Search

Importance: Guidelines for blood pressure (BP) measurement recommend arm support on a desk with the midcuff positioned at heart level. Still, nonstandard positions are used in clinical practice (eg, with arm resting on the lap or unsupported on the side)., Objective: To determine the effect of different arm positions on BP readings., Design, Setting, and Participants: This crossover randomized clinical trial recruited adults between the ages of 18 and 80 years in Baltimore, Maryland, from August 9, 2022, to June 1, 2023., Intervention: Participants were randomly assigned to sets of triplicate BP measurements with the arm positioned in 3 ways: (1) supported on a desk (desk 1; reference), (2) hand supported on lap (lap), and (3) arm unsupported at the side (side). To account for intrinsic BP variability, all participants underwent a fourth set of BP measurements with the arm supported on a desk (desk 2)., Main Outcomes and Measures: The primary outcomes were the difference in differences in mean systolic BP (SBP) and diastolic BP (DBP) between the reference BP (desk 1) and the 2 arm support positions (lap and side): (lap or side - desk 1) - (desk 2 - desk 1). Results were also stratified by hypertensive status, age, obesity status, and access to health care within the past year., Results: The trial enrolled 133 participants (mean [SD] age, 57 [17] years; 70 [53%] female); 48 participants (36%) had SBP of 130 mm Hg or higher, and 55 participants (41%) had a body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or higher. Lap and side positions resulted in statistically significant higher BP readings than desk positions, with the difference in differences as follows: lap, SBP Δ 3.9 (95% CI, 2.5-5.2) mm Hg and DBP Δ 4.0 (95% CI, 3.1-5.0) mm Hg; and side, SBP Δ 6.5 (95% CI, 5.1-7.9) mm Hg and DBP Δ 4.4 (95% CI, 3.4-5.4) mm Hg. The patterns were generally consistent across subgroups., Conclusion and Relevance: This crossover randomized clinical trial showed that commonly used arm positions (lap or side) resulted in substantial overestimation of BP readings and may lead to misdiagnosis and overestimation of hypertension., Trial Registration: ClinicalTrials.gov Identifier: NCT05372328.

Background and Aims: The potential impact of peripheral artery disease (PAD) on kidney outcomes is not well understood. The aim of this study was to explore the association between PAD and end-stage kidney disease (ESKD) and chronic kidney disease (CKD)., Methods: Among 14,051 participants (mean age 54 [SD 6 years]) from the Atherosclerosis Risk in Communities study, we categorized PAD status as symptomatic PAD (intermittent claudication or leg revascularization), asymptomatic PAD (ankle-brachial index [ABI] ≤0.90 without clinical history of symptoms), and ABI 0.91-1.00, 1.01-1.10, 1.11-1.20 (reference), 1.21-1.30, and >1.30. We evaluated their associations with two kidney outcomes: ESKD (the need of renal replacement therapy or death due to kidney disease) and CKD (ESKD cases or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 with a ≥25 % decline from the baseline) using multivariable Cox proportional hazards models., Results: Over ∼30 years of follow-up, there were 598 cases of incident ESKD and 4686 cases of incident CKD. After adjusting for potential confounders, both symptomatic PAD and asymptomatic PAD conferred a significantly elevated risk of ESKD (hazard ratio 2.28 [95 % confidence interval 1.23-4.22] and 1.75 [1.19-2.57], respectively). Corresponding estimates for CKD were 1.54 (1.14-2.09) and 1.63 (1.38-1.93). Borderline low ABI 0.91-1.00 also showed elevated risk of adverse kidney outcomes after adjustment for demographic variables. Largely consistent results were observed across demographic and clinical subgroups., Conclusions: Symptomatic PAD and asymptomatic PAD were independently associated with an elevated risk of ESKD and CKD. These results highlight the importance of monitoring kidney function in persons with PAD, even when symptoms are absent., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.M. reports personal fees from Fukuda Denshi and Kowa Company, Ltd. Outside of the submitted work. The other authors do not have relevant conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To examine the association of left atrial (LA) function with incident chronic kidney disease (CKD) and assess the clinical utility of adding LA function to a CKD risk prediction equation., Patients and Methods: We included 4002 Atherosclerosis Risk in Communities study participants without prevalent CKD (mean ± SD age, 75±5 years; 58% female, 18% Black). Left atrial function (reservoir, conduit, and contractile strain) was evaluated by 2D-echocardiograms on 2011 to 2013. Chronic kidney disease was defined as greater than 25% decline in estimated glomerular filtration rate of less than 60 mL/min/1.73 m 2 , end-stage kidney disease, or hospital records. Cox proportional hazards models were used. Risk prediction and decision curve analyses evaluated 5-year CKD risk by diabetes status., Results: Median follow-up was 7.2 years, and 598 participants developed incident CKD. Incidence rate for CKD was 2.29 per 100 person-years. After multivariable adjustments, the lowest quintile of LA reservoir, conduit, and contractile strain (vs highest quintile) had a higher risk of CKD (hazard ratios [95% CIs]: 1.94 [1.42-2.64], 1.62 [1.19-2.20], and 1.49 [1.12-1.99]). Adding LA reservoir strain to the CKD risk prediction equation variables increased the C-index by 0.026 (95% CI: 0.005-0.051) and 0.031 (95% CI: 0.006-0.058) in participants without and with diabetes, respectively. Decision curve analysis found the model with LA reservoir strain had a higher net benefit than the model with CKD risk prediction equation variables alone., Conclusion: Lower LA function is independently associated with incident CKD. Adding LA function to the CKD risk prediction enhances prediction and yields a higher clinical net benefit. These findings suggest that impaired LA function may be a novel risk factor for CKD., Competing Interests: Dr Eaton reported grant support from the National Institutes of Health to the institution. Dr Herzog reported grant support from the National Heart, Lung, and Blood Institute, National Institutes of Health to the institution, consulting fees from Astra-Zeneca, personal fees from Merck (DSMB) for participation on a Data Safety Monitoring, and stock ownership in Merck, Pfizer and Boston Scientific. Dr Matsushita reported grant supports from the National Institutes of Health and Resolve to Save Lives, consulting fees from Fukuda Denshi and RhythmX AI. Dr Coresh reported grant supports from the National Institutes of Health and National Kidney Foundation, consulting fees from Healthy.IO, and stock ownership in Healthy.IO. Dr Shah reported funding from Novartis and Philips Ultrasound, and consulting fees from Philips Ultrasound and Janssen outside the submitted work. Dr Solomon reported funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI grant to institution, outside the submitted work and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi- Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, SanofiPasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, PureHealth consulting outside the submitted work. The other authors declare no competing interests., (© 2024 The Authors.)

