Faculty Bibliography

OBJECTIVE:Clinical guidelines for people with diabetes recommend chronic kidney disease (CKD) testing at least annually using estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR). We aimed to understand CKD testing among people with type 2 diabetes in the U.S. RESEARCH DESIGN AND METHODS:Electronic health record data were analyzed from 513,165 adults with type 2 diabetes receiving primary care from 24 health care organizations and 1,164 clinical practice sites. We assessed the percentage of patients with both one or more eGFRs and one or more uACRs and each test individually in the 1, 2, and 3 years ending September 2019 by health care organization and clinical practice site. Elevated albuminuria was defined as uACR ≥30 mg/g. RESULTS:The 1-year median testing rate across organizations was 51.6% for both uACR and eGFR, 89.5% for eGFR, and 52.9% for uACR. uACR testing varied (10th-90th percentile) from 44.7 to 63.3% across organizations and from 13.3 to 75.4% across sites. Over 3 years, the median testing rate for uACR across organizations was 73.7%. Overall, the prevalence of detected elevated albuminuria was 15%. The average prevalence of detected elevated albuminuria increased linearly with uACR testing rates at sites, with estimated prevalence of 6%, 15%, and 30% at uACR testing rates of 20%, 50%, and 100%, respectively. CONCLUSIONS:While eGFR testing rates are uniformly high among people with type 2 diabetes, testing rates for uACR are suboptimal and highly variable across and within the organizations examined. Guideline-recommended uACR testing should increase detection of CKD.

Rationale & Objective/UNASSIGNED:Retinopathy and chronic kidney disease (CKD) are typically considered microvascular complications of diabetes, and cardiovascular and cerebrovascular diseases are considered macrovascular complications; however, all may share common pathological mechanisms. This study quantified the association of retinopathy with risk of kidney disease and compared with the association with cardiovascular disease in persons with diabetes. Study Design/UNASSIGNED:Retrospective cohort study. Setting & Participants/UNASSIGNED:1,759 participants in the ARIC study who had diabetes at visit 4 and underwent retinal examination at visit 3. Exposure/UNASSIGNED:Retinopathy. Outcome/UNASSIGNED:), prevalent albuminuria (urinary albumin-creatinine ratio [UACR] > 30 mg/g), incident CKD, incident end-stage kidney disease (ESKD), incident coronary heart disease (CHD), and incident stroke. Analytical Approach/UNASSIGNED:The cross-sectional association of retinopathy with prevalent CKD and albuminuria was assessed by logistic regression. The associations between retinopathy, incident CKD, incident ESKD, incident CHD, and incident stroke were examined using Cox proportional hazards models. Seemingly unrelated regression was used to compare the strength of association between retinopathy and outcomes. Results/UNASSIGNED: = 0.03); all other associations were similar. Limitations/UNASSIGNED:Retinal examination and kidney measurements were taken at different visits. Conclusions/UNASSIGNED:The presence of retinopathy was associated with higher prevalence of kidney disease and higher risk of incident CKD, ESKD, and CHD. These results may suggest that a similar mechanism underlies the development of retinopathy and other adverse outcomes in diabetes.

BACKGROUND AND AIMS:Previous community-based studies have demonstrated sex and race-based disparities in the risk of cardiovascular disease. We sought to examine the association of sex and race with incident peripheral artery disease (PAD-) and critical limb ischemia (CLI-) related hospitalizations. METHODS:In 13,451 Black and White ARIC participants without prevalent PAD at baseline (1987-89), we estimated the cumulative incidence of PAD- and CLI-related hospitalization over a median follow-up of 26 years. We quantified hazard ratios (HRs) using Cox models across four sex- and race-groups. PAD and CLI were defined by hospitalization discharge codes. RESULTS:The cumulative incidence of PAD-related hospitalization was higher in males than females in Whites (5.1% vs. 2.7%; p<0.001) but not in Blacks (5.7% vs. 5.0%; p=0.39). The cumulative incidence of CLI-related hospitalization differed significantly by race more than sex, occurring in 3.1% Black males, 3.1% Black females, 1.4% White males, and 0.8% White females (p<0.001). After risk factor adjustment, the risk of incident PAD-related hospitalization was similar for White males vs. White females [HR 1.14, 95%CI 0.90-1.45], and slightly higher for Black males [HR 1.26, 95%CI 0.92-1.72] and Black females [HR 1.39, 95%CI 1.03-1.87] compared to White females. The adjusted risk of incident CLI-related hospitalization was similar for White males vs. White females [HR 1.15, 95%CI 0.75-1.76], and significantly higher for Black males [HR 1.96, 95%CI 1.22-3.16] and Black females [HR 2.06, 95%CI 1.31-3.24] compared to White females. CONCLUSIONS:These data suggest that there are both sex- and race-specific patterns of PAD-related hospitalization that lead to differences in clinical disease risk and presentation.

