Blood pressure variability in acute stroke: Risk factors and association with functional outcomes at 1 month.

BACKGROUND AND PURPOSE: Blood pressure variability, in acute stroke, may be an important modifiable determinant of functional outcome after stroke. In a large international cohort of participants with acute stroke, it was sought to determine the association of blood pressure variability (in the early period of admission) and functional outcomes, and to explore risk factors for increased blood pressure variability. PATIENTS AND METHODS: INTERSTROKE is an international case-control study of risk factors for first acute stroke. Blood pressure was recorded at the time of admission, the morning after admission and the time of interview in cases (median time from admission 36.7 h). Multivariable ordinal regression analysis was employed to determine the association of blood pressure variability (standard deviation [SD] and coefficient of variance) with modified Rankin score at 1-month follow-up, and logistic regression was used to identify risk factors for blood pressure variability. RESULTS: Amongst 13,206 participants, the mean age was 62.19 ± 13.58 years. When measured by SD, both systolic blood pressure variability (odds ratio 1.13; 95% confidence interval 1.03-1.24 for SD ≥20 mmHg) and diastolic blood pressure variability (odds ratio 1.15; 95% confidence interval 1.04-1.26 for SD ≥10 mmHg) were associated with a significant increase in the odds of poor functional outcome. The highest coefficient of variance category was not associated with a significant increase in risk of higher modified Rankin score at 1 month. Increasing age, female sex, high body mass index, history of hypertension, alcohol use, and high urinary potassium and low urinary sodium excretion were associated with increased blood pressure variability. CONCLUSION: Increased blood pressure variability in acute stroke, measured by SD, is associated with an increased risk of poor functional outcome at 1 month. Potentially modifiable risk factors for increased blood pressure variability include low urinary sodium excretion.

A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation.

Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE) study. Using two-sample Mendelian randomization, individual variants' effects on biomarker concentration were correlated with their effects on eGFR and kidney traits from published genome-wide association studies (GWAS). Genetically altered concentrations of 22 biomarkers were associated with eGFR above a Bonferroni-corrected significance threshold. Five biomarkers were previously identified by GWAS (UMOD, FGF5, LGALS7, NINJ1, COL18A1). Nine biomarkers were within 1 Mb of the lead GWAS variant but the gene for the biomarker was unidentified as the candidate for the GWAS signal (INHBC, TNFRSF11A, TCN2, PXN1, PRTN3, PSMD9, TFPI, ITGB6, CA3). Single-cell transcriptomic data indicated the 22 biomarkers are expressed in kidney tubules, collecting duct, fibroblasts, and immune cells. Pathway analysis showed significant enrichment of identified biomarkers in the extracellular kidney parenchyma. Thus, using genetic regulators of biomarker concentration via proteome-wide Mendelian randomization, we identified 22 biomarkers that appear to causally impact eGFR in either a beneficial or adverse manner. The current study provides rationale for novel therapeutic targets for eGFR and emphasized a role for extracellular proteins produced by tubular cells and fibroblasts for impacting eGFR.

Global mean potassium intake: a systematic review and Bayesian meta-analysis.

PURPOSE: Increasing potassium intake, especially in populations with low potassium intake and high sodium intake, has emerged as an important population-level intervention to reduce cardiovascular events. Current guideline recommendations, such as those made by the World Health Organisation, recommend a potassium intake of  > 3.5 g/day. We sought to determine summary estimates for mean potassium intake and sodium/potassium (Na/K) ratio in different regions of the world. METHODS: We performed a systematic review and meta-analysis. We identified 104 studies, that included 98 nationally representative surveys and 6 multi-national studies. To account for missingness and incomparability of data, a Bayesian hierarchical imputation model was applied to estimating summary estimates of mean dietary potassium intake (primary outcome) and sodium/potassium ratio. RESULTS: Overall, 104 studies from 52 countries were included (n = 1,640,664). Mean global potassium intake was 2.25 g/day (57 mmol/day) (95% credible interval (CI) 2.05-2.44 g/day), with highest intakes in Eastern and Western Europe (mean intake 3.53g/day, 95% CI 3.05-4.01 g/day and 3.29 g/day, 95% CI 3.13-3.47 g/day, respectively) and lowest intakes in East Asia (mean intake 1.89 g/day; 95% CI 1.55-2.25 g/day). Approximately 31% (95% CI, 30-41%) of global population included have an estimated potassium intake  > 2.5 g/day, with 14% (95% CI 11-17%) above 3.5 g/day. CONCLUSION: Global mean potassium intake (2.25 g/day) falls below current guideline recommended intake level of  > 3.5 g/day, with only 14% (95% CI 11-17%) of the global population achieving guideline-target mean intake. There was considerable regional variation, with lowest mean potassium intake reported in Asia, and highest intake in Eastern and Western Europe.

