Publications by authors named "Josef Coresh"

798 Publications

Retinopathy and Risk of Kidney Disease in Persons With Diabetes.

Kidney Med 2021 Sep-Oct;3(5):808-815.e1. Epub 2021 Jul 7.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Rationale & Objective: 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: Retrospective cohort study.

Setting & Participants: 1,759 participants in the ARIC study who had diabetes at visit 4 and underwent retinal examination at visit 3.

Exposure: Retinopathy.

Outcome: Prevalent CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m), 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: 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: During the median follow-up period of 14.2 years, 723 participants developed CKD, and there were 109 ESKD events, 399 CHD events, and 196 stroke events. Compared with the participants without retinopathy, participants with retinopathy were more likely to have reduced eGFR (OR, 1.56 [95% CI, 1.09-2.23]) and UACR > 30 mg/g (OR, 1.61 [95% CI, 1.24-2.10]). Retinopathy was associated with risk of incident CKD (HR, 1.22 [95% CI, 1.02-1.46]), ESKD (HR, 1.69 [95% CI, 1.11-2.58]), CHD (HR, 1.46 [95% CI, 1.15-1.84]), and stroke (HR, 1.43 [95% CI, 1.03-1.97]). A stronger relationship was found between retinopathy and CHD when compared with retinopathy and CKD ( = 0.03); all other associations were similar.

Limitations: Retinal examination and kidney measurements were taken at different visits.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.xkme.2021.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515075PMC
July 2021

Ankle-brachial index and subsequent risk of incident and recurrent cardiovascular events in older adults: The Atherosclerosis Risk in Communities (ARIC) study.

Atherosclerosis 2021 Oct 6;336:39-47. Epub 2021 Oct 6.

Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Background And Aims: The ankle-brachial index (ABI) is a diagnostic test for screening and detecting peripheral artery disease (PAD), as well as a risk enhancer in the AHA/ACC guidelines on the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, our understanding of the association between ABI and cardiovascular risk in contemporary older populations is limited. Additionally, the prognostic value of ABI among individuals with prior ASCVD is not well understood.

Methods: Among 5,003 older adults at ARIC visit 5 (2011-2013) (4,160 without prior ASCVD [median age 74 years, 38% male], and 843 with ASCVD [median age 76 years, 65% male]), we quantified the association between ABI and the risk of heart failure (HF), and composite coronary heart disease and stroke (CHD/stroke) using multivariable Cox regression models.

Results: Over a median follow-up of 5.5 years, we observed 400 CHD/stroke events and 338 HF cases (242 and 199 cases in those without prior ASCVD, respectively). In participants without a history of ASCVD, a low ABI ≤0.9 (relative to ABI 1.11-1.20) was associated with both CHD/stroke and HF (adjusted hazard ratios 2.40 [95% CI: 1.55-3.71] and 2.23 [1.40-3.56], respectively). In those with prior ASCVD, low ABI was not significantly associated with CHD/stroke, but was with HF (7.12 [2.47-20.50]). The ABI categories of 0.9-1.2 and > 1.3 were also independently associated with increased HF risk. Beyond traditional risk factors, ABI significantly improved the risk discrimination of CHD/stroke in those without ASCVD and HF, regardless of baseline ASCVD.

Conclusions: Low ABI was associated with CHD/stroke in those without prior ASCVD and higher risk of HF regardless of baseline ASCVD status. These results support ABI as a risk enhancer for guiding primary cardiovascular prevention and suggest its potential value in HF risk assessment for older adults.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.09.028DOI Listing
October 2021

Stability of Serum Bone-mineral, Kidney, and Cardiac Biomarkers After a Freeze-thaw Cycle: The ARIC Study.

Am J Epidemiol 2021 Oct 13. Epub 2021 Oct 13.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1093/aje/kwab251DOI Listing
October 2021

Clinically recognized varicose veins and physical function in older individuals: the ARIC study.

J Gerontol A Biol Sci Med Sci 2021 Oct 4. Epub 2021 Oct 4.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Although a few studies reported an association between varicose veins and physical function, this potentially bi-directional association has not been systematically evaluated in the general population.

Methods: In 5,580 participants (aged 71-90 years) from the Atherosclerosis Risk in Communities study, varicose veins were identified in outpatient and inpatient administrative data prior to (prevalent cases) and after (incident cases) visit 5 (2011-2013). Physical function was evaluated by the Short Physical Performance Battery (SPPB, score ranging from 0-12). We evaluated 1) cross-sectional association between prevalent varicose veins and physical function, 2) association of prevalent varicose veins with subsequent changes in physical function from visit 5 to visits 6 (2016-2017) and 7 (2018-2019), 3) association of physical function at visit 5 with incident varicose veins during a median follow-up of 3.6 years (105 incident varicose veins among 5,350 participants without prevalent cases at baseline).