Rationale & Objective: Smoking is a modifiable risk factor for various adverse events. However, little is known about the association of smoking with the incidence of acute kidney injury (AKI) in the general population. This study investigated the association of cigarette smoking with the risk of AKI., Study Design: Prospective observational study., Setting & Participants: 14,571 participants (mean age 55±6 years, 55% women, and 25% Black participants) from the ARIC study visit 1 (1987-1989) followed through December 31, 2019., Exposure: Smoking parameters (status, duration, pack-years, intensity, and years since cessation)., Outcome: Incident hospitalization with AKI, defined by a hospital discharge with a diagnostic code relevant to AKI., Analytical Approach: Multivariable Cox regression models., Results: Over a median follow-up period of 26.3 years, 2,984 participants had an incident hospitalization with AKI. Current and former smokers had a significantly higher risk of AKI compared to never smokers after adjusting for potential confounders (HR, 2.22 [95% CI, 2.02-2.45] and 1.12 [1.02-1.23], respectively). A dose-response association was consistently seen for each of smoking duration, pack-years, and intensity with AKI (eg, HR, 1.19 [95% CI, 1.16-1.22] per 10 years of smoking). When years since cessation were considered as a time-varying exposure, the risk of AKI associated with smoking compared with current smokers began to decrease after 10 years, and became similar to never smokers at 30 years (HR for≥30 years, 1.07 [95% CI, 0.97-1.20] vs never smokers)., Limitations: Self-reported smoking measurements and missing outpatient AKI cases., Conclusions: In a community-based cohort, all smoking parameters were robustly associated with the risk of AKI. Smoking cessation was associated with decreased risk of AKI, although the excess risk lasted up to 30 years. Our study supports the importance of preventing smoking initiation and promoting smoking cessation for the risk of AKI., Plain-Language Summary: Smoking is a behavior that is associated with many negative health effects. It is not well understood how smoking relates to the occurrence of acute kidney injury (AKI) in the community. In this study, we looked at data from a group of 14,571 adults who were followed for 26 years to see how different aspects of smoking (such as whether someone smoked, how long they smoked for, how many cigarettes they smoked per day, and whether they quit smoking) were related to AKI. We found that smoking was strongly linked to an increased risk of AKI. This risk decreased after 5-10 years of quitting smoking, but the excess risk lasted up to 30 years. This study shows the importance of preventing people from starting smoking and to encourage smokers to quit to reduce their risk of AKI., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: High dietary calcium and phosphorus may accelerate vascular calcification, but epidemiological data are inconsistent. Most of those studies assessed diet at one point and have not been systematically evaluated., Objectives: The purpose of this study was to assess the associations of dietary calcium and phosphorus intakes in middle age with coronary artery and extra-coronary calcification at older age., Methods: We studied 1,914 participants from the ARIC (Atherosclerosis Risk In Communities) study (mean age 80.5 years) without coronary heart disease who underwent chest computed tomography scans at visit 7 (2018-2019) and completed a 66-item food frequency questionnaire at 2 earlier visits (visit 1 [1987-1989] and visit 3 [1993-1995]). Dietary calcium and phosphorus intakes were averaged between these 2 visits. Calcification was quantified by the Agatston score in coronary artery, ascending aorta, descending aorta, aortic valve ring, aortic valve, and mitral valve., Results: Dietary calcium intake was inversely associated with coronary artery and ascending aorta calcification, whereas the association was not significant for other measures of extra-coronary calcification. For example, the highest vs lowest quartile of calcium intake showed an adjusted OR of 0.66 (95% CI: 0.45-0.98) for coronary artery calcification (Agatston score ≥75th percentile). Dietary phosphorus intake demonstrated similar results, but the magnitude of the association was weaker than dietary calcium intake., Conclusions: Dietary calcium and phosphorus intakes at middle age were not positively associated with vascular and valvular calcification at over 75 years old. Our findings did not support the link between a calcium or phosphorus-rich diet and vascular and valvular calcification., Competing Interests: The ARIC study has been funded in whole or in part with federal funds from the 10.13039/100000050National Heart, Lung, and Blood Institute, 10.13039/100000002National Institutes of Health, 10.13039/100000016Department of Health and Human Services, under contract numbers (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). This specific study was supported by R01HL136592 (multiple PIs: Drs Matsushita and Blaha). Dr Rebholz was supported by a grant from the 10.13039/100000050National Heart, Lung, and Blood Institute (R01 HL153178). Dr Nohara was supported by grants-in-aid from the International Research Fund for Subsidy of Kyusyu University School of Medicine Alumni, Japan. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Streptococcus pneumoniae vaccination effectiveness (VE) in individuals with reduced kidney function is unknown. We estimated pneumococcal conjugate vaccine (PCV13), pneumococcal polysaccharide vaccine (PPSV23), and combined PCV13 and PPSV23 effectiveness against pneumococcal disease in individuals with and without reduced estimated glomerular filtration rate (eGFR)., Methods: All eligible individuals (case and controls) were adults (aged ≥18 years) hospitalized within the Geisinger Health System and required to have S. pneumoniae urinary antigen testing (i.e. test-negative design). Vaccination records were obtained from the electronic health record and statewide vaccination registry. After controlling for the probability of receiving a pneumococcal vaccine, we used multivariable logistic regression models to estimate the odds ratios (ORs) of vaccination between those who did and did not meet the S. pneumoniae case definition. VE was calculated as (1 - OR) × 100%., Results: There were 180 cases and 3889 controls (mean age 69 years, female 48%, white 97%, mean eGFR 71 mL/min/1.73 m 2 ). The adjusted population PCV13 VE was 39% (95% CI 13%-58%), and combination PCV13 and PPSV23 was 39% (95% CI 12%-58%). PPSV23 VE was -3.7% (95% CI -57% to 32%). Stratified by eGFR, adjusted PCV13 VE was consistent in eGFR ≥60 [VE 38% (95% CI 2.9%-61%)] and 30-59 [VE 61% (95% CI 24%-80%)] without significant interaction. VE was not calculable for eGFR <30 due to small sample size., Conclusion: PCV13 vaccination was associated with reduced risk of S. pneumoniae hospitalization in individuals with a reduced eGFR (30-59 mL/min/1.73 m 2 )., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m 2 . This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFR cr ), which may be less accurate in older adults., Objective: To evaluate associations in older adults between eGFR cr versus eGFR based on creatinine and cystatin C levels (eGFR cr-cys ) and 8 outcomes., Design: Population-based cohort study., Setting: Stockholm, Sweden, 2010 to 2019., Participants: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing., Measurements: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury., Results: The associations between eGFR cr-cys and outcomes were monotonic, but most associations for eGFR cr were U-shaped. In addition, eGFR cr-cys was more strongly associated with outcomes than eGFR cr . For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m 2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFR cr-cys and 1.0 (CI, 0.9 to 1.0) for eGFR cr , and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g., Limitation: No GFR measurements., Conclusion: Compared with low eGFR cr in older patients, low eGFR cr-cys was more strongly associated with adverse outcomes and the associations were more uniform., Primary Funding Source: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1138.

Rationale & Objective: Vaccination for influenza is strongly recommended for people with chronic kidney disease (CKD) due to their immunocompromised state. Identifying risk factors for not receiving an influenza vaccine (non-vaccination) could inform strategies for improving vaccine uptake in this high-risk population., Study Design: Longitudinal observational study., Setting & Participants: 3,692 Chronic Renal Insufficiency Cohort Study (CRIC) participants., Exposure: Demographic factors, social determinants of health, clinical conditions, and health behaviors., Outcome: Influenza non-vaccination, which was assessed based on a receipt of influenza vaccine ascertained during annual clinic visits in a subset of participants who were under nephrology care., Analytical Approach: Mixed-effects Poisson models to estimate adjusted prevalence ratios (APRs)., Results: Between 2009 and 2020, the pooled mean vaccine uptake was 72% (mean age, 66 years; 44% female; 44% Black race). In multivariable models, factors significantly associated with influenza non-vaccination were younger age (APR, 2.16 [95% CI, 1.85-2.52] for<50 vs≥75 years), Black race (APR, 1.58 [95% CI, 1.43-1.75] vs White race), lower education (APR, 1.20 [95% CI, 1.04-1.39 for less than high school vs college graduate]), lower annual household income (APR, 1.26 [95% CI, 1.06-1.49] for <$20,000 vs >$100,000), formerly married status (APR, 1.22 [95% CI, 1.09-1.35] vs currently married), and nonemployed status (APR, 1.13 [95% CI, 1.02-1.24] vs employed). In contrast, participants with diabetes (APR, 0.80 [95% CI, 0.73-0.87] vs no diabetes), chronic obstructive pulmonary disease (COPD) (APR, 0.80 [95% CI, 0.70-0.92] vs no COPD), end-stage kidney disease (APR, 0.64 [0.56 to 0.76] vs estimated glomerular filtration rate≥60mL/min/1.73m 2 ), frailty (APR, 0.86 [95% CI, 0.74-0.99] vs no frailty), and ideal physical activity (APR, 0.90 [95% CI, 0.82-0.99] vs. physically inactive) were less likely to have non-vaccination status., Limitations: Possible residual confounding., Conclusions: Among adults with CKD receiving nephrology care, younger adults, Black individuals, and those with adverse social determinants of health were more likely to have the influenza non-vaccination status. Strategies are needed to address these disparities and reduce barriers to vaccination., Plain-Language Summary: Identifying risk factors for not receiving an influenza vaccine ("non-vaccination") in people living with kidney disease, who are at risk of influenza and its complications, could inform strategies for improving vaccine uptake. In this study, we examined whether demographic factors, social determinants of health, and clinical conditions were linked to the status of not receiving an influenza vaccine among people living with kidney disease and receiving nephrology care. We found that younger adults, Black individuals, and those with adverse social determinants of health were more likely to not receive the influenza vaccine. These findings suggest the need for strategies to address these disparities and reduce barriers to vaccination in people living with kidney disease., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Clinical practice guidelines recommend selecting an appropriately sized cuff based on mid-arm circumference prior to measuring blood pressure (BP). To our knowledge, the effect of miscuffing on BP measurement when using an automated BP device has not been quantified., Objective: To determine the effect of using a regular BP cuff vs an appropriately sized BP cuff on automated BP readings., Design, Setting, and Participants: This randomized crossover trial of community-dwelling adults with a wide range of mid-arm circumferences took place between March 16 and October 25, 2021, in Baltimore, Maryland. Participants were recruited via BP screening events at a public food market and a senior housing facility, targeted mailings to prior research participants, placement of study brochures in hypertension clinics at Johns Hopkins University, and referrals from physicians providing hypertension care to adults., Interventions: Participants underwent 4 sets of triplicate BP measurements, with the initial 3 sets using an appropriate, too-small, or too-large BP cuff in random order; the fourth set of triplicate measurements was always completed with an appropriate BP cuff., Main Outcomes and Measures: The primary outcome was the difference in mean BP when measured with a regular BP cuff compared with an appropriate BP cuff. The secondary outcome was the difference in BP when using too-small or too-large BP cuffs vs an appropriate BP cuff across all cuff sizes. Results were also stratified by systolic BP (≥130 mm Hg vs <130 mm Hg) and body mass index (calculated as weight in kilograms divided by height in meters squared; ≥30 vs <30)., Results: A total of 195 adults (mean [SD] age, 54 [16] years; 67 [34%] male; 132 [68%] Black; 100 [51%] with hypertension) were randomized for inclusion. Among individuals requiring a small BP cuff, use of a regular BP cuff resulted in a statistically significant lower BP reading (mean systolic BP difference, -3.6 [95% CI, -5.6 to -1.7] mm Hg). In contrast, among individuals requiring a large or extra-large BP cuff, use of a regular BP cuff resulted in a statistically significant higher BP reading (mean systolic BP difference, 4.8 [95% CI, 3.0-6.6] mm Hg and 19.5 [95% CI, 16.1-22.9] mm Hg, respectively). For the secondary outcome, BP differences with overcuffing and undercuffing by 1 and 2 cuff sizes were greater among those requiring larger BP cuffs. The results were consistent in stratified analyses by systolic BP and body mass index., Conclusions and Relevance: In this randomized crossover trial, miscuffing resulted in strikingly inaccurate BP measurements. This is particularly concerning for settings where 1 regular BP cuff size is routinely used in all individuals, regardless of arm size. A renewed emphasis on individualized BP cuff selection is warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT04610775.

