporting all-cause mortality, cancer-specific mortality, disease-free survival, or recurrence in patients who have colorectal cancer according to diabetic status. INTERVENTION: Meta-analyses were performed by the use of random-effects models. MAIN OUTCOME MEASURES: The primary outcomes measured were all-cause mortality, cancer-specific mortality, and disease-free survival. RESULTS: Twenty-six articles met our inclusion criteria. Patients with colorectal cancer who had diabetes mellitus had a 17% increased risk of all-cause mortality (relative risk, 1.17; 95% CI, 1.09–1.25) and a 12% increased risk of cancer-specific mortality (relative risk, 1.12; 95% CI, 1.01–1.24) in comparison with those who did not have diabetes mellitus. Those with diabetes mellitus also had poorer disease-free survival (relative risk, 1.54; 95% CI, 1.08–2.18) compared with their nondiabetic counterparts. In subgroup analyses, diabetes mellitus was associated with all-cause mortality in both rectal (relative risk, 1.24; 95% CI, 1.07–1.29) and colon cancer patients (relative risk, 1.17; 95% CI, 1.07–1.29). Sensitivity analyses including only patients with nonmetastatic disease identified stronger associations between diabetes mellitus and both all-cause (relative risk, 1.32; 95% CI, 1.21–1.44) and cancer-specific (relative risk, 1.27; 95% CI, 1.06–1.52) mortality. LIMITATIONS: Some studies had short follow-up or did not report mean or median follow-up. The included studies were heterogeneous in study population, diabetes mellitus diagnostic criteria, and outcome ascertainment. CONCLUSION: Patients with colorectal cancer who have diabetes mellitus are at greater risk for all-cause and cancer-specific mortality and have worse disease-free survival than those who do not have diabetes mellitus. Studies are warranted to determine whether the proper treatment could attenuate the excess mortality among patients with colorectal cancer who have diabetes mellitus.

Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease

IMPORTANCE Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD. OBJECTIVE To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013. EXPOSURES The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion. MAIN OUTCOMES AND MEASURES A composite of CVD events defined as congestive heart failure, stroke, or myocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication. RESULTS Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (≥4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09-1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03-1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08-3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001). CONCLUSIONS AND RELEVANCE Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD.

Urinary Sodium and Potassium Excretion and CKD Progression

CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (≥194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (≥67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression.

Increased urinary excretion of angiotensinogen is associated with risk of chronic kidney disease

BACKGROUND The effect of intrarenal renin-angiotensin system (RAS) activity on risk of chronic kidney disease (CKD) has not been well studied in human subjects. METHODS We investigated the association between urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, and risk of CKD in 201 patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) or presence of albuminuria ( ≥ 30 mg/24 h). RESULTS Compared to controls, median urinary angiotensinogen excretion (45.4 versus 7.4 μg/24 h, P < 0.0001) and angiotensinogen-to-creatinine ratio (26.3 versus 4.4 μg/g, P < 0.0001) were significantly higher in patients with CKD. Log-transformed urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were inversely correlated with eGFR (r = -0.59 and -0.57, both P < 0.0001) and positively correlated with log-transformed urinary albumin excretion (r = 0.89 and 0.87, both P < 0.0001). After adjusting for multiple covariables, including the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diuretics and statins, the odds ratios (95% confidence interval) for CKD comparing the highest tertile to the lowest two tertiles of urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were 6.70 (3.43, 13.1; P < 0.0001) and 6.45 (3.34, 12.4; P < 0.0001), respectively. CONCLUSIONS These data indicate the intrarenal RAS may play an important role in the etiology of CKD, and urinary angiotensinogen may be a useful clinical biomarker for the identification of patients at a high risk for CKD.

Elevated plasma levels of endostatin are associated with chronic kidney disease.

Background/Aims: Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD). Methods: We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or presence of albuminuria (≥30 mg/24 h). Results: After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3–357.5) in patients with CKD and 119.4 ng/dl (103.7–134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = –0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of –26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2–45.5; p < 0.0001). Conclusion: These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.

Reproducibility of Blood Pressure Responses to Dietary Sodium and Potassium Interventions The GenSalt Study

Blood pressure responses to dietary sodium and potassium interventions vary among individuals. We studied the long-term reproducibility of blood pressure responses to dietary sodium and potassium intake. We repeated the dietary sodium and potassium interventions among 487 Chinese adults 4.5 years after the original dietary intervention. The identical dietary intervention protocol, which included a 7-day low-sodium feeding (51.3 mmol/d), a 7-day high-sodium feeding (307.8 mmol/d), and a 7-day high-sodium feeding with oral potassium supplementation (60.0 mmol/d), was applied in both the initial and repeated studies. Three blood pressure measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. The results from the 24-hour urinary excretion of sodium and potassium showed excellent compliance with the study diet. Blood pressure responses to dietary intervention in the original and repeated studies were highly correlated. For example, the correlation coefficients (95% confidence interval) for systolic blood pressure levels were 0.77 (0.73–0.80) at baseline, 0.79 (0.75–0.82) during low sodium, 0.80 (0.77–0.83) during high sodium, and 0.82 (0.79–0.85) during high sodium and potassium supplementation interventions (all P<0.0001). The correlation coefficients for systolic blood pressure changes were 0.37 (0.29–0.44) from baseline to low sodium, 0.37 (0.29–0.44) from low to high sodium, and 0.28 (0.20–0.36) from high sodium to high sodium plus potassium supplementation (all P<0.0001). These data indicate that blood pressure responses to dietary sodium and potassium interventions have long-term reproducibility and stable characteristics in the general population.