Self-Rated Health in Middle Age and Risk of Hospitalizations and Death: Recurrent Event Analysis of the ARIC Study.

BACKGROUND: Self-rated health is a simple measure that may identify individuals who are at a higher risk for hospitalization or death. OBJECTIVE: To quantify the association between a single measure of self-rated health and future risk of recurrent hospitalizations or death. PARTICIPANTS: Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of middle-aged men and women with follow-up beginning from 1987 to 1989. MAIN MEASURES: We quantified the associations between initial self-rated health with risk of recurrent hospitalizations and of death using a recurrent events survival model that allowed for dependency between the rates of hospitalization and hazards of death, adjusted for demographic and clinical factors. KEY RESULTS: Of the 14,937 ARIC cohort individuals with available self-rated health and covariate information, 34% of individuals reported "excellent" health, 47% "good," 16% "fair," and 3% "poor" at study baseline. After a median follow-up of 27.7 years, 1955 (39%), 3569 (51%), 1626 (67%), and 402 (83%) individuals with "excellent," "good," "fair," and "poor" health, respectively, had died. After adjusting for demographic factors and medical history, a less favorable self-rated health status was associated with increased rates of hospitalization and death. As compared to those reporting "excellent" health, adults with "good," "fair," and "poor" health had 1.22 (1.07 to 1.40), 2.01 (1.63 to 2.47), and 3.13 (2.39 to 4.09) times the rate of hospitalizations, respectively. The hazards of death also increased with worsening categories of self-rated health, with "good," "fair," and "poor" health individuals experiencing 1.30 (1.12 to 1.51), 2.15 (1.71 to 2.69), and 3.40 (2.54 to 4.56) times the hazard of death compared to "excellent," respectively. CONCLUSIONS: Even after adjusting for demographic and clinical factors, having a less favorable response on a single measure of self-rated health taken in middle age is a potent marker of future hospitalizations and death.

High-sensitivity troponins and mortality in the general population.

AIMS: Cardiac troponin T and I can be measured using a number of high-sensitivity (hs) assays. This study aimed to characterize correlations between four such assays and test their comparative associations with mortality. METHODS AND RESULTS: Among adults without cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey, hs-troponin T was measured using one assay (Roche) and hs-troponin I using three assays (Abbott, Siemens, and Ortho). Cox regression was used to estimate associations with all-cause and cardiovascular mortality. Pearson's correlation coefficients comparing concentrations from each assay ranged from 0.53 to 0.77. There were 2188 deaths (488 cardiovascular) among 9810 participants. Each hs-troponin assay [log-transformed, per 1 standard deviation (SD)] was independently associated with all-cause mortality: hazard ratio (HR) 1.20 [95% confidence interval (CI) 1.13-1.28] for Abbott hs-troponin I; HR 1.10 (95% CI 1.02-1.18) for Siemens hs-troponin I; HR 1.23 (95% CI 1.14-1.33) for Ortho hs-troponin I; and HR 1.31 (95% CI 1.21-1.42) for Roche hs-troponin T. Each hs-troponin assay was also independently associated with cardiovascular mortality (HR 1.44 to 1.65 per 1 SD). Associations of hs-troponin T and all-cause and cardiovascular mortality remained significant after adjusting for hs-troponin I. Furthermore, associations of hs-troponin I remained significant after mutually adjusting for hs-troponin I from the other individual assays: e.g. cardiovascular mortality HR 1.46 (95% CI 1.19-1.79) for Abbott after adjustment for the Siemens assay and HR 1.29 (95% CI 1.09-1.53) for Abbott after adjustment for the Ortho assay. CONCLUSION: This study demonstrates only modest correlations between hs-troponin T and three hs-troponin I assays and that hs-troponin I assays can provide distinct risk information for mortality in the general population.

Associations of N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and mortality in US adults.

BACKGROUND: NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown. AIMS: We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population. METHODS: We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR. RESULTS: Among 11,456 participants (mean age 43 years, 48% female, 71% White, 11% Black), there was an inverse association between NT-proBNP and eGFR, which was stronger in those with more impaired kidney function. Per 15-unit decrease in eGFR, NT-proBNP was 4.3-fold higher for eGFR<30; 1.7-fold higher for eGFR 30 to 60, 1.4-fold higher for eGFR 61 to 90, 1.1-fold higher for eGFR 91 to 120 mL/min/1.73 m2. Over a median 17.6 years of follow-up, 2,275 deaths (622 cardiovascular) occurred. Higher NT-proBNP was associated with higher all-cause (HR per doubling of NT-proBNP: 1.20, 95% CI: 1.16-1.25) and cardiovascular mortality (HR: 1.34, 95% CI 1.25-1.44). Associations were similar across eGFR categories (P-interaction >.10). Adults with NT-proBNP≥450 pg/mL and eGFR<60 mL/min/1.73m2 had 3.4-fold higher all-cause mortality and 5.5-fold higher cardiovascular mortality risk, compared to those with NT-proBNP<125 pg/mL and eGFR>90 mL/min/1.73m2. CONCLUSION: Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population.

Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study.

AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993-1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.0 years, 54% women, 27% black adults), elevated GDF-15 (≥75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.0001). During 23 years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (ΔC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001). CONCLUSIONS/INTERPRETATION: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes.

Glycated Albumin for the Diagnosis of Diabetes in US Adults.

BACKGROUND: There is growing interest in using glycated albumin for the diagnosis of diabetes, especially when standard tests (glucose and hemoglobin A1c [Hb A1c]) are unavailable. However, it is unknown how well glycated albumin identifies diabetes in the general population. METHODS: We measured glycated albumin in stored serum samples from the 1999-2004 National Health and Nutrition Examination Survey. We evaluated the ability of glycated albumin to identify undiagnosed diabetes in US adults aged ≥20 (n = 4785), overall and at thresholds corresponding to clinical cut points for Hb A1c and fasting plasma glucose (FPG). We assessed 4 reference definitions for undiagnosed diabetes: increased FPG (≥126 mg/dL) [≥6.99 mmol/L), increased Hb A1c (≥6.5%), either FPG or Hb A1c increased, or both FPG and Hb A1c increased. RESULTS: Among US adults, glycated albumin had excellent diagnostic accuracy across all 4 definitions of undiagnosed diabetes, with the area under the receiver operating characteristic curve (AUC) ranging from 0.824 to 0.951. Performance was generally consistent across patient demographic and clinical characteristics. Glycated albumin cut points of 16.5% and 17.8% were equivalent to an FPG of 126 mg/dL (6.99 mmol/L; 97th percentile) and Hb A1c of 6.5% (98th percentile) and had low to moderate sensitivity (0.273 to 0.707) but high specificity (0.980 to 0.992) for detecting undiagnosed diabetes. CONCLUSION: The excellent diagnostic performance of glycated albumin to identify diabetes defined by either FPG or Hb A1c suggests that glycated albumin may be useful for identifying adults with undiagnosed diabetes when standard tests are unavailable.

Glycated Albumin and Risk of Mortality in the US Adult Population.

BACKGROUND: Glycated albumin is of growing interest as an alternative biomarker of glycemia. However, the association of glycated albumin with long-term outcomes in the general population is uncharacterized. We evaluated the associations of glycated albumin and hemoglobin A1c (HbA1c) with mortality in US adults. METHODS: We conducted a prospective analysis of 12 915 participants in the National Health and Nutrition Examination Survey 1999-2004. We used Cox regression to characterize associations of glycated albumin and HbA1c with all-cause and cardiovascular mortality through 2014. We categorized glycated albumin based on percentiles corresponding to clinical cut-points for HbA1c. No diagnosed diabetes: <5.0% (<12th percentile), 5.0% to 5.6% (12th-82nd percentile, reference), 5.7% to 6.4% (83rd-97th percentile), and ≥6.5% (≥98th percentile). Diagnosed diabetes: <7.0% (<50th percentile), 7.0% to 8.9% (50th-83rd percentile), and ≥9.0% (≥84th percentile). RESULTS: Among US adults (mean age 46 years), the prevalence of diagnosed diabetes was 6.8%. Glycated albumin and HbA1c were highly correlated (r = 0.76). Over the median 16.8 years follow-up, there were 2818 deaths (652 cardiovascular). Adults with diagnosed diabetes and glycated albumin ≥84th percentile had the highest risk for all-cause mortality [hazard ratio (HR) 3.96, 95% CI 3.06-5.13] and cardiovascular mortality (HR 6.80, 95% CI 4.20-11.03). HbA1c had associations with all-cause and cardiovascular mortality that were similar to those for glycated albumin. CONCLUSIONS: Among US adults, increased values of glycated albumin and HbA1c were associated with all-cause and cardiovascular mortality, particularly in persons with diagnosed diabetes. Glycated albumin may be a useful alternative test of glycemia.