Results: At baseline, varicose veins were recognized in 230 (4.1%) participants and cross-sectionally associated with reduced physical function. Longitudinally, prevalent varicose veins were not significantly associated with a decline in SPPB over time. In contrast, a low SPPB ≤6 was associated with a greater incidence of varicose veins compared to SPPB ≥10 (adjusted hazard ratio 2.13 [95% CI 1.19, 3.81]) .

Conclusion: In community-dwelling older adults, varicose veins and low physical function were associated cross-sectionally. Longitudinally, low physical function was a risk factor for incident varicose veins, but not vice versa. Our findings suggest an etiological contribution of low physical function to incident varicose veins.
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http://dx.doi.org/10.1093/gerona/glab287DOI Listing
October 2021

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

N Engl J Med 2021 Sep 23. Epub 2021 Sep 23.

From the Division of Nephrology (L.A.I., S.J.C., A.S.L.) and the Institute for Clinical Research and Health Policy Studies (H.T.), Tufts Medical Center, Tufts Clinical and Translational Science Institute, Tufts University (H.T.), the Section on Genetics and Epidemiology, Joslin Diabetes Center (A.D.), and the Department of Medicine, Harvard Medical School (A.D.) - all in Boston; the Renal-Electrolyte and Hypertension Division, Perelman School of Medicine (N.D.E.), and the Departments of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics (W.Y.), University of Pennsylvania, Philadelphia; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions (J.C., D.W., Y.S., M.E.G., E.S., S.H.B.), the Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine (D.C.C., M.E.G.), and the Department of Medicine, Division of Nephrology, University of Maryland School of Medicine (R.K.) - all in Baltimore; the Kidney Health Research Collaborative, San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco (M.M.E., M.G.S.), the Division of Nephrology, Department of Medicine, San Francisco VA Health Care System and University of California, San Francisco (M.M.E.), and the Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital and University of California, San Francisco (N.R.P.) - all in San Francisco; the Clinical Trial Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (M.F.); the Division of Biostatistics, Department of Population Health Sciences, University of Utah Health, Salt Lake City (T.G.); the Department of Clinical Chemistry and Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden (A.G.); the Faculty of Medicine, University of Iceland, Reykjavik, and the Icelandic Heart Association, Kopavogur - both in Iceland (V.G.); the Departments of Medicine and Epidemiology, University of Alabama at Birmingham, Birmingham (O.M.G.); the Departments of Laboratory Medicine and Pathology (A.B.K., J.C.S.), Pediatrics (M.M.), and Medicine (M.M.), University of Minnesota, Minneapolis, and the Division of Nephrology and Hypertension, Mayo Clinic, Rochester (A.D.R., V.E.T.) - all in Minnesota; the Faculty of Medical Sciences, University Medical Center Groningen, Groningen, the Netherlands (G.N.); the Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ (R.G.N.); the Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland (E.D.P.); Rush University Medical Center, Chicago (R.R.); and Steno Diabetes Center Copenhagen and the Department of Clinical Medicine, University of Copenhagen - both in Copenhagen (P.R.).

Background: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct.

Methods: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.

Results: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.

Conclusions: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
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http://dx.doi.org/10.1056/NEJMoa2102953DOI Listing
September 2021

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases.

J Am Soc Nephrol 2021 Sep 21. Epub 2021 Sep 21.

J Coresh, Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, United States.

Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.
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http://dx.doi.org/10.1681/ASN.2020111599DOI Listing
September 2021

Resistance to antihypertensive treatment and long-term risk: The Atherosclerosis Risk in Communities study.

J Clin Hypertens (Greenwich) 2021 Sep 21. Epub 2021 Sep 21.

Minneapolis VA Health Care System and University of Minnesota, Minneapolis, MN, USA.

More stringent blood pressure (BP) goals have led to greater prevalence of apparent resistant hypertension (ARH), yet the long-term prognostic impact of ARH diagnosed according to these goals in the general population remains unknown. We assessed the prognostic impact of ARH according to contemporary BP goals in 9612 participants of the Atherosclerosis Risk in Communities (ARIC) study without previous cardiovascular disease. ARH, defined as BP above goal (traditional goal <140/90 mmHg, more stringent goal <130/80 mmHg) despite the use of ≥3 antihypertensive drug classes or any BP with ≥4 antihypertensive drug classes (one of which was required to be a diuretic) was compared with controlled hypertension (BP at goal with 1-3 antihypertensive drug classes). Cox regression models were adjusted for age, sex, race, study center, BMI, heart rate, smoking, eGFR, LDL, HDL, triglycerides, and diabetes. Using the traditional BP goal, 133 participants (3.8% of the treated) had ARH. If the more stringent BP goal was instead applied, 785 participants (22.6% of the treated) were reclassified from controlled hypertension to uncontrolled hypertension (n = 725) or to ARH (n = 60). Over a median follow-up time of 19 years, ARH was associated with increased risk for a composite end point (all-cause mortality, hospitalization for myocardial infarction, stroke, or heart failure) regardless of whether traditional (adjusted HR 1.50, 95% CI: 1.23-1.82) or more stringent (adjusted HR 1.43, 95% CI: 1.20-1.70) blood pressure goals were applied. We conclude that in patients free from cardiovascular disease, ARH predicted long-term risk regardless of whether traditional or more stringent BP criteria were applied.
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http://dx.doi.org/10.1111/jch.14269DOI Listing
September 2021

Proteins Associated with Risk of Kidney Function Decline in the General Population.