Anger or emotional upset and heavy physical exertion as triggers of stroke: the INTERSTROKE study.

AIMS: In INTERSTROKE, we explored the association of anger or emotional upset and heavy physical exertion with acute stroke, to determine the importance of triggers in a large, international population. METHODS AND RESULTS: INTERSTROKE was a case-control study of first stroke in 32 countries. Using 13 462 cases of acute stroke we adopted a case-crossover approach to determine whether a trigger within 1 hour of symptom onset (case period), vs. the same time on the previous day (control period), was associated with acute stroke. A total of 9.2% (n = 1233) were angry or emotional upset and 5.3% (n = 708) engaged in heavy physical exertion during the case period. Anger or emotional upset in the case period was associated with increased odds of all stroke [odds ratio (OR) 1.37, 99% confidence interval (CI), 1.15-1.64], ischaemic stroke (OR 1.22, 99% CI, 1.00-1.49), and intracerebral haemorrhage (ICH) (OR 2.05, 99% CI 1.40-2.99). Heavy physical exertion in the case period was associated with increased odds of ICH (OR 1.62, 99% CI 1.03-2.55) but not with all stroke or ischaemic stroke. There was no modifying effect by region, prior cardiovascular disease, risk factors, cardiovascular medications, time, or day of symptom onset. Compared with exposure to neither trigger during the control period, the odds of stroke associated with exposure to both triggers were not additive. CONCLUSION: Acute anger or emotional upset was associated with the onset of all stroke, ischaemic stroke, and ICH, while acute heavy physical exertion was associated with ICH only.

Early Metformin in Gestational Diabetes: A Randomized Clinical Trial.

Importance: Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective: To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants: Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks' postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions: Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures: The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results: Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, -6.9% [95% CI, -15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance: Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02980276; EudraCT: 2016-001644-19.

Role of Proxy Respondents in International Stroke Research: Experience of the INTERSTROKE Study.

INTRODUCTION: Measuring patient-reported information in stroke research is challenging. To overcome this, use of proxy respondents is often a necessary strategy. In this study, we report on use and effect of proxy respondents on patient case-mix in a large international epidemiologic stroke study (INTERSTROKE). METHODS: This was a cross-sectional study of 13,458 cases of acute first stroke in 32 countries. A standardized study questionnaire recording behavioural cardiovascular risk factors was administered to the patient, and if unable to communicate adequately, a valid proxy, or both. We used logistic regression to evaluate the association of age, sex, education, occupation, stroke severity, and region with need for proxy respondent, and report odds ratio (OR) with 95% confidence interval (CI). RESULTS: Among 13,458 participants with acute stroke, questionnaires were completed by patients alone in 41.4% (n = 5,573), combination of patient and proxy together in 21.7% (n = 2,918), and proxy alone in 36.9% (n = 4,967). Use of proxy alone was greater in participants with severe stroke (4.7% with modified-Rankin score of 0 vs. 80.5% in those with score 5; OR 187.13; 95% CI: 119.61-308.22), older persons (43.8% of those aged 80 years and over vs. 33.2% of those aged less than 40 years; age per decade OR 1.09; 95% CI: 1.06-1.12), women (40.7% vs. 34.3% of men; OR 1.32 95% CI: 1.22-1.43), and those less educated (58.9% of those never educated vs. 25.7% of those who attended third level education; OR 7.84; 95% CI: 6.78-9.08). CONCLUSION: Use of proxy respondents enhances the generalizability of international research studies of stroke, by increasing representation of women, patients with severe stroke, older age, and lower education.

Association of Oral Anticoagulation With Stroke in Atrial Fibrillation or Heart Failure: A Comparative Meta-Analysis.