Association Between Acute Kidney Injury and Dementia in the Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) causes biochemical changes in the brain in animal models and is associated with adverse neurological complications in hospitalized patients. This study tested the association between AKI and incident dementia in a community-based cohort. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adult participants in the Atherosclerosis Risk in Communities (ARIC) study who experienced hospitalized AKI compared with participants hospitalized for other reasons (primary analysis, mean follow-up period 4.3 years) or participants without hospitalized AKI (secondary analysis). PREDICTORS: Incident AKI, defined by ICD codes from hospital records. OUTCOME: Incident dementia, diagnosed based on a combination of neurocognitive testing, informant interviews, ICD codes, and death certificates. ANALYTICAL APPROACH: In the primary analysis, we estimated the propensity for hospitalized AKI and matched these participants with those hospitalized for another reason to examine the association of AKI with subsequent onset of dementia (N = 1,708). In the secondary analysis, we estimated the association between time-varying hospitalized AKI and subsequent onset of dementia using multivariable Cox proportional hazards regression models, adjusted for age, sex, race/center, education, smoking status, body mass index, baseline estimated glomerular filtration rate, baseline urinary albumin-creatinine ratio, systolic blood pressure, coronary heart disease, diabetes, hypertension, apolipoprotein E (APOE) ε4 allele, and C-reactive protein. RESULTS: The mean age in the propensity-matched cohort was 76.1 ± 6.5 (SD) years, and 53.2% of the participants were women. People who were hospitalized with AKI had a higher risk of dementia (HR, 1.25 [95% CI, 1.02-1.52]; P = 0.03) compared with those without a hospitalization for AKI. The associations were slightly stronger in the time-varying analysis (HR, 1.69 [95% CI, 1.48-1.92]; P < 0.001). Other risk factors for dementia included older age, male sex, higher albuminuria, diabetes, current smoker status, and presence of the APOE risk alleles. LIMITATIONS: Observational study, with AKI identified through diagnosis codes. CONCLUSIONS: Participants who experienced a hospitalization for AKI were at increased risk of dementia.

Growth Differentiation Factor (GDF)-15 and Cardiometabolic Outcomes among Older Adults: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: Laboratory studies suggest an involvement of growth differentiation factor 15 (GDF-15) in metabolic dysregulation. However, the utility of GDF-15 for assessing risk of cardiometabolic outcomes has not been rigorously examined among older adults. METHODS: We conducted a cross-sectional analysis of older adults who attended visit 6 (2016-2017) of the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to quantify cross-sectional associations of GDF-15 (in quartiles) with prevalent diabetes, obesity, atherosclerotic cardiovascular disease (ASCVD), subclinical myocardial stress/injury (assessed by NT-proB-type Natriuretic Peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT]), and heart failure (HF). RESULTS: Among 3792 ARIC study participants (mean age 80 years, 59% women, 23% Blacks and 77% Whites, mean GDF-15: 2094.9 pg/mL [SD: 1395.6]), higher GDF-15 concentrations (highest vs. lowest quartile) were positively associated with diabetes (adjusted odds ratio [aOR]:] : 2.48, 95% CI : 1.89, 3.26), ASCVD (aOR: 1.57, 95% CI: 1.16, 2.11), increased hscTnT (aOR: 2.27, 95%CI: 1.54, 3.34), increased NT-proBNP (aOR: 1.98, 95%CI: 1.46, 2.70), and HF (aOR: 3.22, 95%CI : 2.13, 4.85), in models adjusted for demographics and traditional cardiovascular risk factors. CONCLUSIONS: In this sample of older US black and whites, increased GDF-15 was positively associated with diabetes, ASCVD, HF, and markers of subclinical myocardial stress or injury. These results illustrate the diverse aspects of the link between GDF-15 and diseases states, and its potential utility as robust biomarker of adverse cardiometabolic outcomes.

Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population. METHODS: We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro-B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, ß-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A1c [Hb A1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016-2017; age 71-94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors. RESULTS: In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44-3.22]; no diabetes: OR, 2.31 [95%CI, 1.76-3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08-1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22-1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A1c (OR, 1.76 [95% CI, 1.22-2.54]), fructosamine (OR, 1.71 [95% CI, 1.19-2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03-2.03]) with PN were significant only among participants with diabetes. CONCLUSIONS: Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Alcohol Consumption and Risk of Hospitalizations and Mortality in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Public health recommendations on the benefits and harms of moderate alcohol intake require a thorough and unbiased understanding of all potential effects of various levels and patterns of alcohol consumption. We seek to evaluate the associations between patterns of current and past alcohol consumption with hospitalizations and mortality. METHODS: Data came from a prospective cohort of 12,327 adults (56% women, 78% white, mean age 60 years) participating in the Atherosclerosis Risk in Communities study visit 3 (1993 to 1995). Current and past alcohol consumption was based on self-report. Hospitalizations and mortality were ascertained through December 31, 2017. Negative binomial and Cox proportional hazards regressions were used. RESULTS: 24.8% of the study population reported never drinking, 48.3% reported currently drinking without a history of heavy drinking, 4.2% reported currently drinking with a history of heavy drinking, 19.2% reported being former drinkers without a history of heavy drinking, and 3.4% reported being former drinkers with a history of heavy drinking. Compared to those who reported drinking ≤1 to 7 drinks/wk, never drinkers (incident rate ratio [IRR]: 1.21 (95% confidence interval 1.13, 1.29) and former drinkers with (IRR: 1.43 [1.26, 1.63]) or without (IRR: 1.21 [1.13, 1.30]) a history of heavy drinking had a positive association with all-cause hospitalization (p < 0.001). Those who reported drinking ≤1 to 7 drinks/wk had the lowest all-cause mortality rate (19.2 per 1,000 person-years [18.4, 20.1]) and former drinkers with a history of heavy drinking had the highest (43.7 per 1,000 person-years [39.0, 49.1]). CONCLUSIONS: The positive associations with hospitalization and mortality were stronger among never and former drinkers compared to those who consume ≤1 to 7 drinks/wk. Former drinkers with a history of heavy drinking had a stronger positive association with adverse health outcomes than former drinkers without a history of heavy drinking, highlighting the impact of this pattern of alcohol consumption.

Association of Isolated Diastolic Hypertension as Defined by the 2017 ACC/AHA Blood Pressure Guideline With Incident Cardiovascular Outcomes.

IMPORTANCE: In the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, the definition of hypertension was lowered from a blood pressure (BP) of greater than or equal to 140/90 to greater than or equal to 130/80 mm Hg. The new diastolic BP threshold of 80 mm Hg was recommended based on expert opinion and changes the definition of isolated diastolic hypertension (IDH). OBJECTIVE: To compare the prevalence of IDH in the United States, by 2017 ACC/AHA and 2003 Joint National Committee (JNC7) definitions, and to characterize cross-sectional and longitudinal associations of IDH with outcomes. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of the National Health and Nutrition Examination Survey (NHANES 2013-2016) and longitudinal analyses of the Atherosclerosis Risk in Communities (ARIC) Study (baseline 1990-1992, with follow-up through December 31, 2017). Longitudinal results were validated in 2 external cohorts: (1) the NHANES III (1988-1994) and NHANES 1999-2014 and (2) the Give Us a Clue to Cancer and Heart Disease (CLUE) II cohort (baseline 1989). EXPOSURES: IDH, by 2017 ACC/AHA (systolic BP <130 mm Hg, diastolic BP ≥80 mm Hg) and by JNC7 (systolic BP <140 mm Hg, diastolic BP ≥90 mm Hg) definitions. MAIN OUTCOMES AND MEASURES: Weighted estimates for prevalence of IDH in US adults and prevalence of US adults recommended BP pharmacotherapy by the 2017 ACC/AHA guideline based solely on the presence of IDH. Risk of incident atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD) in the ARIC Study. RESULTS: The study population included 9590 adults from the NHANES (mean [SD] baseline age, 49.6 [17.6] years; 5016 women [52.3%]) and 8703 adults from the ARIC Study (mean [SD] baseline age, 56.0 [5.6] years; 4977 women [57.2%]). The estimated prevalence of IDH in the NHANES was 6.5% by the 2017 ACC/AHA definition and 1.3% by the JNC7 definition (absolute difference, 5.2% [95% CI, 4.7%-5.7%]). Among those newly classified as having IDH, an estimated 0.6% (95% CI, 0.5%-0.6%) also met the guideline threshold for antihypertensive therapy. Compared with normotensive ARIC participants, IDH by the 2017 ACC/AHA definition was not significantly associated with incident ASCVD (n = 1386 events; median follow-up, 25.2 years; hazard ratio [HR], 1.06 [95% CI, 0.89-1.26]), HF (n = 1396 events; HR, 0.91 [95% CI, 0.76-1.09]), or CKD (n = 2433 events; HR, 0.98 [95% CI, 0.65-1.11]). Results were also null for cardiovascular mortality in the 2 external cohorts (eg, HRs of IDH by the 2017 ACC/AHA definition were 1.17 [95% CI, 0.87-1.56] in the NHANES [n = 1012 events] and 1.02 [95% CI, 0.92-1.14] in CLUE II [n = 1497 events]). CONCLUSIONS AND RELEVANCE: In this analysis of US adults, the estimated prevalence of IDH was more common when defined by the 2017 ACC/AHA BP guideline compared with the JNC7 guideline. However, IDH was not significantly associated with increased risk for cardiovascular outcomes.