J Am Soc Nephrol 2021 Sep;32(9):2291-2302

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD.

Methods: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR.

Results: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and -trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2).

Conclusions: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline.
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http://dx.doi.org/10.1681/ASN.2020111607DOI Listing
September 2021

Metabolite Biomarkers of CKD Progression in Children.

Clin J Am Soc Nephrol 2021 08;16(8):1178-1189

Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background And Objectives: Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression.

Design, Setting, Participants, & Measurements: We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR.

Results: Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR <60 ml/min per 1.73 m, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9).

Conclusions: Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.
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http://dx.doi.org/10.2215/CJN.00220121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455058PMC
August 2021

Comparison of proteomic methods in evaluating biomarker-AKI associations in cardiac surgery patients.

Transl Res 2021 Jul 31. Epub 2021 Jul 31.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (r) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median r was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater r in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (r > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays.
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http://dx.doi.org/10.1016/j.trsl.2021.07.005DOI Listing
July 2021

Duration of Diabetes and Incident Heart Failure: The ARIC (Atherosclerosis Risk In Communities) Study.

JACC Heart Fail 2021 Aug;9(8):594-603

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objectives: This study assessed the association of diabetes duration with incident heart failure (HF).

Background: Diabetes increases HF risk. However, the independent effect of diabetes duration on incident HF is unknown.

Methods: We included 9,734 participants (mean age 63 years, 58% women, 22% Black) at ARIC (Atherosclerosis Risk In Communities) Visit 4 (1996-1998) without HF or coronary heart disease. We calculated diabetes duration at Visit 4 (baseline), utilizing diabetes status at the first 4 ARIC visits spaced 3 years apart, and self-reported diagnosis date for those with diabetes diagnosed before Visit 1. We used Cox regression to estimate associations of diabetes duration with incident HF, accounting for intercurrent coronary heart disease and other risk factors. We performed analyses stratified by age (<65 years or ≥65 years), race, sex, and glycemic control (hemoglobin A [HbA] consistently <7%, vs HbA ≥7%), with tests for interaction.

Results: Over 22.5 years of follow-up, there were 1,968 HF events. Compared to those without diabetes, HF risk rose with longer diabetes duration, with the highest risk among those with ≥15 y diabetes duration (HR: 2.82; 95% CI: 2.25-3.63). Each 5-year increase in diabetes duration was associated with a 17% (95% CI: 11-22) relative increase in HF risk. Similar results were observed across HF subtypes. The HF and diabetes duration associations were stronger among those aged <65 years, those with HbA ≥7%, those with a body mass index ≥30 kg/m, women, and Blacks (all P interactions <0.05).

Conclusions: Delaying diabetes onset may augment HF prevention efforts, and therapies to improve HF outcomes might target those with long diabetes duration.
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http://dx.doi.org/10.1016/j.jchf.2021.06.005DOI Listing
August 2021

Serum albumin and risks of hospitalization and death: Findings from the Atherosclerosis Risk in Communities study.

J Am Geriatr Soc 2021 Oct 23;69(10):2865-2876. Epub 2021 Jul 23.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objectives: To determine whether lower serum albumin in community-dwelling, older adults is associated with increased risk of hospitalization and death independent of pre-existing disease.

Design: Prospective cohort study of participants in the fifth visit of the Atherosclerosis Risk in Communities (ARIC) study. Baseline data were collected from 2011 to 2013. Follow-up was available to December 31, 2017. Replication was performed in Geisinger, a health system in rural Pennsylvania.

Setting: For ARIC, four US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and suburbs of Minneapolis, Minnesota.

Participants: A total of 4947 community-dwelling men and women aged 66 to 90 years.

Exposure: Serum albumin.

Main Outcomes: Incident all-cause hospitalization and death.