Rationale & Objective: Heart-kidney crosstalk is recognized as the cardiorenal syndrome. We examined the association of cardiac function and structure with the risk of kidney failure with replacement therapy (KFRT) in a chronic kidney disease (CKD) population., Study Design: Prospective observational cohort study., Setting & Participants: 3,027 participants from the Chronic Renal Insufficiency Cohort Study., Exposure: Five preselected variables that assess different aspects of cardiac structure and function: left ventricular mass index (LVMI), LV volume, left atrial (LA) area, peak tricuspid regurgitation (TR) velocity, and left ventricular ejection fraction (EF) as assessed by echocardiography., Outcome: Incident KFRT (primary outcome), and annual estimated glomerular filtration rate (eGFR) slope (secondary outcome)., Analytical Approach: Multivariable Cox models and mixed-effects models., Results: The mean age of the participants was 59±11 SD years, 54% were men, and mean eGFR was 43±17mL/min/1.73m 2 . Between 2003 and 2018 (median follow-up, 9.9 years), 883 participants developed KFRT. Higher LVMI, LV volume, LA area, peak TR velocity, and lower EF were each statistically significantly associated with an increased risk of KFRT, with corresponding HRs for the highest versus lowest quartiles (lowest vs highest for EF) of 1.70 (95% CI, 1.27-2.26), 1.50 (95% CI, 1.19-1.90), 1.43 (95% CI, 1.11-1.84), 1.45 (95% CI, 1.06-1.96), and 1.26 (95% CI, 1.03-1.56), respectively. For the secondary outcome, participants in the highest versus lowest quartiles (lowest vs highest for EF) had a statistically significantly faster eGFR decline, except for LA area (ΔeGFR slope per year, -0.57 [95% CI, -0.68 to-0.46] mL/min/1.73m 2 for LVMI, -0.25 [95% CI, -0.35 to-0.15] mL/min/1.73m 2 for LV volume, -0.01 [95% CI, -0.12 to-0.01] mL/min/1.73m 2 for LA area, -0.42 [95% CI, -0.56 to-0.28] mL/min/1.73m 2 for peak TR velocity, and -0.11 [95% CI, -0.20 to-0.01] mL/min/1.73m 2 for EF, respectively)., Limitations: The possibility of residual confounding., Conclusions: Multiple aspects of cardiac structure and function were statistically significantly associated with the risk of KFRT. These findings suggest that cardiac abnormalities and incidence of KFRT are potentially on the same causal pathway related to the interaction between hypertension, heart failure, and coronary artery diseases., Plain-Language Summary: Heart disease and kidney disease are known to interact with each other. In this study, we examined whether cardiac abnormalities, as assessed by echocardiography, were linked to the subsequent progression of kidney disease among people living with chronic kidney disease (CKD). We found that people with abnormalities in heart structure and function had a greater risk of progression to advanced CKD that required kidney replacement therapy and had a faster rate of decline in kidney function. Our study indicates the potential role of abnormal heart structure and function in the progression of kidney disease among people living with CKD., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT)., Methods and Results: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence., Conclusion: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed., Competing Interests: Conflict of interest: P.B.M. reports grants and personal fees from Boehringer Ingelheim; personal fees and non-financial support from Napp, Astrazeneca; personal fees from GSK, Pharmacosmos, and Astellas, outside the submitted work. J.J.C. is a Statistical Editor for the European Heart Journal. K.M. reports grants from NIDDK, during the conduct of the study; grants and personal fees from Kyowa Kirin, personal fees from Akebia, Kowa, and Fukuda Denshi, outside the submitted work. M.E.G. reports grants from National Kidney Foundation and from Kidney Disease Improving Global Outcomes outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation during the conduct of the study; consulting at Healthy.io and scientific advisor to SomaLogic outside the submitted work. J.Ch. reports grants from National Health and Medical Research Council of Australia and grants and personal fees from Servier International outside the submitted work. L.C. reports consulting from CSL Vifor, honorarium for giving a talk from Fresenius Medical Care, and grants from NIH-NIDDK outside the submitted work. A.R.C. reports personal fees from Novartis, Amgen, Reata; grants from Novo Nordisk, Bayer, outside the submitted work. D.d.Z. reports personal fees from Merck during the conduct of the study, Bayer, Boehringer Ingelheim, and Travere outside the submitted work. M.E. reports institutional grants from Astellas pharma, AstraZeneca, and Vifor Pharma; honoraria form Astellas pharma, AstraZeneca, Baxter healthcare, and Fresenius Medical Care; support for attending meetings from Baxter healthcare, participation on a DSMB or Advisory Board for Astellas pharma, AstraZeneca, and Vifor pharma, and a leadership or fiduciary role on the Steering Committee of the Swedish Renal Registry, outside the submitted work. O.M.G. reports personal fees from Akebia, Amgen, AstraZeneca, Reata, Ardelyx, and QED, outside the submitted work. H.J.L.H. reports grants and honoraria for steering committee to his institution from Abbvie; grants and honoraria for steering committee and payments for advisory boards to his institution from AstraZeneca; honoraria for steering committee and payments for advisory boards from Bayer; grants and honoraria for steering committee and payments for advisory boards to his institution from Boehringer Ingelheim; honoraria for steering committee to his institution from CSL Behring, Chinook, Dimerix, Gilead; grants and honoraria for steering committee to his institution from Janssen, honoraria for steering committee to his institution from Eli Lilly, Merck, Mitsubishi Tanabe; grants and honoraria for steering committee to his institution from Novo Nordisk; and honoraria for steering committee to his institution from Travere Pharmaceuticals outside the submitted work. W.G.H. reports SHARP was funded by Merck & Co., Inc., Whitehouse Station, NJ USA, during the conduct of the study; he received grants from Boehringer Ingelheim and Eli Lilly; grants and fellowship from MRC UK, and fellowship from Kidney Research UK outside the submitted work. R.W.M. reports grants from NIHR and Kidney Research UK during the conduct of the study. G.N.N. reports personal fees, non-financial support, and other support (Scientific Cofounder, have equity/stock options, royalties and consulting) from Renalytix; personal fees and non-financial support from Pensieve Health; non-financial support and other support (Scientific Cofounder, have equity/stock options) from Nexus I Connect, Sole proprietor of Data2Wisdom LLC; personal fees from Variant Bio, Qiming Capital, Cambridge Consulting, Daiichi Sankyo, and Menarini Health, outside the submitted work. M.R. reports grants from NIH during the conduct of the study. N.S. reports being a current employee of GSK and employed at AMGA at the time of this study. B.S. reports grants from AstraZeneca, GlaxoSmithKline, and Fresenius Medical Care outside the submitted work. D.C.W. reports personal fees from AstraZeneca during the conduct of the study; personal fees from Amgen, Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Merck Sharp and Dohme, Tricida, Vifor and Zydus; and personal fees from AstraZeneca outside the submitted work. J.v.d.B. reports being an employee and stakeholder of Binnovate Digital Health BV outside the submitted work. All other co-authors have nothing to disclose. Some of the data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: OSA has been linked to microaspiration, systemic inflammation, and suboptimal immune function., Research Question: Is OSA prospectively associated with risk of hospitalization for pneumonia, respiratory, and total infections?, Study Design and Methods: Prospective cohort. Participants in the Atherosclerosis Risk in Communities (ARIC) study (N = 1,586) underwent polysomnography in 1996-1998 and were followed up through 2018 for infection-related hospitalizations. The apnea-hypopnea index (AHI; events/h) was used to categorize participants as having severe OSA (≥ 30), moderate OSA (15-29), mild OSA (5-14), or a normal breathing pattern (< 5). Cox regression was used to calculate hazard ratios (HRs) and 95% CIs., Results: ARIC participants were on average 62.7 (SD = 5.5) years of age, and 52.8% were female. Severe OSA was present in 6.0%, moderate OSA in 12.7%, mild OSA in 30.0%, and normal breathing in 51.3%. A total of 253 hospitalizations with pneumonia occurred over a median 20.4 (max, 22.9) years' follow-up. Participants with severe OSA were at 1.87 times (95% CI, 1.19-2.95) higher risk of hospitalization with pneumonia compared with those with a normal breathing pattern after adjustment for demographics and lifestyle behaviors. Results were attenuated modestly after adjustment for BMI (1.62 [0.99-2.63]), and prevalent asthma and COPD (1.62 [0.99-2.63]). A similar pattern existed for hospitalization with respiratory infection and composite infection (demographic and behavior-adjusted HRs: 1.47 [0.96-2.25] and 1.48 [1.07-2.04], respectively)., Interpretation: Severe OSA was associated with increased risk of hospitalizations with pneumonia in this community-based cohort. OSA patients may benefit from more aggressive efforts to prevent pneumonia and other infectious conditions., (Copyright © 2023. Published by Elsevier Inc.)