Alcohol consumption and incident diabetes: The Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the prospective association between baseline and 9 year change in alcohol consumption and long-term risk of diabetes and whether these associations might be modified by sex and/or BMI. METHODS: We conducted a prospective analysis of 12,042 Atherosclerosis Risk in Communities (ARIC) study participants without prevalent diabetes (55% women, 78% white, mean age 54 years). Alcohol consumption was assessed at visit 1 (1987-1989) and visit 4 (1996-1998). We used Cox models to estimate hazard ratios for diabetes risk by baseline drinking categories and change in alcohol consumption, stratified by sex and obesity status. RESULTS: During a median follow-up of 21 years, there were 3795 incident cases of diabetes. Among women, consuming 8-14 drinks/week was associated with a significantly lower risk of diabetes (HR 0.75, 95% CI 0.58, 0.96) compared with current drinkers consuming ≤1 drink/week. Among men, consuming 8-14 drinks/week was associated with a borderline significant lower risk of diabetes (HR 0.84, 95% CI 0.70, 1.00) and consuming >14 drinks/week was associated with a significantly lower risk of diabetes (HR 0.81, 95% CI 0.67, 0.97) (pinteraction < 0.01 for sex). For both sexes, among current drinkers, there was a significant decreasing trend in diabetes risk as the alcohol consumption increased. The association was modified by BMI (pinteraction = 0.042 for women, pinteraction < 0.001 for men). In women, the inverse association was only seen among overweight and obese participants. In men, the inverse association was more pronounced among obese participants. On average, drinking status did not change substantially over the 9 year period. For men with alcohol intake ≥7 drinks/week at baseline, decreasing alcohol intake was associated with higher risk of diabetes (HR per daily drink decrease 1.12, 95% CI 1.02, 1.23). CONCLUSIONS/INTERPRETATION: In this community-based population, there was an inverse association between alcohol consumption and diabetes risk. The amount of the alcohol consumption associated with lower risk was different in women and men, and the association was more pronounced among participants with higher BMI.

Hospitalization Risk among Older Adults with Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease (CKD) risk staging is based on estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). However, the relationship between all-cause hospitalization risk and the current CKD staging system has not been well studied among older adults, despite a high prevalence of CKD and a high risk of hospitalization in old age. METHODS: Among 4,766 participants of the Atherosclerosis Risk in Communities study, CKD was staged according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, using creatinine-based eGFR (eGFRcr) and ACR. Incidence rates of all-cause hospitalization associated with each CKD risk group were analyzed using negative binomial regression. Additionally, cause-specific hospitalization risks for cardiovascular, infectious, kidney, and other diseases were estimated. The impacts of using cystatin C-based eGFR (eGFRcys) to estimate the prevalence of CKD and risks of hospitalization were also quantified. RESULTS: Participants experienced 5,548 hospitalizations and 29% had CKD. Hospitalization rates per 1,000 person-years according to KDIGO risk categories were 208-223 ("low risk"), 288-376 ("moderately increased risk"), 363-548 ("high risk"), and 499-1083 ("very high risk"). The increased risk associated with low eGFR and high ACR persisted in adjusted analyses, examinations of cause-specific hospitalizations, and when CKD was staged by eGFRcys or eGFRcr-cys, a combined equation based on both creatinine and cystatin C. In comparison to eGFRcr, staging by eGFRcys increased the prevalence of CKD to 50%, but hospitalization risks remained similarly high. DISCUSSION/CONCLUSION: In older adults, decreased eGFR, increased ACR, and KDIGO risk stages based on a combination of these measures, were strong risk factors for hospitalization. These relationships were consistent, regardless of the marker used to estimate GFR, but the use of cystatin C resulted in a substantially higher prevalence of CKD than the use of creatinine. Older adults in the population with very high risk stages of CKD have hospitalization rates exceeding 500 per 1,000 person-years.

Confluence of Epidemics of Hepatitis C, Diabetes, Obesity, and Chronic Kidney Disease in the United States Population.