Background and Purpose: Atrial fibrillation and heart failure with reduced ejection fraction (HFrEF) are common sources of cardioembolism. While oral anticoagulation is strongly recommended for atrial fibrillation, there are marked variations in guideline recommendations for HFrEF due to uncertainty about net clinical benefit. This systematic review and meta-analysis evaluates the comparative association of oral anticoagulation with stroke and other cardiovascular risk in populations with atrial fibrillation or HFrEF in sinus rhythm and identify factors mediating different estimates of net clinical benefit. Methods: PubMed and Embase were searched from database inception to November 20, 2019 for randomized clinical trials comparing oral anticoagulation to control. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall and within atrial fibrillation and HFrEF trials. Differences in treatment effect were assessed by estimating I2 among all trials and testing the between-trial-population P-interaction. The primary outcome measure was all stroke. Secondary outcome measures were ischemic stroke, hemorrhagic stroke, mortality, myocardial infarction, and major hemorrhage. Results: Twenty-one trials were eligible for inclusion, 15 (n=19 332) in atrial fibrillation (mean follow-up: 23.1 months), and 6 (n=9866) in HFrEF (mean follow-up: 23.9 months). There were differences in primary outcomes between trial populations, with all-cause mortality included for 95.2% of HFrEF trial population versus 0.38% for atrial fibrillation. Mortality was higher in controls groups of HFrEF populations (19.0% versus 9.6%) but rates of stroke lower (3.1% versus 7.0%) compared with atrial fibrillation. The association of oral anticoagulation with all stroke was consistent for atrial fibrillation (odds ratio, 0.51 [95% CI, 0.42­0.63]) and HFrEF (odds ratio, 0.61 [95% CI, 0.47­0.79]; I2=12.4%; P interaction=0.31). There were no statistically significant differences in the association of oral anticoagulation with cardiovascular events, mortality or bleeding between populations. Conclusions: The relative association of oral anticoagulation with stroke risk, and other cardiovascular outcomes, is similar for patients with atrial fibrillation and HFrEF. Differences in the primary outcomes employed by trials in HFrEF, compared with atrial fibrillation, may have contributed to differing conclusions of the relative efficacy of oral anticoagulation.

Renal Impairment and Risk of Acute Stroke: The INTERSTROKE Study.

BACKGROUND: Previous studies reported an association of renal impairment with stroke, but there are uncertainties underpinning this association. AIMS: We explored if the association is explained by shared risk factors or is independent and whether there are regional or stroke subtype variations. METHODS: INTERSTROKE is a case-control study and the largest international study of risk factors for first acute stroke, completed in 27 countries. We included individuals with available serum creatinine values and calculated estimated glomerular filtration rate (eGFR). Renal impairment was defined as eGFR <60 mL/min/1.73 m2. Multivariable conditional logistic regression was used to determine the association of renal function with stroke. RESULTS: Of 21,127 participants, 41.0% were female, the mean age was 62.3 ± 13.4 years, and the mean eGFR was 79.9 ± 23.5 mL/min/1.73 m2. The prevalence of renal impairment was higher in cases (22.9% vs. 17.7%, p < 0.001) and differed by region (p < 0.001). After adjustment, lower eGFR was associated with increased odds of stroke. Renal impairment was associated with increased odds of all stroke (OR 1.35; 95% CI: 1.24-1.47), with higher odds for intracerebral hemorrhage (OR 1.60; 95% CI: 1.35-1.89) than ischemic stroke (OR 1.29; 95% CI: 1.17-1.42) (pinteraction 0.12). The largest magnitudes of association were seen in younger participants and those living in Africa, South Asia, or South America (pinteraction < 0.001 for all stroke). Renal impairment was also associated with poorer clinical outcome (RRR 2.97; 95% CI: 2.50-3.54 for death within 1 month). CONCLUSION: Renal impairment is an important risk factor for stroke, particularly in younger patients, and is associated with more severe stroke and worse outcomes.

Stroke Severity in Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

OBJECTIVES: An assessment of the comparative incidence of fatal or disabling stroke may influence choice of intervention for patients with severe aortic stenosis. We explored whether transcatheter aortic valve implantation (TAVI) is associated with a lower incidence of fatal or disabling stroke, compared to surgical aortic valve replacement (SAVR). MATERIALS & METHODS: We classified stroke into two categories; fatal or disabling, or non-disabling, and completed meta-analyses for each. We explored randomised controlled trials to assess the effect publication year, predicted operative risk, and route of TAVI access. RESULTS: There was no difference between treatment groups per 100 person years of follow up for disabling or non-disabling stroke outcomes. In a stratified analysis by year of publication, there was a lower rate of fatal or disabling stroke with TAVI in trials published after 2015, compared to those published in 2015 or before (p-interaction = 0.01 at 30 days). Higher proportions of transfemoral route access (>90%), more common in recent trials, were associated with a lower rate of fatal or disabling stroke (p-interaction = 0.03 at 30 days). Lower average surgical risk scores were associated with lower rates of fatal or disabling stroke (p = 0.02 at 30 days). CONCLUSION: We found that treatment of aortic stenosis with TAVI compared with SAVR was not associated with an overall reduced risk in fatal or disabling stroke. Subgroup analyses suggested a lower risk of fatal or disabling stroke with TAVI in situations which reflect contemporary practice.