Results: Among the 4947 participants, mean age was 75.5 years (SD: 5.12) and mean baseline serum albumin concentration was 4.05 g/dL (SD: 0.30). Over a median follow-up period of 4.42 years (interquartile interval: 4.16-5.05), 553 participants (11.2%) died and 2457 participants (49.7%) were hospitalized at least once. The total number of hospitalizations was 5725. In analyses adjusted for demographics and numerous clinical characteristics, including tobacco use, obesity, frailty, cardiovascular disease, kidney disease, diabetes C-reactive protein (CRP), cognitive status, alcohol use, medication use, respiratory disease, and systolic blood pressure, 1 g/dL lower baseline serum albumin concentration was associated with higher risk of both hospitalization (incidence rate ratio [IRR]: 1.58; 95% confidence interval [CI]: 1.36-1.82; p < 0.001) and death (hazard ratio [HR]: 1.67; 95% CI: 1.24-2.24; p < 0.001). Associations were weaker with older age but not different by frailty status or level of high-sensitivity CRP. Associations between serum albumin, hospitalizations, and death were also similar in a real-world cohort of primary care patients.

Conclusions: Lower baseline serum albumin was significantly associated with increased risk of both all-cause hospitalization and death, independent of pre-existing disease. Older adults with low serum albumin should be considered a high-risk population and targeted for interventions to reduce the risk of adverse outcomes.
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http://dx.doi.org/10.1111/jgs.17313DOI Listing
October 2021

Metabolomics of Dietary Acid Load and Incident Chronic Kidney Disease.

J Ren Nutr 2021 Jul 19. Epub 2021 Jul 19.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Electronic address:

Objective: Blood biomarkers of dietary intake are more objective than self-reported dietary intake. Metabolites associated with dietary acid load were previously identified in 2 chronic kidney disease (CKD) populations. We aimed to extend these findings to a general population, replicating their association with dietary acid load, and investigating whether the individual biomarkers were prospectively associated with incident CKD.

Methods: Among 15,792 participants in the Atherosclerosis Risk in Communities cohort followed up from 1987 to 1989 (baseline) to 2019, we evaluated 3,844 black and white men and women with dietary and metabolomic data in cross-sectional and prospective analyses. We hypothesized that a higher dietary acid load (using equations for potential renal acid load and net endogenous acid production) was associated with lower serum levels of 12 previously identified metabolites: indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine, threonate, oxalate, chiro-inositol, methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate. In addition, we hypothesized that lower serum levels of these 12 metabolites were associated with higher risk of incident CKD.

Results: Eleven out of 12 metabolites were significantly inversely associated with dietary acid load, after adjusting for demographics, socioeconomic status, health behaviors, health status, and estimated glomerular filtration rate: indolepropionylglycine, indolepropionate, N-methylproline, threonate, oxalate, chiro-inositol, catechol sulfate, hippurate, methyl glucopyranoside (α + β), stachydrine, and tartronate. N-methylproline was inversely associated with incident CKD (hazard ratio: 0.95, 95% confidence interval: 0.91, 0.99, P = .01). The metabolomic biomarkers of dietary acid load significantly improved prediction of elevated dietary acid load estimated using dietary data, beyond covariates (difference in C statistics: 0.021-0.077, P ≤ 1.08 × 10).

Conclusion: Inverse associations between candidate biomarkers of dietary acid load were replicated in a general population. N-methylproline, representative of citrus fruit consumption, is a promising marker of dietary acid load and could represent an important pathway between dietary acid load and CKD.
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http://dx.doi.org/10.1053/j.jrn.2021.05.005DOI Listing
July 2021

Upper Reference Limits for High-Sensitivity Cardiac Troponin T and N-Terminal Fragment of the Prohormone Brain Natriuretic Peptide in Patients With CKD.

Am J Kidney Dis 2021 Jul 19. Epub 2021 Jul 19.

Division of Nephrology, School of Medicine, University of Maryland, Baltimore, Maryland.

Rationale & Objective: The utility of conventional upper reference limits (URL) for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population.

Study Design: Observational study.

Setting & Participants: We studied participants of the Chronic Renal Insufficiency Cohort (CRIC) with CKD and no self-reported history of cardiovascular disease.

Exposure: Estimated glomerular filtration rate (eGFR).

Outcome: NT-proBNP and hsTnT at baseline.

Analytical Approach: We described the proportion of participants above the conventional URL for NT-proBNP (125pg/mL) and hsTnT (14ng/L) overall and by eGFR. We then estimated 99th percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99th percentile, we modeled the association of eGFR with NT-proBNP and hsTnT.

Results: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above the conventional URL, respectively. In those with eGFR <30mL/min/1.73m, 71% and 68% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, respectively. Among all CKD participants, the 99th percentile for NT-proBNP was 3,592 (95% CI, 2,470-4,849) pg/mL and for hsTnT it was 126 (95% CI, 100-144) ng/L. Each 15mL/min/1.73m decrement in eGFR was associated with a ~40% higher threshold for the 99th percentile of NT-proBNP (1.43 [95% CI, 1.21-1.69]) and hsTnT (1.45 [95% CI, 1.31-1.60]).