BACKGROUND & AIMS: Obesity, kidney disease, and diabetes are common conditions that can affect outcomes of patients with chronic hepatitis C. The authors aimed to quantify the burden of these comorbid conditions among adults with chronic hepatitis C in the United States and to estimate the risk of death among people with chronic hepatitis C and comorbidities. METHODS: The authors conducted cross-sectional and prospective analyses of 13,726 participants in the third National Health and Nutrition Examination Survey (NHANES III) and 23,691 participants of NHANES 1999-2012. Serum samples were analyzed for the presence of antibodies to hepatitis C virus (anti-HCV); in samples found to be positive for anti-HCV, the authors quantified HCV RNA (viral load). Individuals with anti-HCV and detectable HCV RNA were considered to have chronic hepatitis C. Comorbidities were defined using self-reported, physical examination, and laboratory data, as available. The authors used logistic models and predictive margins to estimate the adjusted prevalence of comorbidities in patients with chronic hepatitis C. The authors used Poisson regression models to estimate adjusted mortality rates based on chronic hepatitis C status, with or without comorbidities. Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause, cardiovascular, and cancer mortality according to chronic hepatitis C status, with and without comorbidities. RESULTS: Among persons with chronic hepatitis C, the demographic-adjusted prevalence estimate of diabetes was 17.9% (95% CI, 11.2%-27.5%) and of obesity was 20.9% (95% CI, 12.4%-29.5%). Overall, 69.6% of persons with chronic hepatitis C had at least 1 major cardiometabolic comorbidity (95% CI, 62.1%-76.2%). Only 38% of adults with chronic hepatitis C reported a diagnosis of liver disease. Chronic hepatitis C was associated with a substantially increased risk of death (HR, 2.45), especially in the presence of diabetes (HR, 3.24) or chronic kidney disease (HR, 4.39). CONCLUSION: In an analysis of NHANES data, the authors found that individuals with chronic hepatitis C have a high burden of major cardiometabolic comorbidities. Diabetes and chronic kidney disease, in particular, are associated with substantial excess mortality in persons with chronic hepatitis C.

Frailty, Kidney Function, and Polypharmacy: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Frail individuals are at increased risk for poor outcomes, including adverse drug events. Kidney function is often compromised in frailty and is a key consideration in medication choice and dosing; however, creatinine-based measures of kidney function may be biased in frail individuals. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 4,987 community-dwelling older men and women with complete data who participated in visit 5 of the Atherosclerosis Risk in Communities (ARIC) Study (2011-2013). PREDICTORS: Kidney measures included glomerular filtration rate (GFR) estimated using serum creatinine (eGFRcr) and serum cystatin C level (eGFRcys) and urine albumin-creatinine ratio. OUTCOME: Frailty, defined using established criteria of 3 or more frailty characteristics (weight loss, slowness, exhaustion, weakness, and low physical activity). RESULTS: 341 (7%) participants were classified as frail, 1,475 (30%) had eGFRcr<60mL/min/1.73m2, 2,480 (50%) had eGFRcys<60mL/min/1.73m2, and 1,006 (20%) had albuminuria with albumin excretion ≥ 30mg/g. Among frail participants, prevalences of eGFRcr and eGFRcys<60mL/min/1.73m2 were 45% and 77%, respectively. Adjusted for covariates, frailty showed a moderate association with eGFRcr and a strong association with eGFRcys and albumin-creatinine ratio. Frail individuals with eGFRcr of 60 to <75mL/min/1.73m2 were frequently reclassified to lower eGFR categories using eGFRcys (49% to 45-<60, 32% to 30-<45, and 3% to <30mL/min/1.73m2). Hyperpolypharmacy (taking ≥10 classes of medications) was more common in frail individuals (54% vs 38% of nonfrail), including classes requiring kidney clearance (eg, digoxin) and associated with falls and subsequent complications (eg, hypnotic/sedatives and anticoagulants). LIMITATIONS: Cross-sectional study design. CONCLUSIONS: Frail individuals had a high prevalence of reduced kidney function, with large discrepancies when reduced kidney function was classified by eGFRcys versus eGFRcr. Given the substantial medication burden and uncertainty in chronic kidney disease classification, confirmation of kidney function with alternative biomarkers may be warranted to ensure careful prescribing practices in this vulnerable population.

Thyroid function, reduced kidney function and incident chronic kidney disease in a community-based population: the Atherosclerosis Risk in Communities study.

BACKGROUND: Reduced kidney function is a common public health problem that increases risk for a wide variety of adverse outcomes, making the identification of potentially modifiable factors associated with the development of incident chronic kidney disease (CKD) important. Alterations in the hypothalamic-pituitary-thyroid axis have been linked to reduced kidney function, but the association of thyroid function with the development of incident CKD is largely uncharacterized. METHODS: Concentrations of thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3) and thyroid peroxidase antibody (TPOAb) were quantified in 12 785 black and white participants of the ongoing community-based prospective Atherosclerosis Risk in Communities study. Thyroid markers and clinical categories of thyroid dysfunction (euthyroidism, combined subclinical and overt hypothyroidism, combined subclinical and overt hyperthyroidism) were also evaluated for their association with reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m2) at study baseline and with incident CKD over a median follow-up time of 19.6 years. RESULTS: Higher TSH and FT4 as well as lower T3 concentrations were strongly and independently associated with reduced kidney function at study baseline. The clinical entities hypothyroidism and hyperthyroidism were also associated with higher odds of baseline reduced kidney function, but this was not significant. However, none of the markers of thyroid function nor different clinical categories of thyroid dysfunction (hypothyroidism, hyperthyroidism or TPOAb positivity) were associated with incident CKD in adjusted analyses. CONCLUSIONS: Elevated TSH, FT4 and reduced T3 concentrations were associated with reduced kidney function cross-sectionally. The lack of association with the development of incident CKD suggests that altered thyroid function in the general population is not causally related to CKD development, but screening for thyroidal status may be especially relevant in persons with reduced kidney function.