Background GDF15 (growth differentiation factor 15) is a potent predictor of bleeding in people with cardiovascular disease. However, whether GDF15 is associated with bleeding in individuals without a history of cardiovascular disease is unknown. Methods and Results The study population was from the ARIC (Atherosclerosis Risk in Communities) study. We studied the association of GDF15 with hospitalized bleeding events among 9205 participants (1993-1995) without prior bleeding and cardiovascular disease (mean age 60 years, 57% women, 21% Black). Plasma levels of GDF15 were measured in relative fluorescence units using DNA-based aptamer technology. Bleeding was ascertained using discharge codes. We examined hazard ratios (HRs) of incident bleeding using Cox models and risk prediction with the addition of GDF15 to clinical predictors of bleeding. There were 1328 hospitalizations with bleeding during a median follow-up of 22.5 years. The majority (76.5%) were because of gastrointestinal bleeding. The absolute incidence rate of bleeding per 1000 person-years was 11.64 in the highest quartile of GDF15 versus 5.22 in the lowest quartile. The highest versus lowest quartile of GDF15 demonstrated an adjusted HR of 2.00 (95% CI, 1.69-2.35) for total bleeding. The findings were consistent when we examined bleeding as the primary discharge diagnosis. The addition of GDF15 to clinical predictors of bleeding improved the C-statistic by 0.006 (0.002-0.011) from 0.684 to 0.690, P =0.008. Conclusions Higher levels of GDF15 were associated with bleeding events and improved the risk prediction beyond clinical predictors in individuals without cardiovascular disease.

Importance: Factors associated with the risk of dementia remain to be fully understood. Systemic infections are hypothesized to be such factors and may be targets for prevention and screening., Objective: To investigate the association between hospitalization with infection and incident dementia., Design, Setting, and Participants: Data from the community-based Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study, were used. Enrollment occurred at 4 research centers in the US, initiated in 1987 to 1989. The present study includes data up to 2019, for 32 years of follow-up. Data analysis was performed from April 2021 to June 2022., Exposures: Hospitalizations with infections were identified via medical record review for selected International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, from baseline until administrative censoring or dementia diagnosis. Participants were considered unexposed until first hospitalization with infection and exposed thereafter. Selected infection subtypes were also considered., Main Outcomes and Measures: Incident dementia and time-to-event data were identified through surveillance of ICD-9 and ICD-10 hospitalization and death certificate codes, in-person assessments, and telephone interviews. A sensitivity analysis was conducted excluding cases occurring within 3 years or beyond 20 years from exposure. Data were collected before study hypothesis formulation., Results: Of the 15 792 ARIC study participants, an analytical cohort of 15 688 participants who were dementia free at baseline and of Black or White race were selected (8658 female [55.2%]; 4210 Black [26.8%]; mean [SD] baseline age, 54.7 [5.8] years). Hospitalization with infection occurred among 5999 participants (38.2%). Dementia was ascertained in 2975 participants (19.0%), at a median (IQR) of 25.1 (22.2-29.1) years after baseline. Dementia rates were 23.6 events per 1000 person-years (95% CI, 22.3-25.0 events per 1000 person-years) among the exposed and 5.7 events per 1000 person-years (95% CI, 5.4-6.0 events per 1000 person-years) among the unexposed. Patients hospitalized with infection were 2.02 (95% CI, 1.88-2.18; P < .001) and 1.70 (95% CI, 1.55-1.86; P < .001) times more likely to experience incident dementia according to unadjusted and fully adjusted Cox proportional hazards models compared with individuals who were unexposed. When excluding individuals who developed dementia less than 3 years or more than 20 years from baseline or the infection event, the adjusted hazard ratio was 5.77 (95% CI, 4.92-6.76; P < .001). Rates of dementia were significantly higher among those hospitalized with respiratory, urinary tract, skin, blood and circulatory system, or hospital acquired infections. Multiplicative and additive interactions were observed by age and APOE-ε genotype., Conclusions and Relevance: Higher rates of dementia were observed among participants who experienced hospitalization with infection. These findings support the hypothesis that infections are factors associated with higher risk of dementias.

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: -0.03%[-0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[-1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To quantify the association of peripheral artery disease (PAD) with infection risk because PAD has been understudied despite recognition of atherosclerotic cardiovascular disease as a risk factor for infection., Methods: Among 5082 participants of the Atherosclerosis Risk in Communities study (aged 71 to 90 years during 2011-2013), we assessed the association of PAD status, based on clinical history and ankle-brachial index (ABI), with infection-related hospitalization (through December 2019) using multivariable Cox regression. We also cross-classified participants by PAD and coronary heart disease (CHD)/stroke status at baseline, with implications for polyvascular disease., Results: During the median follow-up of 6.5 years, there were 1677 infection-related hospitalizations. Peripheral artery disease (clinical history or ABI ≤0.90) was independently associated with the risk of overall infection (adjusted hazard ratio [HR], 1.66 [95% CI, 1.42 to 1.94] vs ABI of 1.11 to 1.20), as was borderline low ABI of 0.91 to 1.00 (adjusted HR, 1.75 [95% CI, 1.47 to 2.07]). Results were consistent across major types of infection (ie, cellulitis, bloodstream infection, pneumonia, and urinary tract infection). For overall infection, PAD plus CHD/stroke had the highest HR of hospitalized infection (1.9), and PAD alone and CHD/stroke alone showed similar HRs of 1.6. For subtypes of infection, PAD alone had the highest HR of approximately 2 for bloodstream infection; PAD alone and PAD plus CHD/stroke had a similar risk of urinary tract infection with HR of approximately 1.7., Conclusion: Peripheral artery disease and borderline low ABI were robustly associated with infection-related hospitalization of older adults. The contribution of PAD to infection risk was comparable to that of CHD/stroke, warranting clinical attention to PAD for the prevention of infectious diseases., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Recent literature suggests improvement in kidney function after percutaneous valvular replacement therapies, implying a pathophysiological contribution of valvular heart disease to chronic kidney disease (CKD). However, this association has not been investigated epidemiologically. We aimed to assess the association of valvular abnormality with prevalent and incident CKD., Study Design: Cross-sectional and prospective analyses., Setting & Participants: Community-dwelling participants (mean age 75.5 [standard deviation 5.1] years) from the Atherosclerosis Risk in Communities study (2011-2013)., Exposure: Valvular abnormality defined as echocardiography-based aortic stenosis, aortic regurgitation, and mitral regurgitation., Outcomes: Prevalent CKD was defined as estimated glomerular filtration rate (eGFR]) <60 mL/min/1.73 m 2 . Incident CKD was defined as progression to eGFR <60 mL/min/1.73 m 2 with ≥25% decline or hospitalization/deaths with CKD diagnosis., Analytical Approach: We cross-sectionally evaluated the association between valvular abnormality and prevalent CKD with logistic regression in 5,216 participants. Then, 3,752 participants without prevalent CKD were analyzed for incident CKD using Cox models., Results: There were 1.4% (n = 74) with any aortic stenosis, 10.6% (n = 555) with any aortic regurgitation, and 43.1% (n = 2,249) with any mitral regurgitation. After adjustment for potential confounders, any mitral regurgitation and moderate/severe aortic regurgitation showed significant associations with prevalent CKD (adjusted OR, 1.17 [95% CI, 1.03-1.34] and 2.82 [95% CI, 1.12-7.10]), as did any aortic stenosis in a sensitivity analysis with prevalent CKD defined including albuminuria ≥30 mg/g (1.83 [95% CI, 1.10-3.05]). Only any aortic stenosis showed an independent association with incident CKD (adjusted HR, 2.12 [95% CI, 1.13-4.00])., Limitations: Despite a relatively large study population, some subgroups had small numbers. Although we minimized reverse causation, we cannot completely rule it out., Conclusions: Different valvular abnormality types were associated with prevalent CKD. Only aortic stenosis was robustly associated with incident CKD. These findings suggest an etiological link between valvular abnormality and CKD, highlighting the importance of clinical attention to kidney function in individuals with aortic stenosis., (© 2022 The Authors.)