Physical Activity and Anger or Emotional Upset as Triggers of Acute Myocardial Infarction: The INTERHEART Study.

BACKGROUND: Physical exertion, anger, and emotional upset are reported to trigger acute myocardial infarction (AMI). In the INTERHEART study, we explored the triggering association of acute physical activity and anger or emotional upset with AMI to quantify the importance of these potential triggers in a large, international population. METHODS: INTERHEART was a case-control study of first AMI in 52 countries. In this analysis, we included only cases of AMI and used a case-crossover approach to estimate odds ratios for AMI occurring within 1 hour of triggers. RESULTS: Of 12 461 cases of AMI 13.6% (n=1650) engaged in physical activity and 14.4% (n=1752) were angry or emotionally upset in the case period (1 hour before symptom onset). Physical activity in the case period was associated with increased odds of AMI (odds ratio, 2.31; 99% confidence interval [CI], 1.96-2.72) with a population-attributable risk of 7.7% (99% CI, 6.3-8.8). Anger or emotional upset in the case period was associated with an increased odds of AMI (odds ratio, 2.44; 99% CI, 2.06-2.89) with a population-attributable risk of 8.5% (99% CI, 7.0-9.6). There was no effect modification by geographical region, prior cardiovascular disease, cardiovascular risk factor burden, cardiovascular prevention medications, or time of day or day of onset of AMI. Both physical activity and anger or emotional upset in the case period were associated with a further increase in the odds of AMI (odds ratio, 3.05; 99% CI, 2.29-4.07; P for interaction <0.001). CONCLUSIONS: Physical exertion and anger or emotional upset are triggers associated with first AMI in all regions of the world, in men and women, and in all age groups, with no significant effect modifiers.

Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study.

BACKGROUND: Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents. METHODS: We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35-70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11,963). FINDINGS: We included 114,970 adults, of whom 12,904 (11%) were from high-income countries (HICs), 24,408 (21%) were from upper-middle-income countries (UMICs), 48,845 (43%) were from lower-middle-income countries (LMICs), and 28,813 (25%) were from low-income countries (LICs). Median follow-up was 4.3 years (IQR 3.0-6.0). Current drinking was reported by 36,030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0.76 [95% CI 0.63-0.93]), but increased alcohol-related cancers (HR 1.51 [1.22-1.89]) and injury (HR 1.29 [1.04-1.61]). High intake was associated with increased mortality (HR 1.31 [1.04-1.66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0.84 [0.77-0.92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1.07 [0.95-1.21]; pinteraction<0.0001). INTERPRETATION: Current alcohol consumption had differing associations by clinical outcome, and differing associations by income region. However, we identified sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

Diet and Major Renal Outcomes: A Prospective Cohort Study. The NIH-AARP Diet and Health Study.

BACKGROUND: Chronic kidney disease (CKD) is prevalent and associated with significant morbidity and mortality. Dietary modification may be an approach to reducing CKD. DESIGN: In this prospective cohort study, we evaluated the association between diet quality, sodium and potassium intakes, and major renal outcomes. A total of 544,635 community-dwelling adults, aged 51 to 70 years, living in 6 states and 2 urban areas in the United States, from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Using a food frequency questionnaire completed at baseline, we assessed diet quality using the Alternate Healthy Eating Index (AHEI), Healthy Eating Index (HEI), Mediterranean Diet Score (MDS), Recommended Food Score, and Dietary Approaches to Stop Hypertension (DASH) scores. This was also used to estimate daily sodium and potassium intakes. MAIN OUTCOME MEASURES: Multivariable adjusted competing risks regression calculated sub-hazard ratios (sHRs) for a composite of death due to a renal cause and dialysis, with death due to a nonrenal cause as the competing event. RESULTS: During a mean of 14.3-year follow-up, a total of 4,848 participants died from a renal cause or initiated dialysis. Four diet quality scores (AHEI, HEI, MDS, and DASH) were significantly associated with the composite renal outcome; the Recommended Food Score was not. Compared to the lowest score quintile, the highest quintiles of AHEI (sHR 0.71; 95% confidence interval [CI] 0.65-0.79), HEI (sHR 0.82; 95% CI 0.74-0.91), MDS (sHR 0.84; 95% CI 0.74-0.95), and DASH (sHR 0.85; 95% CI 0.77-0.94) were associated with a reduced hazard of the composite. The highest sodium quintile (sHR 1.17; 95% CI 1.02-1.33 for sodium intake > 3.6 g/day) was associated with an increased hazard, whereas the highest potassium quintile (sHR 0.83 [0.73-0.95]) with a reduced hazard. CONCLUSIONS: Our findings support an association between healthy dietary patterns and reduced risk of major renal outcomes and provide observational evidence to inform dietary guideline recommendations for CKD prevention.