Kidney Function and Fracture Risk: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: People with end-stage renal disease are at high risk for bone fracture. Less is known about fracture risk in milder chronic kidney disease and whether chronic kidney disease-associated fracture risk varies by sex or assessment with alternative kidney markers. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 10,955 participants from the Atherosclerosis Risk in Communities (ARIC) Study followed up from 1996 to 2011. PREDICTOR: Kidney function as assessed by creatinine-based estimated glomerular filtration rate (eGFRcr), urine albumin-creatinine ratio, and alternative filtration markers. OUTCOMES: Fracture-related hospitalizations determined by diagnostic code. MEASUREMENTS: Baseline kidney markers; hospitalizations identified by self-report during annual telephone contact and active surveillance of local hospital discharge lists. RESULTS: Mean age of participants was 63 years, 56% were women, and 22% were black. During a median follow-up of 13 years, there were 722 incident fracture-related hospitalizations. Older age, female sex, and white race were associated with higher risk for fracture (P<0.001). The relationship between eGFRcr and fracture risk was nonlinear: <60mL/min/1.73m(2), lower eGFRcr was associated with higher fracture risk (adjusted HR per 10mL/min/1.73m(2) lower, 1.24; 95% CI, 1.05-1.47); there was no statistically significant association for ≥60mL/min/1.73m(2) in the primary analysis. In contrast, there was a graded association between other markers of kidney function and subsequent fracture, including albumin-creatinine ratio (HR per doubling, 1.10; 95% CI, 1.06-1.14), cystatin C-based eGFR (HR per 1-SD decrease, 1.15; 95% CI, 1.06-1.25), and 1/ß2-microglobulin (HR per 1-SD decrease, 1.26, 95% CI, 1.15-1.37). LIMITATIONS: No bone mineral density assessment; one-time measurement of kidney function. CONCLUSIONS: Both low eGFR and higher albuminuria were significant risk factors for fracture in this community-based population. The shape of the association in the upper ranges of eGFR varied by the filtration marker used in estimation.

Modeling the Impact of Biomarker-Guided Versus ASCVD Risk-Guided Drug Treatment in US Adults With Stage 1 Hypertension: The National Health and Nutrition Examination Survey, 1999 to 2004.

BACKGROUND: Guidelines recommend antihypertensive medication for adults with both stage 1 hypertension (systolic blood pressure, 130-139 mm Hg or diastolic blood pressure, 80-89 mm Hg) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥10%. Cardiac biomarkers could facilitate a more targeted approach to the treatment of stage 1 hypertension. METHODS: We studied 1999 to 2004 National Health and Nutrition Examination Survey participants aged ≥20 years with untreated stage 1 hypertension without heart failure or ASCVD. We measured hs-cTnI (high-sensitivity cardiac troponin I), hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in stored serum. We used the Pooled Cohort Equations to predict 10-year ASCVD risk. All participants had linked mortality follow-up through December 31, 2019. RESULTS: Overall, 17.5% of US adults (32.2 million) had untreated stage 1 hypertension. Among these 32.2 million persons, 15.7% had ASCVD risk ≥10%, 5.6% had elevated hs-cTnI, 4.7% had elevated hs-cTnT, and 9.5% had elevated NT-proBNP. Among adults aged 65 to 79 years with untreated stage 1 hypertension, 80.5% had ASCVD risk ≥10%, 13.0% had elevated hs-cTnI, 15.2% had elevated hs-cTnT, and 29.4% had elevated NT-proBNP. Less than half of the adults aged ≥80 years with untreated stage 1 hypertension had elevated biomarkers. The cardiovascular disease mortality rates among all adults with untreated stage 1 hypertension and with either ASCVD risk ≥10%, elevated hs-cTnI, elevated hs-cTnT, or elevated NT-proBNP were 7.51, 7.74, 8.75, and 5.87 per 1000 person-years, respectively. CONCLUSIONS: Cardiac biomarkers may be more selective for informing risk-based treatment decisions in stage 1 hypertension, particularly among adults aged ≥65 years.