Objective: To assess whether echocardiographic parameters of left ventricular (LV) structure and function relate to the long-term risk of incident end-stage kidney disease (ESKD)., Patients and Methods: We conducted a prospective cohort study analyzing 2137 Black participants from the Jackson site of the Atherosclerosis Risk in Communities Study from January 1, 1993, through July 31, 2017. Echocardiographic parameters of LV structure and function were obtained from 1993 to 1995. The primary outcome incident ESKD was identified through the linkage to the United States Renal Data System. Cox proportional hazards models were used to estimate the hazard ratios (HRs) according to each echocardiographic parameter., Results: There were 117 incident ESKD cases during a median follow-up of 22.2 (interquartile range, 15.0-23.3) years. Multivariable Cox models revealed that a higher LV mass index was significantly associated with the risk of ESKD (HR, 2.38; 95% CI, 1.21 to 4.68 for highest vs lowest quartile, P = 0.012). The HRs were significant and even higher for LV posterior wall thickness, with slightly higher HRs when their measures in end-systole (HR for highest vs lowest quartile, 4.38; 95% CI, 1.94 to 9.92, P < 0.001) vs end-diastole (HR, 3.50; 95% CI, 1.53 to 8.01, P = 0.003) were used. The associations were not significant for LV function parameters., Conclusion: In Black individuals residing in the community, echocardiographic parameters of LV structure, including LV wall thickness, were robustly associated with the risk of subsequently incident ESKD. These results have potential implications for novel prevention and management strategies for persons with abnormal LV structure., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Although a few studies reported an association between varicose veins and physical function, this potentially bidirectional association has not been systematically evaluated in the general population., Method: 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 to 12). We evaluated (i) cross-sectional association between prevalent varicose veins and physical function, (ii) association of prevalent varicose veins with subsequent changes in physical function from visit 5 to visits 6 (2016-2017) and 7 (2018-2019), and (iii) 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% confidence interval = 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The association of periodontal disease with atherosclerotic cardiovascular diseases is well known, but not specifically with incident peripheral artery disease (PAD). Therefore, we studied the associations of periodontal disease with incident PAD in a population-based setting., Methods: Among 9,793 participants (aged 53-75 years) without prevalent PAD, self-reported history of periodontal disease was ascertained. Of these, 5,872 participants underwent full-mouth examinations from which periodontal status was defined using the US Centers for Disease Control and Prevention-American Academy of Periodontology (CDC-AAP) definition. We quantified the association of periodontal disease with incident PAD (defined by hospital admission diagnosis or procedures) using multivariable Cox regression models., Results: During a median follow-up of 20.1 years, 360 participants (3.6%) developed PAD. In models accounting for potential confounders including diabetes and smoking pack-years, there was higher hazard of PAD in participants with self-reported tooth loss because of periodontal disease (hazard ratio:1.54 [95% CI:1.20-1.98]), history of periodontal disease treatment (1.37 [1.05-1.80]), and periodontal disease diagnosis (1.38 [1.09-1.74]), compared to their respective counterparts. The clinical measure of periodontal disease (n = 5,872) was not significantly associated with incident PAD in the fully adjusted model (e.g., 1.53 [0.94-2.50] in CDC-AAP-defined severe periodontal disease versus no disease)., Conclusion: We observed a modest association of self-reported periodontal disease, especially when resulting in tooth loss, with incident PAD in the general population. Nonetheless, a larger study with the clinical measure of periodontal disease is warranted., (© 2021 American Academy of Periodontology.)

Objective: Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population., Design and Methods: We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993-1995, mean age: 58 years) and late life (visit 5, 2011-2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models., Results: The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36-1.90), or 1.37 (1.15-1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77)., Conclusions: Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.

Objective: To investigate longitudinal changes in the blood concentration of fibroblast growth factor 23 (FGF23) from midlife to late life and their major predictors in the general population., Patients and Methods: In 14,444 participants of the Atherosclerosis Risk in Communities Study, we analyzed the association of 31,095 measurements of serum intact FGF23 with age using data from 3 visits (visit 2 [N=13,460; mean age, 57 years]; visit 3 [N=12,323; mean age, 60 years]; and visit 5 [N=6122; mean age, 76 years]) and a linear mixed-effects model. Among 5804 participants who had FGF23 measurements at both visits 3 and 5, we explored predictors of FGF23 change from midlife to late life using linear regression models. Prespecified risk factors were estimated glomerular filtration rate, body mass index, ever smoking, ever drinker, diabetes, hypertension, history of cardiovascular disease, total cholesterol, and high-density lipoprotein cholesterol., Results: Median FGF23 concentrations were 41.9 pg/mL (interquartile interval [IQI], 33.9 to 51.8 pg/mL) at visit 2, 38.3 pg/mL (IQI, 30.6 to 48.3 pg/mL) at visit 3, and 55.0 pg/mL (IQI, 44.4 to 70.3 pg/mL) at visit 5. A linear mixed-effects model showed that the association of FGF23 with age was nonlinear, with a slight decline or no change in age 45-60 years and a monotonic increase in age greater than or equal to 65 years (FGF23, +10 to 15 pg/mL per 10 years of age). In a multivariable linear regression model, significantly greater increases in FGF23 were noted, with midlife estimated glomerular filtration rate less than 60 mL/min per 1.73 m 2 vs more than or equal to 60 mL/min per 1.73 m 2 (ΔFGF23, +4.4 pg/mL [95% CI, 0.9 to 8.0]), diabetes vs no diabetes (ΔFGF23, +6.2 pg/mL [95% CI, 4.1 to 8.3]), and hypertension vs no hypertension (ΔFGF23, +4.1 pg/mL [95% CI, 2.7 to 5.4])., Conclusion: FGF23 did not show any major changes in midlife but increased linearly in late life. Reduced kidney function, diabetes, and hypertension were robustly associated with a greater increase in FGF23. Further investigations are needed to understand the potential mechanisms linking these conditions to an increase in FGF23 concentrations., (© 2022 The Authors.)

Aims: Heart failure increases the risk of kidney disease progression. However, whether cardiac function and structure are associated with the risk of incident chronic kidney disease (CKD) is not well characterized in a community setting., Methods and Results: Among 4188 participants (mean age 75 years and 22% blacks) of the Atherosclerosis Risk in Communities Study without prevalent CKD in 2011-13, we examined the association of echocardiographic measures of left ventricular (LV) mass index, ejection fraction, left atrial volume index (LAVi), right ventricular (RV) fractional area change, and peak RV-right atrium (RA) gradient, with the subsequent risk of incident CKD, as defined by >25% decline to estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, hospitalization with CKD diagnosis, or incident end-stage kidney disease. Multivariable Cox regression models were used to estimate hazard ratios (HRs). The risk of incident CKD was monotonically increased with each of higher LV mass index [adjusted HR 2.61 (1.92-3.55) for highest quartile (Q4) vs. lowest (Q1)], lower ejection fraction [1.54 (1.17-2.04) for Q1 vs. Q4], higher LAVi [2.12 (1.56-2.89) for Q4 vs. Q1], and higher peak RV-RA gradient [2.17 (1.45-3.25) for Q4 vs. Q1] but not with RV function. The associations were consistent between subgroups by sex and race., Conclusion: Among community-dwelling older individuals, LV mass index, ejection fraction, LAVi, and peak RV-RA gradient were independently associated with the risk of incident CKD. Our results further support that heart disease is associated with the risk of kidney disease progression and suggest the value of echocardiography for assessing cardiac and kidney health in older populations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Fibroblast growth factor 23 (FGF-23) regulates phosphorus and is associated with cardiovascular disease (CVD), particularly in patients with chronic kidney disease. However, data are limited regarding its contribution to different CVD subtypes across wide age ranges in the general population., Methods: Using data from ARIC, we evaluated the associations of FGF-23 with heart failure (HF), coronary heart disease (CHD), stroke, and composite CVD (any CVD event) in 12,039 participants at mid-life (visit 3 [1993-1995], mean age 60.0 [SD 5.7] years) and 5608 of the same participants at late-life (visit 5 [2011-2013], 75.5 [5.1] years)., Results: During a median of 9.0 years from visit 3 and 6.9 years from visit 5, we observed 1636 and 1137 composite CVD events, respectively. Higher FGF-23 at visit 5, but not necessarily at visit 3, was significantly associated with the risk of CVD independently of potential confounders including kidney function (adjusted HRs for top vs. bottom quartile, 1.56 [95% CI, 1.30-1.87] at visit 5 and 1.10 [95% CI, 0.95-1.27] at visit 3, p -for-difference < 0.001). We observed similar patterns in key demographic and clinical subgroups without interactions. Among CVD subtypes, HF was the only subtype robustly associated with higher FGF-23 at both visits., Conclusion: Higher FGF-23 concentrations at late-life but not necessarily at mid-life were independently associated with the risk of CVD. Among CVD subtypes tested, only HF showed robust associations with FGF-23 at both mid-life and late-life.