Patterns of alcohol consumption and myocardial infarction risk: observations from 52 countries in the INTERHEART case-control study.

BACKGROUND: Although moderate alcohol use is associated with protection against myocardial infarction (MI), it is not known whether this effect is generalizable to populations worldwide. It is also uncertain whether differences in the pattern of alcohol use (and in particular heavy episodic consumption) between different regions negate any beneficial effect. METHODS AND RESULTS: We included 12 195 cases of first MI and 15 583 age- and sex-matched controls from 52 countries. Current alcohol use was associated with a reduced risk of MI (compared with nonusers: adjusted odds ratio, 0.87; 95% confidence interval, 0.80-0.94; P=0.001); however, the strength of this association was not uniform across different regions (region-alcohol interaction P<0.001). Heavy episodic drinking (≥6 drinks) within the preceding 24 hours was associated with an increased risk of MI (odds ratio, 1.4; 95% confidence interval, 1.1-1.9; P=0.01). This risk was particularly elevated in older individuals (for age >65 years: odds ratio, 5.3; 95% confidence interval, 1.6-18; P=0.008). CONCLUSIONS: In most participants, low levels of alcohol use are associated with a moderate reduction in the risk of MI; however, the strength of this association may not be uniform across different countries. An episode of heavy drinking is associated with an increased risk of acute MI in the subsequent 24 hours, particularly in older individuals.

Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management.

We congratulate the KDIGO (Kidney Disease: Improving Global Outcomes) work group on their comprehensive work in a broad subject area and agreed with many of the recommendations in their clinical practice guideline on the evaluation and management of chronic kidney disease. We concur with the KDIGO definitions and classification of kidney disease and welcome the addition of albuminuria categories at all levels of glomerular filtration rate (GFR), the terminology of G categories rather than stages to describe level of GFR, the division of former stage 3 into new G categories 3a and 3b, and the addition of the underlying diagnosis. We agree with the use of the heat map to illustrate the relative contributions of low GFR and albuminuria to cardiovascular and renal risk, though we thought that the highest risk category was too broad, including as it does people at disparate levels of risk. We add an albuminuria category A4 for nephrotic-range proteinuria and D and T categories for patients on dialysis or with a functioning renal transplant. We recommend target blood pressure of 140/90mm Hg regardless of diabetes or proteinuria, and against the combination of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors. We recommend against routine protein restriction. We concur on individualization of hemoglobin A1c targets. We do not agree with routine restriction of sodium intake to <2g/d, instead suggesting reduction of sodium intake in those with high intake (>3.3g/d). We suggest screening for anemia only when GFR is <30mL/min/1.73m(2). We recognize the absence of evidence on appropriate phosphate targets and methods of achieving them and do not agree with suggestions in this area. In drug dosing, we agree with the recommendation of using absolute clearance (ie, milliliters per minute), calculated from the patient's estimated GFR (which is normalized to 1.73m(2)) and the patient's actual anthropomorphic body surface area. We agree with referral to a nephrologist when GFR is <30mL/min/1.73m(2) (and for many other scenarios), but suggest urine albumin-creatinine ratio > 60mg/mmol or proteinuria with protein excretion > 1g/d as the referral threshold for proteinuria.

Dietary sodium and cardiovascular disease.