Derivation and Validation of ICD-10 Codes for Identifying Incident Stroke.

Importance: Claims data with International Statistical Classification of Diseases, Tenth Revision (ICD-10) codes are routinely used in clinical research. However, the use of ICD-10 codes to define incident stroke has not been validated against expert-adjudicated outcomes in the US population. Objective: To develop and validate the accuracy of an ICD-10 code list to detect incident stroke events using Medicare inpatient fee-for-service claims data. Design, Setting, and Participants: This cohort study used data from 2 prospective population-based cohort studies, the Atherosclerosis Risk in Communities (ARIC) study and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, and included participants aged 65 years or older without prior stroke who had linked Medicare claims data. Stroke events in the ARIC and REGARDS studies were identified via active surveillance and adjudicated by expert review. Medicare-linked ARIC data (2016-2018) were used to develop a list of ICD-10 codes for incident stroke detection. The list was validated using Medicare-linked REGARDS data (2016-2019). Data were analyzed from September 1, 2022, through September 30, 2023. Exposures: Stroke events detected in Medicare claims vs expert-adjudicated stroke events in the ARIC and REGARDS studies. Main Outcomes and Measures: The main outcomes were sensitivity and specificity of incident stroke detection using ICD-10 codes. Results: In the ARIC study, there were 110 adjudicated incident stroke events among 5194 participants (mean [SD] age, 80.1 [5.3] years) over a median follow-up of 3.0 (range, 0.003-3.0) years. Most ARIC participants were women (3160 [60.8%]); 993 (19.1%) were Black and 4180 (80.5%) were White. Using the primary diagnosis code on a Medicare billing claim, the ICD-10 code list had a sensitivity of 81.8% (95% CI, 73.3%-88.5%) and a specificity of 99.1% (95% CI, 98.8%-99.3%) to detect incident stroke. Using any diagnosis code on a Medicare billing claim, the sensitivity was 94.5% (95% CI, 88.5%-98.0%) and the specificity was 98.4% (95% CI, 98.0%-98.8%). In the REGARDS study, there were 140 adjudicated incident strokes among 6359 participants (mean [SD] age, 75.8 [7.0] years) over a median follow-up of 4.0 (range, 0-4.0) years. More than half of the REGARDS participants were women (3351 [52.7%]); 1774 (27.9%) were Black and 4585 (72.1%) were White. For the primary diagnosis code, the ICD-10 code list had a sensitivity of 70.7% (95% CI, 63.2%-78.3%) and a specificity of 99.1% (95% CI, 98.9%-99.4%). For any diagnosis code, the ICD-10 code list had a sensitivity of 77.9% (95% CI, 71.0%-84.7%) and a specificity of 98.9% (95% CI, 98.6%-99.2%). Conclusions and Relevance: These findings suggest that ICD-10 codes could be used to identify incident stroke events in Medicare claims with moderate sensitivity and high specificity.

Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.

OBJECTIVE: Autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are found in patients with statin-associated immune-mediated necrotizing myopathy and, less commonly, in statin-unexposed patients with autoimmune myopathy. The main objective of this study was to define the association of anti-HMGCR antibody levels with disease activity. METHODS: Anti-HMGCR levels, creatine kinase (CK) levels, and strength were assessed in anti-HMGCR-positive patients. Associations of antibody level with CK level and strength at visit 1 were analyzed in 55 patients, 40 of whom were exposed to statins. In 12 statin-exposed and 5 statin-unexposed patients with serum from 5 serial visits, the evolution of antibody levels, CK levels, and strength was investigated. RESULTS: Antibody levels were associated with CK levels (P < 0.001), arm strength (P < 0.05), and leg strength (P < 0.05) at visit 1, but these associations were only significant among statin-exposed patients in stratified analyses. With immunosuppressive treatment over 26.2 ± 12.6 months (mean ± SD), antibody levels declined (P < 0.05) and arm abduction strength improved (P < 0.05) in the 17 patients followed up longitudinally. The separate analysis showed that statin-exposed patients developed decreased antibody levels (P < 0.01), decreased CK levels (P < 0.001), improved arm strength (P < 0.05), and improved hip flexion strength (P < 0.05) with treatment. Anti-HMGCR antibody levels did not normalize in any patient. CONCLUSION: In the entire cohort, initial anti-HMGCR levels correlated with indicators of disease activity; with immunosuppressive treatment, antibody levels declined and arm strength improved. Statin-exposed patients had significant improvements in CK levels and strength whereas statin-unexposed patients did not, suggesting a phenotypic difference between statin-exposed and statin-unexposed anti-HMGCR-positive patients.