BACKGROUND:and incorporates age, sex, GFR, and urine albumin-creatinine ratio (ACR) to forecast individual risk of kidney failure. Implementing the KFRE in electronic medical records is challenging, however, due to low ACR testing in clinical practice. The aim of this study was to determine, when ACR is missing, whether to impute ACR from protein-to-creatinine ratio (PCR) or dipstick protein for use in the four-variable KFRE, or to use the three-variable KFRE, which does not require ACR. METHODS:were categorized on the basis of the availability of ACR testing within the previous 3 years. For patients missing ACR, we extracted urine PCR and dipstick protein results, comparing the discrimination of the three-variable KFRE (age, sex, GFR) with the four-variable KFRE estimated using imputed ACR from PCR and dipstick protein levels. RESULTS:. The proportion with ACR testing was 19% within the previous 3 years. An additional 2% had an available PCR and 36% had a dipstick protein; the remaining 43% had no form of albuminuria testing. The four-variable KFRE had significantly better discrimination than the three-variable KFRE among patients with ACR testing, PCR testing, and urine dipstick protein levels, even with imputed ACR for the latter two groups. Calibration of the four-variable KFRE was acceptable in each group, but the three-variable equation showed systematic bias in the groups that lacked ACR or PCR testing. CONCLUSIONS:Implementation of the KFRE in electronic medical records should incorporate ACR, even if only imputed from PCR or urine dipstick protein levels.

OBJECTIVE:) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996-1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08-1.36); RLP-C, 1.18 (1.08-1.29); LDL-TG, 1.18 (1.05-1.33); HDL-C, 1.39 (1.16-1.67); and Apo-E-HDL, 1.27 (1.07-1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD. CONCLUSIONS:Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones. Graphic Abstract: A graphic abstract is available for this article.

BACKGROUND/OBJECTIVES:APOL1 high-risk genotypes confer an increased risk for kidney disease, but their clinical significance among older adults remains unclear. We aimed to determine whether APOL1 genotype status (high risk = 2 risk alleles; low risk = 0-1 risk alleles) and self-reported race (Black; White) are associated with number of hospitalizations, incident chronic kidney disease (CKD), end-stage renal disease (ESRD), and mortality among older adults participating in a community-based cohort study. DESIGN:Observational longitudinal cohort study. SETTING:The Atherosclerosis Risk in Communities (ARIC) study. PARTICIPANTS:Community-dwelling older adults (mean age = 75.8 years; range = 66-90 years). RESULTS:, and albuminuria. These associations persisted after additional adjustments for clinical/socioeconomic factors and APOL1 genotype (incident CKD: HR = 1.38; 95% CI = 1.06-1.81; ESRD: HR = 3.20; 95% CI = 1.16-8.86). CONCLUSION:Among older Black adults, APOL1 high-risk genotypes were associated with lower kidney function and therefore higher risk of ESRD. Racial disparities in incident kidney disease persisted in older age and were not fully explained by APOL1.

RATIONALE & OBJECTIVE:Physical activity is associated with lower risk for cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) Study. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:14,537 participants aged 45 to 64 years. PREDICTORS:Baseline physical activity status was assessed using the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active. OUTCOMES:at follow-up and≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or initiation of kidney replacement therapy. ANALYTICAL APPROACH:Cox proportional hazards regression. RESULTS:At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow-up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk for CKD compared with the inactive group (HRs for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007). LIMITATIONS:Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, participants who were not Black or White were excluded. CONCLUSIONS:Highly active participants had lower risk for developing CKD compared with inactive participants.

AIMS/OBJECTIVE:We aimed to investigate the association between endothelial dysfunction, assessed by brachial flow-mediated dilation (FMD), and the incidence of heart failure (HF) in the community-based Multi-Ethnic Study of Atherosclerosis. METHODS AND RESULTS/RESULTS:Brachial artery FMD was measured in a nested case-cohort sample including 3496 of 6814 Multi-Ethnic Study of Atherosclerosis participants without prevalent cardiovascular disease (mean age 61 years, 50% women). Multivariable probability-weighted Cox proportional hazards analysis was used to examine the association between FMD and incident HF. We also investigated the association between FMD and HF with reduced vs. preserved ejection fraction [HFrEF (left ventricular ejection fraction <45%) vs. HFpEF (left ventricular ejection fraction ≥45%)]. During follow-up (median 12 years), 149 participants developed incident HF (incidence rate 3.7 events per 1000 person years). There were 56 HFrEF and 69 HFpEF events (incidence rates 1.4 and 1.7 events per 1000 person years, respectively). In multivariable models adjusted for established HF risk factors (age, sex, race/ethnicity, body mass index, systolic blood pressure, antihypertensive treatment, heart rate, diabetes mellitus, history of myocardial infarction, current smoker, and former smoker status), individuals in the highest quartile of FMD (reflecting better endothelial function) had a lower HF risk compared with individuals in the lowest quartile [hazard ratio 0.53, 95% confidence interval (CI) 0.31-0.95]. Lower risk according to higher FMD was particularly evident for HFrEF, but not for HFpEF (hazard ratio per standard deviation increase 0.79, 95% CI 0.64-0.97 vs. 0.99, 95% CI 0.78-1.26, respectively). Results remained similar after adjustment for baseline natriuretic peptide levels. The addition of FMD to established HF risk factors generally rendered no or only modest improvement in C-statistics [C-statistics for model with established HF risk factors: 0.774, and with the addition of FMD: 0.776 (delta C 0.002, 95% confidence interval -0.002 to 0.006)]. CONCLUSIONS:Endothelial dysfunction was independently associated with HF in this community cohort, suggesting a pathophysiological contribution of endothelial function to the development of HF, in particular HFrEF. However, the value of FMD measurements for HF risk prediction seems limited.