Although an essential nutrient, higher sodium intake is associated with increasing blood pressure (BP), forming the basis for current population-wide sodium restriction guidelines. While short-term clinical trials have achieved low intake (<2.0 g/day), this has not been reproduced in long-term trials (>6 months). Guidelines assume that low sodium intake will reduce BP and reduce cardiovascular disease (CVD), compared to moderate intake. However, current observational evidence suggests a J-shaped association between sodium intake and CVD; the lowest risks observed with 3-5 g/day but higher risk with <3 g/day. Importantly, these observational data also confirm the association between higher intake (>5 g/day) and increased risk of CVD. Although lower intake may reduce BP, this may be offset by marked increases in neurohormones and other adverse effects which may paradoxically be adverse. Large randomised clinical trials with sufficient follow-up are required to provide robust data on the long-term effects of sodium reduction on CVD incidence. Until such trials are completed, current evidence suggests that moderate sodium intake for the general population (3-5 g/day) is likely the optimum range for CVD prevention.

The relationship between estimated sodium and potassium excretion and subsequent renal outcomes.

Patients are often advised to reduce sodium and potassium intake, but supporting evidence is limited. To help provide such evidence we estimated 24 h urinary sodium and potassium excretion in 28,879 participants at high cardiovascular risk who were followed for a mean of 4.5 years in the ONTARGET and TRANSCEND trials. The primary outcome was eGFR decline of 30% or more or chronic dialysis. Secondary outcomes were eGFR decline of 40% or more or chronic dialysis, doubling of serum creatinine or chronic dialysis, an over 5%/year loss of eGFR, progression of albuminuria, and hyperkalemia. Multinomial logit regression with multivariable fractional polynomials, adjusted for confounders, determined the association between urinary sodium and potassium excretion and renal outcomes, with death as a competing risk. The primary outcome occurred in 2,052 (7.6%) patients. There was no significant association between sodium and any renal outcome (primary outcome odds ratio 0.99; 95% CI 0.89-1.09 for highest [median 6.2 g/day] vs. lowest third [median 3.3 g/day]). Higher potassium was associated with lower odds of all renal outcomes (primary outcome odds ratio 0.74; 95% CI 0.67-0.82 for highest [median 2.7 g/day] vs. lowest third [median 1.7 g/day], except hyperkalemia nonsignificant. Thus, urinary potassium, but not sodium, excretion predicted clinically important renal outcomes. Our findings do not support routine low sodium and potassium diets for prevention of renal outcomes in people with vascular disease with or without chronic kidney disease.

Vascular risk factors, cardiovascular disease and functional impairment in community-dwelling adults.

BACKGROUND: Older adults report preservation of functional independence as one of the most important constructs of successful ageing. Vascular risk factors may increase the risk of functional impairment due to clinical and subclinical vascular disease. OBJECTIVE: To describe the association between vascular risk factors and impaired ability to perform daily living activities, independent of established cardiovascular disease. METHODS: We conducted an analysis of the Clarity Cohort, which is a cross-sectional study of 9,816 community-dwelling Irish adults. Of the total cohort, 3,499 completed standardized self-reported health questionnaires, which included questions on activities of daily living. Functional impairment was defined as self-reported impairment in self-care, mobility or household tasks. Using logistic regression analyses, we determined the association between vascular risk factors and functional impairment, independent of demographics, prior coronary artery disease, stroke, congestive heart failure, and peripheral vascular disease. RESULTS: Functional impairment was reported in 40.4% (n = 1,413) of the cohort overall and in 23% of those with established cardiovascular disease. The mean age was 66.2 ± 10.3 years, 52% of the cohort were aged over 65 and 45.6% were male. Some difficulty with instrumental activities of daily living was reported by 35.4% (n = 1,240) while 29.4% (n = 1,029) reported some difficulty with basic activities of daily living. On multivariable analysis, older age [OR 1.03 (1.02, 1.04) per year], current smoking [OR 1.43 (1.08, 1.89)], atrial fibrillation [OR 1.68 (1.07, 2.65)], former alcohol use [OR 1.87 (1.36, 2.57)] and prior stroke [OR 1.91 (1.24, 2.93)] were associated with an increased risk of functional impairment. Older age leaving education [OR 0.96 (0.94, 0.99)], non-use of alcohol [OR 0.76 (0.61, 0.93)] and increased high-density lipoprotein levels [OR 0.70 (0.56, 0.88)] were associated with reduced risk of functional impairment. CONCLUSIONS: Independent of established cardiovascular disease, some vascular risk factors are associated with functional impairment. Modification of these risk factors is expected to have a large impact on preservation of functional independence through prevention of overt and covert vascular disease.