Limitations: Study included ambulatory patients, and we could not test the accuracy of the URL of NT-proBNP and hsTnT in the acute care setting.

Conclusions: In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction.
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http://dx.doi.org/10.1053/j.ajkd.2021.06.017DOI Listing
July 2021

Chronic Kidney Disease Testing Among Primary Care Patients With Type 2 Diabetes Across 24 U.S. Health Care Organizations.

Diabetes Care 2021 09 7;44(9):2000-2009. Epub 2021 Jul 7.

Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

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.
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http://dx.doi.org/10.2337/dc20-2715DOI Listing
September 2021

Plasma Metabolomic Signatures of Healthy Dietary Patterns in the Chronic Renal Insufficiency Cohort (CRIC) Study.

J Nutr 2021 Oct;151(10):2894-2907

Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA.

Background: In individuals with chronic kidney disease (CKD), healthy dietary patterns are inversely associated with CKD progression. Metabolomics, an approach that measures many small molecules in biofluids, can identify biomarkers of healthy dietary patterns.

Objectives: We aimed to identify known metabolites associated with greater adherence to 4 healthy dietary patterns in CKD patients.

Methods: We examined associations between 486 known plasma metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, and alternate Mediterranean diet (aMED) in 1056 participants (aged 21-74 y at baseline) in the Chronic Renal Insufficiency Cohort (CRIC) Study. Usual dietary intake was assessed using a semiquantitative FFQ. We conducted multivariable linear regression models to study associations between healthy dietary patterns and individual plasma metabolites, adjusting for sociodemographic characteristics, health behaviors, and clinical factors. We used principal component analysis to identify groups of metabolites associated with individual food components within healthy dietary patterns.

Results: After Bonferroni correction, we identified 266 statistically significant diet-metabolite associations (HEI: n = 60; AHEI: n = 78; DASH: n = 77; aMED: n = 51); 78 metabolites were associated with >1 dietary pattern. Lipids with a longer acyl chain length and double bonds (unsaturated) were positively associated with all 4 dietary patterns. A metabolite pattern low in saturated diacylglycerols and triacylglycerols, and a pattern high in unsaturated triacylglycerols was positively associated with intake of healthy food components. Plasmalogens were negatively associated with the consumption of nuts and legumes and healthy fat, and positively associated with the intake of red and processed meat.

Conclusions: We identified many metabolites associated with healthy dietary patterns, indicative of food consumption. If replicated, these metabolites may be considered biomarkers of healthy dietary patterns in patients with CKD.
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http://dx.doi.org/10.1093/jn/nxab203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485904PMC
October 2021

Glucose Patterns in Very Old Adults: A Pilot Study in a Community-Based Population.

Diabetes Technol Ther 2021 Aug 19. Epub 2021 Aug 19.

Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Continuous glucose monitoring (CGM) provides nuanced information on glucose patterns, but data in very old adults are scarce. To evaluate CGM patterns in very old adults. Pilot study. Participants recruited from one center during visit 7 (2019) of the community-based Atherosclerosis Risk in Communities (ARIC) Study. We enrolled 27 adults (8 with type 2 diabetes and 19 without diabetes) who wore a CGM sensor (Abbott Libre Pro) for up to 14 days. Clinical and laboratory measures, including hemoglobin A1c (HbA1c), were obtained. Mean CGM glucose, standard deviation (SD), coefficient of variation (CV), time-in-range (TIR) 70-180 mg/dL, and hypoglycemia. Mean age was 81 (range 77-91 years) and mean CGM wear time was 13.2 days. In persons without diabetes, there was a wide range of CGM parameters: range of mean glucose, 83.7-124.5 mg/dL, SD 12.2-27.3 mg/dL, CV 14.0%-26.7%, and TIR 71.1%-99.5%. In persons with diabetes, the range of mean CGM glucose was 105.5-223.0 mg/dL, SD, 22.3-86.6 mg/dL, CV 18.2%-38.8%, TIR 38.7%-98.3%. The Pearson's correlation of mean glucose with HbA1c was high overall (0.90); but, for some participants with similar HbA1c, glucose patterns differed substantially. There was a high prevalence of hypoglycemia (glucose <70 or <54 mg/dL) in both persons with and without diabetes. There was high feasibility and acceptability of CGM in very old adults. Low readings on CGM are common, even in nondiabetic older adults; the clinical relevance of these low values is unclear. CGM may provide complementary information to HbA1c in some older adults.
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http://dx.doi.org/10.1089/dia.2021.0156DOI Listing
August 2021

The ARIC (Atherosclerosis Risk In Communities) Study: JACC Focus Seminar 3/8.

J Am Coll Cardiol 2021 Jun;77(23):2939-2959

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research to improve health.
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http://dx.doi.org/10.1016/j.jacc.2021.04.035DOI Listing
June 2021

Trends in Diabetes Treatment and Control in U.S. Adults, 1999-2018.