Aims/hypothesis: The aim of this work was to assess the association between diabetes and risk for infection-related hospitalisation and mortality., Methods: We conducted a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Diabetes was defined as a fasting glucose ≥7 mmol/l or non-fasting glucose ≥11.1 mmol/l, self-report of a diagnosis of diabetes by a physician, or current diabetes medication use. Hospitalisation for infection was ascertained from hospital discharge records. Participants were followed from 1987-1989 to 2019., Results: We included 12,379 participants (mean age 54.5 years; 24.7% Black race; 54.3% female sex). During a median follow-up of 23.8 years, there were 4229 new hospitalisations for infection. After adjusting for potential confounders, people with (vs without) diabetes at baseline had a higher risk for hospitalisation for infection (HR 1.67 [95% CI 1.52, 1.83]). Results were generally consistent across infection type but the association was especially pronounced for foot infection (HR 5.99 [95% CI 4.38, 8.19]). Diabetes was more strongly associated with hospitalisation for infection in younger participants and Black people. Overall infection mortality was low (362 deaths due to infection) but the adjusted risk was increased for people with diabetes (HR 1.72 [95% CI 1.28, 2.31])., Conclusions/interpretation: Diabetes confers significant risk for infection-related hospitalisation. Enhancing prevention and early treatment of infection in those with diabetes is needed to reduce infection-related morbidity and mortality., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

[Figure: see text].

Abstract: We examined the association between diuretic administration before the diagnosis of minimal change disease and the incidence of acute kidney injury. Moreover, we examined whether the use of diuretics affected the time to complete remission in adults with such disease.The present study was a single-center, retrospective, observational cohort study. We included 107 patients with biopsy-proven minimal change disease who were treated at a tertiary referral center in Japan between January 1, 2000 and March 31, 2019. All biopsy specimens were examined by a board-certified renal pathologist. The patients were considered to have minimal change disease when the kidney biopsy specimen had no glomerular lesions or only mild focal mesangial prominence (not exceeding 3 or 4 cells per segment) by light microscopy and/or foot process effacement by electron microscopy. Logistic regression and Kaplan-Meier curve analyses were performed, comparing the data of patients who received diuretics or not.The median age was 47 (28-66) years, 52% of patients were women, and the median proteinuria dosage was 8.3 (5.3-11.2) g/d. When minimal change disease was diagnosed, 27% of patients were taking diuretics. Within 30 days after the diagnosis, acute kidney injury occurred in 27% of patients. On multivariable logistic regression analysis, the use of diuretics was significantly associated with a higher risk of acute kidney injury. The use of diuretics was also associated with a longer time to complete remission.Diuretic administration can be associated with an elevated acute kidney injury risk and longer remission time in adult patients with newly diagnosed minimal change disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Acute infections are known triggers of cardiovascular disease (CVD) but how this association varies across infection types is unknown. We hypothesized while acute infections increase CVD risk, the strength of this association varies across infection types., Method: Acute coronary heart disease (CHD) and ischemic stroke cases were identified in the Atherosclerosis Risk in Communities Study (ARIC). ICD-9 codes from Medicare claims were used to identify cellulitis, pneumonia, urinary tract infections (UTI), and bloodstream infections. A case-crossover design and conditional logistic regression were used to compare infection types among acute CHD and stroke cases 14, 30, 42, and 90 days before the event with two corresponding control periods (1 and 2 years prior)., Results: Of the 1312 acute CHD cases, 116 had a UTI, 102 had pneumonia, 43 had cellulitis, and 28 had a bloodstream infection 90 days before the CHD event. Pneumonia (OR = 25.53 (9.21,70.78)), UTI (OR = 3.32 (1.93, 5.71)), bloodstream infections (OR = 5.93 (2.07, 17.00)), and cellulitis (OR = 2.58 (1.09, 6.13)) were associated with higher acute CHD risk within 14 days of infection. Of the 727 ischemic stroke cases, 12 had cellulitis, 27 had pneumonia, 56 had a UTI, and 5 had a bloodstream infection within 90 days of the stroke. Pneumonia (OR = 5.59 (1.77, 17.67)) and UTI (OR = 3.16 (1.68, 5.94)) were associated with higher stroke risk within 14 days of infection., Conclusions: Patients with pneumonia, UTI, or bloodstream infection appear to be at a 2.5 to 25.5 fold elevated CVD risk following infection. Preventive therapies during this high-risk period should be considered., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Low serum 25-hydroxyvitamin D levels have been identified as a risk factor for acute kidney injury (AKI) among critically ill patients. Whether low 25-hydroxyvitamin D levels are associated with long-term incidence of hospitalization with AKI in the general population is unknown., Methods: Among 12,380 participants (mean age, 57 years; 24% black) in the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 2 (1990-1992), we explored the association of serum 25-hydroxyvitamin D with incident hospitalization with AKI. Multivariable Cox models were used to estimate hazard ratios (HRs). We also examined the association of serum fibroblast growth factor 23 (FGF23) with AKI., Results: During a median follow-up of 24.3 years, 2145 participants had incident hospitalization with AKI (crude incidence rate: 8.3; 95% confidence interval [CI]: 8.0-8.7, per 1,000 person-years). In multivariable Cox models (including adjustment for kidney function), lower 25-hydroxyvitamin D and higher FGF23 levels were each significantly associated with an increased risk of AKI (HR: 1.35; 95% CI: 1.17-1.54, for lowest vs. highest quartile for 25-hydroxyvitamin D, and HR: 1.19; 95% CI: 1.05-1.36, for highest vs. lowest quartile for FGF23). The association was consistent across demographic and clinical subgroups, regardless of whether AKI was the primary diagnosis for hospitalization, and when adjusting for incident chronic kidney disease (CKD) or cardiovascular disease (CVD) as a time-varying covariate., Conclusion: Among middle- to older-age adults in the community, low 25-hydroxyvitamin D and high FGF23 levels were independently associated with an increased risk of AKI. Future studies should explore underlying mechanisms linking these bone mineral metabolism markers with kidney injury., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: Circulating lipids have been implicated as important modulators of immune response, and altered lipid levels correlate with the severity of infection. However, long-term prognostic implications of lipid levels regarding future infection risk remain unclear. The current project aims to explore whether baseline lipid levels are associated with risk of future serious infection, measured by hospitalization for pneumonia., Methods: A retrospective analysis was performed in 13,478 participants selected from the Atherosclerosis Risk in Communities (ARIC) study, a large community-based longitudinal cohort in the United States with a median follow-up time of >20 years. First incident of hospitalization for pneumonia was identified through hospital discharge records. Cox proportional hazard models were used to assess the association of baseline major lipid levels (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides) with time to first pneumonia hospitalization., Results: A total of 1969 (14.61%) participants had a pneumonia hospitalization during a median follow-up time of 21.5 years. The hazard ratio (HR) for pneumonia hospitalization was 0.90 (95% confidence interval, 0.87-0.92) for every 10-mg/dL increase in baseline HDL-C, and 1.02 (95% confidence interval, 1.02-1.03) for every 10-mg/dL increase in baseline triglycerides. HDL-C and triglycerides both remained significant predictors of pneumonia hospitalization after multivariable adjustment. Such associations were not seen with baseline LDL-C or total cholesterol levels., Conclusion: Lower baseline HDL-C and higher triglyceride levels were strongly associated with increased risk of long-term pneumonia hospitalization in a large longitudinal US cohort., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized., Methods: We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996-1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs)., Results: During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59-2.21] for ≥14 ng/L, 1.36 [1.18-1.57] for 9-13 ng/L, and 1.16 [1.03-1.30] for 5-8 ng/L compared to <5 ng/L). The graded association was also observed for NTproBNP (HR, 2.27 [1.93-2.68] for ≥272.7 pg/mL, 1.67 [1.45-1.93] for 142.4-272.6 pg/mL, and 1.31 [1.17-1.47] for 64.0-142.3 pg/mL compared to <64.0 pg/mL). The addition of hs-cTnT and NTproBNP to a model with established predictors significantly improved 10-year risk prediction for hospitalization with AKI (Δc-statistic, 0.015 [95%CI, 0.006-0.024])., Conclusions: In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: Coronavirus disease 2019 (COVID-19) has become a global pandemic associated with significant morbidity and mortality. This review summarizes findings up to date on the relationship between cardiovascular disease (CVD) and COVID-19., Recent Findings: Preexisting CVD is a common condition among patients with COVID-19 and is associated with increased disease severity and mortality. Conversely, COVID-19 has various clinical manifestations on cardiovascular system, including thrombotic events and cardiac dysfunction. The pandemic has impacted healthcare utilization among patients with CVD, which may have led to potential delay in access to the healthcare system during acute events not directly COVID-19-related., Summary: While COVID-19 vaccine is being developed and distributed, controlling CVD risk factors and adherence to recommendations of existing immunization (e.g., influenza vaccine) are key in protecting the health of individuals with CVD during the COVID-19 pandemic. Further research is needed to understand the epidemiological and pathophysiological basis for the interaction between CVD and COVID-19., Competing Interests: Conflict of InterestJunichi Ishigami, Minghao Kou, and Ning Ding declare that they have no conflict of interest. Kunihiro Matsushita reports grants from Resolve to Save Lives, during the conduct of the study., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021.)