N Engl J Med 2021 Jun;384(23):2219-2228

From the Welch Center for Prevention, Epidemiology, and Clinical Research and the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore.

Background: Documenting current trends in diabetes treatment and risk-factor control may inform public health policy and planning.

Methods: We conducted a cross-sectional analysis of data from adults with diabetes in the United States participating in the National Health and Nutrition Examination Survey (NHANES) to assess national trends in diabetes treatment and risk-factor control from 1999 through 2018.

Results: Diabetes control improved from 1999 to the early 2010s among the participants but subsequently stalled and declined. Between the 2007-2010 period and the 2015-2018 period, the percentage of adult NHANES participants with diabetes in whom glycemic control (glycated hemoglobin level, <7%) was achieved declined from 57.4% (95% confidence interval [CI], 52.9 to 61.8) to 50.5% (95% CI, 45.8 to 55.3). After major improvements in lipid control (non-high-density lipoprotein cholesterol level, <130 mg per deciliter) in the early 2000s, minimal improvement was seen from 2007-2010 (52.3%; 95% CI, 49.2 to 55.3) to 2015-2018 (55.7%; 95% CI, 50.8 to 60.5). From 2011-2014 to 2015-2018, the percentage of participants in whom blood-pressure control (<140/90 mm Hg) was achieved decreased from 74.2% (95% CI, 70.7 to 77.4) to 70.4% (95% CI, 66.7 to 73.8). The percentage of participants in whom all three targets were simultaneously achieved plateaued after 2010 and was 22.2% (95% CI, 17.9 to 27.3) in 2015-2018. The percentages of participants who used any glucose-lowering medication or any blood-pressure-lowering medication were unchanged after 2010, and the percentage who used statins plateaued after 2014. After 2010, the use of combination therapy declined in participants with uncontrolled blood pressure and plateaued for those with poor glycemic control.

Conclusions: After more than a decade of progress from 1999 to the early 2010s, glycemic and blood-pressure control declined in adult NHANES participants with diabetes, while lipid control leveled off. (Funded by the National Heart, Lung, and Blood Institute.).
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http://dx.doi.org/10.1056/NEJMsa2032271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385648PMC
June 2021

Association between Circulating Protein C Levels and Incident Dementia: The Atherosclerosis Risk in Communities Study.

Neuroepidemiology 2021 2;55(4):306-315. Epub 2021 Jun 2.

Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Introduction: Hemostasis depends on the delicate balance between coagulants and anticoagulants. Higher levels of circulating coagulants have been associated with higher risk of cerebral infarctions and dementia. In contrast, higher levels of circulating protein C, an endogenous anticoagulant, have been associated with lower risk of cerebral infarctions, and the association between protein C levels and the risk of dementia is unknown. The goal of this study was to evaluate the association of circulating protein C levels in midlife and late life with incident dementia.

Methods: Circulating protein C levels were measured using blood samples collected at the midlife baseline (1987-1989) and the late-life baseline (2011-2013) among 14,462 and 3,614 participants, respectively, in the Atherosclerosis Risk in Communities study. Protein C levels were measured using enzyme-linked immunosorbent assay at midlife and a modified aptamer-based assay at late life. Participants were followed up to 2013 from midlife and up to 2017 from late life. Incident dementia was ascertained during the follow-up periods using in-person cognitive and functional assessment, informant interviews, and International Classification of Diseases codes at hospitalization discharge and on death certificates. Cause-specific Cox regression models were used to evaluate the association between quintiles of circulating protein C and incident dementia.

Results: From midlife (mean age of 54), 1,389 incident dementia events were observed over a median follow-up of 23 years. From late life (mean age of 75), 353 incident dementia events were observed over a median follow-up of 4.9 years. At both midlife and late life, circulating protein C had an inverse association with incident dementia after adjusting for demographic, vascular, and hemostatic risk factors, incident stroke as time-dependent covariate, and incorporating stabilized weights based on propensity scores (quintile 5 vs. quintile 1 as the reference, midlife hazard ratio 0.80, 95% confidence interval 0.66-0.96, p value for trend 0.04; late-life hazard ratio 0.84, 95% confidence interval: 0.55-1.28, p value for trend 0.04).

Discussion/conclusion: Circulating protein C has an inverse association with incident dementia independent of established risk factors, including stroke. Our results suggest studying anticoagulants in addition to coagulants can increase our understanding on the relationship between hemostasis and dementia.
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http://dx.doi.org/10.1159/000516287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292178PMC
June 2021

Using GFR, Albuminuria, and Their Changes in Clinical Trials and Clinical Care.

Am J Kidney Dis 2021 09 28;78(3):333-334. Epub 2021 May 28.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1053/j.ajkd.2021.04.003DOI Listing
September 2021

Psychosocial factors and subsequent risk of hospitalizations with peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) Study.

Atherosclerosis 2021 07 9;329:36-43. Epub 2021 May 9.

Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Background And Aims: Psychosocial factors are associated with increased risk of cardiovascular disease (CVD). However, associations with peripheral artery disease (PAD) remain uncharacterized. We aimed to compare associations of psychosocial factors with the risk of PAD and two other major atherosclerotic CVD: coronary heart disease (CHD) and ischemic stroke, in the Atherosclerosis Risk in Communities (ARIC) Study.

Methods: In 11,104 participants (mean age 56.7 [SD 5.7] years) without a clinical history of PAD and CHD/stroke at baseline (1990-1992), we evaluated four psychosocial domains: depressive/fatigue symptoms by the Maastricht Questionnaire, social support by the Interpersonal Evaluation List, social networks by the Lubben Scale, and trait anger by the Spielberger Scale. PAD was defined as hospitalizations with diagnosis or related procedures. CHD included adjudicated coronary heart disease and stroke included ischemic stroke.

Results: We observed 397 PAD and 1940 CHD/stroke events during a median follow-up of 23.1 years. Higher depressive/fatigue symptoms and less social support were significantly associated with incident PAD (adjusted hazard ratios for top vs. bottom quartile 1.65 [95%CI, 1.25-2.19] and 1.40 [1.05-1.87], respectively). When these factors were simultaneously modeled, only depressive/fatigue symptoms remained significant. Incident CHD/stroke was not associated with either of depressive/fatigue symptoms or social support. Social networks and trait anger were not independently associated with PAD or CHD/stroke.

Conclusions: Depressive/fatigue symptoms and social support (especially the former) were independently associated with the risk of hospitalizations with PAD but not CHD/stroke in the general population. Our results support the importance of depressive/fatigue symptoms in vascular health and suggest the need of including PAD when studying the impact of psychosocial factors on CVD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277672PMC
July 2021

Cognitive decline in older adults: What can we learn from optical coherence tomography (OCT)-based retinal vascular imaging?

J Am Geriatr Soc 2021 Sep 19;69(9):2524-2535. Epub 2021 May 19.

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Introduction: Accumulated vascular damage contributes to the onset and progression of vascular dementia and possibly to Alzheimer's disease. Here we evaluate the feasibility and utility of using retinal imaging of microvascular markers to identify older adults at risk of cognitive disease.

Methods: The "Eye Determinants of Cognition" (EyeDOC) study recruited a biracial, population-based sample of participants from two sites: Jackson, MS, and Washington Co, MD. Optical coherence tomographic angiography (OCTA) was used to capture vessel density (VD) from a 6 × 6 mm scan of the macula in several vascular layers from 2017 to 2019. The foveal avascular zone (FAZ) area was also estimated. Image quality was assessed by trained graders at a reading center. A neurocognitive battery of 10 tests was administered at three time points from 2011 to 2019 and incident mild cognitive impairement (MCI)/dementia cases were ascertained. Linear mixed-effects models were used to evaluate associations of retinal vascular markers with cognitive factor score change over time.

Results: Nine-hundred and seventy-six older adults (mean age of 78.7 (± 4.4) years, 44% black) were imaged. Gradable images were obtained in 55% (535/976), with low signal strength (66%) and motion artifact (22%) being the largest contributors to poor quality. Among the 297 participants with both high-quality images and no clinically significant retinal pathology, the average decline in global cognitive function factor score was -0.03 standard deviations per year. In adjusted analyses, no associations of VD or FAZ with longitudinal changes in either global cognitive function or with incident MCI/dementia were found.

Conclusions: In this large biracial community sample of older adults representative of the target population for retinal screening of cognitive risk, we found that obtaining high-quality OCTA scans was infeasible in a nearly half of older adults. Among the select sample of healthier older adults with scans, OCTA markers were not predictive of cognitive impairment.
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http://dx.doi.org/10.1111/jgs.17272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440348PMC
September 2021

Hearing impairment and missing cognitive test scores in a population-based study of older adults: The Atherosclerosis Risk in Communities neurocognitive study.

Alzheimers Dement 2021 Apr 12. Epub 2021 Apr 12.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Introduction: Hearing impairment is associated with poor cognitive test performance in older adults. However, hearing's impact on cognitive test completion is poorly described, and missing cognitive data due to hearing impairment could misestimate the association.

Methods: We investigated if hearing impairment is associated with missing neurocognitive scores in 3678 adults (72-94 years). Hearing impairment was defined by the better-ear pure tone average of speech-frequency thresholds (0.5-4 kHz) >25 decibels.