Background: Little is known about the health sequelae of pneumonia in persons with chronic kidney disease (CKD)., Methods: We studied adults with CKD in Stockholm during 2006-11, who not previously been diagnosed with lower respiratory tract infections. We used multivariable-adjusted Cox regression with pneumonia as a time-varying exposure to estimate hazard ratios (HRs) [95% confidence intervals (CIs)] for the events of death, major adverse cardiovascular events (MACEs), acute kidney injury (AKI), CKD progression or hospitalization for urinary tract infections (UTIs)/sepsis. Cataract and knee/joint replacement served as negative control outcomes., Results: We identified 71 931 adults (mean age 79 years, 59% women), of whom 8379 (12%) were diagnosed with pneumonia during follow-up; incident pneumonia was associated with 10 times higher adjusted mortality risk during the first 90 days [HR = 10.0, 95% confidence interval (CI) 9.5-10.5] and double the mortality beyond 90 days from pneumonia diagnosis (HR = 2.0; 95% CI 1.9-2.1). Incident pneumonia was similarly associated with higher adjusted risk of MACE (<90 days: HR = 12.6; 95% CI 12.0-13.3; ≥90 days: HR = 1.5; 95% CI 1.4-1.6). The adjusted risk of CKD progression and UTI/sepsis hospitalization was highest within 90 days from pneumonia but remained elevated thereafter. For AKI, the association with incident pneumonia was only seen within 90 days. Neither cataract nor knee/joint replacement was related to pneumonia., Conclusions: Incident pneumonia was associated with increased risks of MACE, CKD progression, severe UTI/sepsis and death, with risks highest soon after pneumonia diagnosis but extending beyond 90 days. Our findings highlight the susceptibility for adverse outcomes of CKD patients following pneumonia diagnosis, and may inform clinical decisions regarding vaccination strategies., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Aims: The cardiorenal syndrome refers to a bidirectional relationship between the kidney and the heart. However, epidemiological evidence of cardiovascular disease (CVD) as a risk factor for chronic kidney disease (CKD) progression is actually scarce., Methods and Results: We examined the slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before vs. after an incident hospitalization with heart failure (HF) (n = 20 420), coronary heart disease (CHD) (n = 18 152), or stroke (n = 1808) using data from a complete laboratory data collection in Stockholm, Sweden between 2006 and 2011. eGFR slopes were estimated using mixed-effect models with unstructured residual correlation. Overall, incident hospitalization with HF and CHD, but not stroke, was significantly associated with a subsequent accelerated decline in eGFR, with a faster eGFR decline and greater slope change after HF than CHD. The pre-event vs. post-event eGFR slopes (mL/min/1.73 m 2 per year) were -1.67 (-1.77 to -1.57) vs. -2.76 (-2.82 to -2.71), with a Δslope of -1.09 (-1.16 to -1.02) for HF; -1.09 (-1.20 to -0.98) vs. -1.87 (-1.92 to -1.81), with a Δslope of -0.78 (-0.85 to -0.70) for CHD; and -1.00 (-1.37 to -0.63) vs. -0.99 (-1.19 to -0.78), with a Δslope of 0.02 (-0.24 to 0.27) for stroke. The accelerated declines in eGFR after HF and CHD were consistent across the spectrum of eGFR, although pre-event eGFR slopes were steeper in lower eGFR (e.g. pre-event eGFR slope for HF -0.64 (-0.76 to -0.53) for eGFR ≥60 mL/min/1.73 m 2 , -1.43 (-1.57 to -1.30) for eGFR 30-59 mL/min/1.73 m 2 , and -2.42 (-2.71 to -2.12) for eGFR <30 mL/min/1.73 m 2 )., Conclusions: Incident hospitalization with cardiac diseases (i.e. HF and CHD) was significantly associated with a subsequent acceleration of eGFR decline., (© 2020 European Society of Cardiology.)

Background: Whether cardiovascular disease (CVD) and its traditional risk factors predict severe coronavirus disease 2019 (COVID-19) is uncertain, in part, because of potential confounding by age and sex., Methods: We performed a systematic review of studies that explored pre-existing CVD and its traditional risk factors as risk factors of severe COVID-19 (defined as death, acute respiratory distress syndrome, mechanical ventilation, or intensive care unit admission). We searched PubMed and Embase for papers in English with original data (≥10 cases of severe COVID-19). Using random-effects models, we pooled relative risk (RR) estimates and conducted meta-regression analyses., Results: Of the 661 publications identified in our search, 25 papers met our inclusion criteria, with 76,638 COVID-19 patients including 11,766 severe cases. Older age was consistently associated with severe COVID-19 in all eight eligible studies, with RR >~5 in >60-65 versus <50 years. Three studies showed no change in the RR of age after adjusting for covariate(s). In univariate analyses, factors robustly associated with severe COVID-19 were male sex (10 studies; pooled RR = 1.73, [95% CI 1.50-2.01]), hypertension (8 studies; 2.87 [2.09-3.93]), diabetes (9 studies; 3.20 [2.26-4.53]), and CVD (10 studies; 4.97 [3.76-6.58]). RR for male sex was likely to be independent of age. For the other three factors, meta-regression analyses suggested confounding by age. Only four studies reported multivariable analysis, but most of them showed adjusted RR ~2 for hypertension, diabetes, and CVD. No study explored renin-angiotensin system inhibitors as a risk factor for severe COVID-19., Conclusions: Despite the potential for confounding, these results suggest that hypertension, diabetes, and CVD are independently associated with severe COVID-19 and, together with age and male sex, can be informative for predicting the risk of severe COVID-19., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Objective: To evaluate whether the incidence of infectious diseases increases the long-term risk for incident end-stage renal disease (ESRD) in the general population., Patients and Methods: In 10,290 participants of the Atherosclerosis Risk in Communities Study who attended visit 4 (1996-1998), we evaluated the association of incident hospitalization with major infections (pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis) with subsequent risk for ESRD through September 30, 2015. Hospitalization with major infection was entered into multivariable Cox models as a time-varying exposure to estimate the hazard ratios., Results: Mean age was 63 years, and of 10,290 individuals, 56% (n=5781) were women, 22% (n=2252) were black, and 7% (n=666) had an estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 . During a median follow-up of 17.4 years, there were 2642 incident hospitalizations with major infection and 281 cases of ESRD (132 cases after hospitalization with major infection). The risk for ESRD was higher following major infection compared with while free of major infection (crude incidence rate, 10.9 vs 1.0 per 1000 person-years). In multivariable time-varying Cox analysis, hospitalization with major infection was associated with a 3.3-fold increased risk for ESRD (hazard ratio, 3.34; 95% CI, 2.56-4.37). The association was similar across pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis, and remained significant across subgroups of age, sex, race, diabetes, history of cardiovascular disease, and chronic kidney disease., Conclusion: Hospitalization with major infection was independently and robustly associated with subsequent risk for ESRD. Whether preventive approaches against infection have beneficial effects on kidney outcomes may deserve future investigations., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Ankle-brachial index (ABI), the first-line diagnostic test for peripheral artery disease, can be falsely elevated when ankle arteries are incompressible, showing a J-shaped association with mortality. In this situation, toe-brachial index (TBI) is the recommended test. However, whether TBI provides additional prognostic information beyond ABI in patients on hemodialysis is unknown., Methods: In this retrospective cohort study of 247 Japanese prevalent hemodialysis patients (mean age 66.8 [SD 11.6] years), we evaluated mortality (116 deaths over a median follow-up of 5.2 years) related to quartiles of ABI and TBI, as well as three categories of low ABI (≤0.9), normal/high ABI (> 0.9) + low TBI (≤0.6), and normal/high ABI + normal TBI (> 0.6) using multivariable Cox models., Results: ABI showed a J-shaped association with mortality (adjusted hazard ratio 2.72 [95% CI, 1.52-4.88] in the lowest quartile and 1.59 [95% CI, 0.87-2.90] in the highest quartile vs. the second highest). Lower TBI showed a potentially dose-response association with mortality (e.g., adjusted hazard ratios 2.63 [95% CI, 1.36-5.12] and 2.89 [95% CI, 1.49-5.61] in the lowest two quartiles vs. the highest). When three categories by both ABI and TBI were analyzed, those with low ABI (≤0.9) experienced the highest risk followed by normal/high ABI (> 0.9) + low TBI (≤0.6). Among patients with normal/high ABI (> 0.9), the increased mortality risk in individuals with low TBI (≤0.6) compared to those with normal TBI (> 0.6) were significant (adjusted hazard ratio 1.84 [95% CI, 1.12-3.02])., Conclusions: Lower TBI was independently associated with mortality in patients on hemodialysis and has the potential to classify mortality risk in patients with normal/high ABI. Our results support the importance of evaluating TBI in addition to ABI in this clinical population.

Background: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population., Methods: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding., Results: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF- α , high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases)., Conclusions: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection., (Copyright © 2020 by the American Society of Nephrology.)

Rationale & Objective: Influenza vaccination is recommended for all adults but particularly for older adults and those with high-risk conditions. Reduced kidney function is an important high-risk condition, but the effectiveness of influenza vaccination across kidney function is uncharacterized. We assessed the effectiveness of influenza vaccination among older adults with and without reduced kidney function., Study Design: Observational cohort study., Setting & Participants: 454,634 person-seasons among 110,968 individuals 65 years or older in the Geisinger Health System between the 2005 and 2015 influenza seasons, with baseline characteristics matched between those with and without vaccination using inverse probability weighting., Exposures: Status of influenza vaccination., Outcomes: Incident hospitalization with pneumonia/influenza, coronary heart disease, and heart failure during influenza season stratified by estimated glomerular filtration rate (eGFR; ≥ 60, 30-59, and < 30mL/min/1.73m 2 )., Analytical Approach: Pooled logistic regression analysis to estimate adjusted ORs., Results: In the 2014-2015 influenza season, the prevalence of influenza vaccination was 63.3% without evident difference across eGFR categories. The incidence of hospitalization was higher in lower eGFRs (eg, 2.2% per person-season among those not vaccinated with eGFR < 30 vs 0.7% with ≥ 60mL/min/1.73m 2 for pneumonia/influenza). Overall, influenza vaccination was associated with lower odds of hospitalization with pneumonia/influenza (OR, 0.86; 95% CI, 0.79-0.93), coronary heart disease (OR, 0.93; 95% CI, 0.88-0.97), and heart failure (OR, 0.92; 95% CI, 0.86-0.99). When assessing by eGFR categories, the association was consistent in eGFR ≥ 30, but not significant in < 30mL/min/1.73m 2 (ORs of 1.04 [95% CI, 0.79-1.36] for pneumonia/influenza, 1.03 [95% CI, 0.87-1.23] for coronary heart disease, and 1.10 [95% CI, 0.92-1.33] for heart failure)., Limitations: Possible unmeasured confounding., Conclusions: Influenza vaccination was associated with lower risk for hospitalizations with pneumonia/influenza and major cardiac diseases in eGFR ≥ 30mL/min/1.73m 2 . Studies are needed to explore optimal vaccination strategies for eGFR < 30mL/min/1.73m 2 ., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background hs-cTnT (high-sensitivity cardiac troponin T), but not NT-proBNP (N-terminal pro-B natriuretic peptide), has been shown to predict bleeding in patients with atrial fibrillation. Whether these biomarkers are independently associated with bleeding in the general population is unknown. Methods and Results We used Cox proportional hazards models to examine the association of hs-cTnT and NT-proBNP with incident bleeding (defined by International Classification of Diseases, Ninth Revision [ ICD-9 ] codes) among 9550 middle-aged men and women without a history of cardiovascular disease or bleeding. There were 847 hospitalizations with bleeding (92% from gastrointestinal bleeding) during a median follow-up of 9.0 years. Serum levels of hs-cTnT were associated with bleeding in a graded fashion, with a hazard ratio of 1.28 (95% CI, 1.06-1.59) for 6 to <9 ng/L, 1.52 (1.21-1.91) for 9 to <14, and 2.05 (1.56-2.69) for ≥14 versus <3 ng/L. For NT-proBNP, the highest category (≥264 versus <42 pg/mL) showed a hazard ratio of 2.00 (1.59-2.61), and the remaining 3 categories had hazard ratios ranging from 1.2 to 1.3. Individuals in the highest category of both hs-cTnT and NT-proBNP had a hazard ratio of 3.03 (1.97-4.68) compared with those in the lowest categories. Conclusions In a community-based population, elevated hs-cTnT and NT-proBNP were associated with bleeding-related hospitalizations. These biomarkers may have a high utility in identifying people at high risk for bleeding. There is a need for research on the underlying mechanisms linking subclinical cardiac abnormalities and bleeding.

Background: Cardiorenal syndrome is a well known concept, bolstered by extensive investigations of CKD as a risk factor of cardiovascular disease. However, data on whether cardiovascular disease increases long-term risk of ESKD are sparse., Methods: We assessed the association of incident hospitalization with major cardiovascular diseases (heart failure, atrial fibrillation, coronary heart disease, and stroke) with subsequent risk of ESKD among individuals enrolled in the Atherosclerosis Risk in Communities study; the analysis included 9047 individuals without prevalent cardiovascular disease at their fourth study visit. Each relevant incident cardiovascular disease event was entered into multivariable Cox proportional hazard models as a time-varying exposure to estimate hazard ratios., Results: During a median follow-up of 17.5 years, there were 2598 cases of hospitalization with cardiovascular disease (heart failure, n =1269; atrial fibrillation, n =1337; coronary heart disease, n =696; and stroke, n =559) and 210 cases of incident ESKD. The incidence of major cardiovascular disease was associated with increased risk of ESKD, with the highest risk for heart failure (hazard ratio, 11.40; 95% confidence interval, 8.38 to 15.50), followed by coronary heart disease, atrial fibrillation, and stroke. When we analyzed heart failure with preserved ejection fraction and heart failure with reduced ejection fraction separately, the risk was nominally higher for heart failure with preserved ejection fraction., Conclusions: Major incident cardiovascular disease events were associated with ESKD, independent of kidney risk factors. In particular, heart failure showed a very strong association with ESKD. Our findings highlight the importance of monitoring and managing kidney disease in patients with cardiovascular disease. The potentially distinct contribution to ESKD of heart failure with preserved versus reduced ejection fraction deserves future investigation., (Copyright © 2020 by the American Society of Nephrology.)

Whether persons without prevalent cardiovascular disease (CVD) but elevated levels of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) are at high risk of infection is unknown. Using 1996-2013 data from the Atherosclerosis Risk in Communities Study, we estimated hazard ratios for incident hospitalization with infection in relation to plasma hs-cTnT and NT-proBNP concentrations among participants without prevalent CVD and contrasted them with hazard ratios for persons with prevalent CVD (coronary heart disease, heart failure, or stroke). In a multivariable Cox model, prevalent CVD was significantly associated with risk of hospitalization with infection (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.19, 1.45). Among participants without prevalent CVD, hs-cTnT and NT-proBNP were independently associated with infection risk in a graded fashion (e.g., HR = 1.44 (95% CI: 1.24, 1.69) for hs-cTnT ≥14 ng/L and HR = 1.28 (95% CI: 1.14, 1.44) for hs-cTnT 9-13 ng/L vs. <3 ng/L; HR = 1.57 (95% CI: 1.35, 1.81) for NT-proBNP ≥248.1 pg/mL and HR = 1.19 (95% CI: 1.06, 1.34) for NT-proBNP 137.2-248.0 pg/mL vs. <48.1 pg/mL). The 15-year cumulative incidences of hospitalization with infection were similar for participants with prevalent CVD and participants who did not have prevalent CVD but had hs-cTnT ≥14 ng/L or NT-proBNP ≥248.1 pg/mL. Thus, hs-cTnT and NT-proBNP were independently associated with infection risk. Persons without CVD but with elevated hs-cTnT or NT-proBNP levels should be recognized to have similar infection risks as persons with prevalent CVD., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale & Objective: Pneumococcal vaccine is recommended for adults 65 years and older and those younger than 65 years with clinical indications (eg, diabetes, lung/heart disease, kidney failure, and nephrotic syndrome). Its cost-effectiveness in less severe chronic kidney disease (CKD) is uncharacterized., Study Design: Cost-effectiveness analysis., Setting & Population: US adults aged 50 to 64 and 65 to 79 years stratified by CKD risk status: no CKD (estimated glomerular filtration rate≥60mL/min/1.73m 2 and urinary albumin-creatinine ratio<30mg/g), CKD with moderate risk, CKD with high risk, and kidney failure (estimated glomerular filtration rate<15mL/min/1.73m 2 ) or nephrotic-range albuminuria (urinary albumin-creatinine ratio≥2,000mg/g). Data sources were the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, Centers for Disease Control and Prevention, and the Atherosclerosis Risk in Communities (ARIC) Study., Intervention(s): Vaccination compared to no vaccination., Outcomes: Incremental cost-effectiveness ratios based on US dollars per quality-adjusted life-year (QALY)., Model, Perspective, & Timeframe: Markov model, US health sector perspective, and lifetime horizon., Results: The prevalence of pneumococcal vaccination in NHANES 1999 to 2004 was 56.6% (aged 65-79 years), 28.5% (aged 50-64 years with an indication), and 9.7% (aged 50-64 years without an indication), with similar prevalences across CKD risk status. Pneumococcal vaccination was overall cost-effective (