Results: Hearing impairment was associated with greater missingness on all auditory-only tests, including Logical Memory (prevalence ratio [PR] comparing ≥ moderate impairment vs normal hearing:1.68, 95% confidence interval [CI] 1.26, 2.25) and Digits Backwards (PR 1.62; 95% CI 1.21, 2.17); and two non-auditory tests, Boston Naming (PR 1.61; 95% CI 1.21, 2.17) and Trail Making B (PR 1.55; 95% CI 1.29, 1.86). Models that imputed missing cognitive scores showed the strongest hearing-cognition associations.

Discussion: Older adults with hearing impairment are less likely to complete cognitive testing, thereby underestimating the hearing impairment-cognition relationship.
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http://dx.doi.org/10.1002/alz.12339DOI Listing
April 2021

Frequent Premature Atrial Contractions Are Associated With Poorer Cognitive Function in the Atherosclerosis Risk in Communities (ARIC) Study.

Mayo Clin Proc 2021 05 9;96(5):1147-1156. Epub 2021 Apr 9.

Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN.

Objective: To evaluate the association of premature atrial contraction (PAC) frequency with cognitive test scores and prevalence of dementia or mild cognitive impairment (MCI).

Materials And Methods: We conducted a cross-sectional analysis using Atherosclerosis Risk in Communities study visit 6 (January 1, 2016, through December 31, 2017) data. We included 2163 participants without atrial fibrillation (AF) (age mean ± SD, 79±4 years; 1273 (58.9%) female; and 604 (27.97.0% Black) who underwent cognitive testing and wore a leadless, ambulatory electrocardiogram monitor for 14 days. We categorized PAC frequency based on the percent of beats: less than 1%, minimal; 1% to <5%, occasional; greater than or equal to 5%, frequent. We derived cognitive domain-specific factor scores (memory, executive function, language, and global z-score). Dementia and MCI were adjudicated.

Results: During a mean analyzable time of 12.6±2.6 days, 339 (15.7%) had occasional PACs and 107 (4.9%) had frequent PACs. Individuals with frequent PACs (vs minimal) had lower executive function factor scores by 0.30 (95% CI, -0.46 to -0.14) and lower global factor scores by 0.20 (95% CI, -0.33 to -0.07) after multivariable adjustment. Individuals with frequent PACs (vs minimal) had higher odds of prevalent dementia or MCI after multivariable adjustment (odds ratio, 1.74; 95% CI, 1.09 to 2.79). These associations were unchanged with additional adjustment for stroke.

Conclusion: In community-dwelling older adults without AF, frequent PACs were cross-sectionally associated with lower executive and global cognitive function and greater prevalence of dementia or MCI, independently of stroke. Our findings lend support to the notion that atrial cardiomyopathy may be a driver of AF-related outcomes. Further research to confirm these associations prospectively and to elucidate underlying mechanisms is warranted.
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http://dx.doi.org/10.1016/j.mayocp.2021.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106627PMC
May 2021

Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension.

Kidney Int 2021 08 8;100(2):430-439. Epub 2021 Apr 8.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.
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http://dx.doi.org/10.1016/j.kint.2021.03.026DOI Listing
August 2021

Panel Reactive Antibody and the Association of Early Steroid Withdrawal with Kidney Transplant Outcomes.

Transplantation 2021 Apr 5. Epub 2021 Apr 5.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD. Department of Biostatistics, Johns Hopkins School of Public Health, Baltimore, MD. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Early steroid withdrawal (ESW) is a viable maintenance immunosuppression strategy in low-risk kidney transplant recipients. A low panel reactive antibody (PRA) may indicate low-risk condition amenable to ESW. We aimed to identify the threshold value of PRA above which ESW may pose additional risk, and to compare the association of ESW with transplant outcomes across PRA strata.

Methods: We studied 121,699 deceased-donor kidney-only recipients in 2002-2017 from SRTR. Using natural splines and ESW-PRA interaction terms, we explored how the associations of ESW with transplant outcomes change with increasing PRA values, and identified a threshold value for PRA. Then, we assessed whether PRA exceeding the threshold modified the associations of ESW with 1-year acute rejection, death-censored graft failure, and death.

Results: The association of ESW with acute rejection exacerbated rapidly when PRA exceeded 60. Among PRA≤60 recipients, ESW was associated with a minor increase in rejection (aOR=1.001.051.10) and with a tendency of decreased graft failure (aHR=0.910.971.03). However, among PRA>60 recipients, ESW was associated with a substantial increase in rejection (aOR=1.191.271.36; interaction p<0.001) and with a tendency of increased graft failure (aHR=0.981.081.20; interaction p=0.028). The association of ESW with death was similar between PRA strata (PRA≤60, aHR=0.910.961.01; and PRA>60, aHR=0.900.991.09; interaction p=0.5).

Conclusions: Our findings show that the association of ESW with transplant outcomes is less favorable in recipients with higher PRA, especially those with PRA>60, suggesting a possible role of PRA in the risk assessment for ESW.
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http://dx.doi.org/10.1097/TP.0000000000003777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490476PMC
April 2021
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