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  • 1. Afshin, A
    et al.
    Forouzanfar, M. H
    Reitsma, M. B
    Sur, P
    Estep, K
    Lee, A
    Marczak, L
    Mokdad, A. H
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Murray, C. J. L
    Health effects of overweight and obesity in 195 countries over 25 years2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 1, p. 13-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain.

    METHODS: We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015.

    RESULTS: In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease.

    CONCLUSIONS: The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem.

  • 2. Ahmad, Shafqat
    et al.
    Hammar, Ulf
    Kennedy, Beatrice
    Salihovic, Samira
    Ganna, Andrea
    Lind, Lars
    Sundström, Johan
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Karolinska Institutet, Stockholm.
    Berne, Christian
    Fall, Tove
    Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: a Multi-Cohort Non-Targeted Metabolomics Observational and Mendelian Randomization Study2022In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 71, no 2, p. 329-339Article in journal (Refereed)
    Abstract [en]

    Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.

  • 3.
    Ahmad, Shafqat
    et al.
    Uppsala University, Uppsala;Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA..
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Karolinska Institutet, Stockholm.
    Larsson, Susanna C.
    Karolinska Institutet, Stockholm; Uppsala University, Uppsala.
    Genetically Predicted Circulating Copper and Risk of Chronic Kidney Disease: A Mendelian Randomization Study2022In: Nutrients, E-ISSN 2072-6643, Vol. 14, no 3, article id 509Article in journal (Refereed)
    Abstract [en]

    Elevated circulating copper levels have been associated with chronic kidney disease (CKD), kidney damage, and decline in kidney function. Using a two sample Mendelian randomization approach where copper-associated genetic variants were used as instrumental variables, genetically predicted higher circulating copper levels were associated with higher CKD prevalence (odds ratio 1.17; 95% confidence interval 1.04, 1.32; p-value = 0.009). There was suggestive evidence that genetically predicted higher copper was associated with a lower estimated glomerular filtration rate and a more rapid kidney damage decline. In conclusion, we observed that elevated circulating copper levels may be a causal risk factor for CKD. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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  • 4.
    Andersen, Kasper
    et al.
    Uppsala University, Uppsala, Sweden.
    Lind, Lars
    Uppsala University, Uppsala, Sweden.
    Ingelsson, Erik
    Uppsala University, Uppsala, Sweden.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala University, Uppsala, Sweden.
    Byberg, Liisa
    Uppsala University, Uppsala, Sweden.
    Michaëlsson, Karl
    Uppsala University, Uppsala, Sweden.
    Sundström, Johan
    Uppsala University, Uppsala, Sweden.
    Skeletal muscle morphology and risk of cardiovascular disease in elderly men2015In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 22, no 2, p. 231-239Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: While it is well known that physical inactivity is a major risk factor for cardiovascular disease, there is still a search for the mechanisms by which exercise exerts its positive effect. Skeletal muscle fibre type can be affected to some extent by exercise, and different fibre types possess different anti-inflammatory and glucometabolic properties that may influence cardiovascular disease risk.

    DESIGN: Population-based cohort study.

    METHODS: We investigated relations of skeletal muscle morphology to risk of cardiovascular events in a sample of 466 71-year-old men without cardiovascular disease, of which 295 were physically active (strenuous physical activity at least 3 h/week).

    RESULTS: During a median of 13.1 years of follow up, 173 major cardiovascular events occurred. Among physically active men, 10% higher proportion of type-I (slow-twitch oxidative) fibres was associated with a hazard ratio (HR) of 0.84 (95% confidence interval 0.74-0.95) for cardiovascular events, and 10% higher proportion of type-IIx (fast-twitch glycolytic) fibres was associated with a HR of 1.24 (1.06-1.45), adjusting for age. Similar results were observed in several sets of multivariable-adjusted models. No association of muscle fibre type with risk of cardiovascular events was observed among physically inactive men.

    CONCLUSIONS: Higher skeletal muscle proportion of type-I fibres was associated with lower risk of cardiovascular events and a higher proportion of type-IIx fibres was associated with higher risk of cardiovascular events. These relations were only observed in physically active men. Skeletal muscle fibre composition may be a mediator of the protective effects of exercise against cardiovascular disease.

  • 5. Arefalk, Gabriel
    et al.
    Hergens, Maria-Pia
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Michaëlsson, Karl
    Lind, Lars
    Ye, Weimin
    Nyrén, Olof
    Lambe, Mats
    Sundström, Johan
    Smokeless tobacco (snus) and risk of heart failure: results from two Swedish cohorts2010In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 28, no suppl.A, p. E48-E49Article in journal (Refereed)
  • 6. Arefalk, Gabriel
    et al.
    Hergens, Maria-Pia
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Michaëlsson, Karl
    Lind, Lars
    Ye, Weimin
    Nyrén, Olof
    Lambe, Mats
    Sundström, Johan
    Smokeless tobacco (snus) and risk of heart failure: results from two Swedish cohorts2012In: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 19, no 5, p. 1120-1127Article in journal (Refereed)
    Abstract [en]

    Background: Oral moist snuff (snus) is discussed as a safer alternative to smoking, and its use is increasing. Based on its documented effect on blood pressure, we hypothesized that use of snus increases the risk of heart failure.

    Design: Two independent Swedish prospective cohorts; the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based sample of 1076 elderly men, and the Construction Workers Cohort (CWC), a sample of 118,425 never-smoking male construction workers. Methods: Cox proportional hazards models were used to investigate possible associations of snus use with risk of a first hospitalization for heart failure.

    Results: In ULSAM, 95 men were hospitalized for heart failure, during a median follow up of 8.9 years. In a model adjusted for established risk factors including past and present smoking exposure, current snus use was associated with a higher risk of heart failure [hazard ratio (HR) 2.08, 95% confidence interval (CI) 1.03-4.22] relative to non-use. Snus use was particularly associated with risk of non-ischaemic heart failure (HR 2.55, 95% CI 1.12-5.82). In CWC, 545 men were hospitalized for heart failure, during a median follow up of 18 years. In multivariable-adjusted models, current snus use was moderately associated with a higher risk of heart failure (HR 1.28, 95% CI 1.00-1.64) and non-ischaemic heart failure (HR 1.28, 95% CI 0.97-1.68) relative to never tobacco use.

    Conclusion: Data from two independent cohorts suggest that use of snus may be associated with a higher risk of heart failure.

  • 7. Arking, Dan E
    et al.
    Pulit, Sara L
    Crotti, Lia
    van der Harst, Pim
    Munroe, Patricia B
    Koopmann, Tamara T
    Sotoodehnia, Nona
    Rossin, Elizabeth J
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Newton-Cheh, Christopher
    Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 8, p. 826-836Article in journal (Refereed)
    Abstract [en]

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

  • 8.
    Artzi-Medvedik, Rada
    et al.
    Ben-Gurion University of the Negev, Beer-Sheva, Israel; Maccabi Health Services, Southern District, Omer, Israel.
    Kob, Robert
    Friedrich-Alexander-Universität Erlangen-Nürnberg, Nürnberg, Germany.
    Di Rosa, Mirko
    Italian National Research Center on Aging (IRCCS INRCA), Ancona, Italy.
    Lattanzio, Fabrizia
    Italian National Research Center on Aging (IRCCS INRCA), Ancona, Italy.
    Corsonello, Andrea
    Italian National Research Center on Aging (IRCCS INRCA), Ancona, Italy.
    Yehoshua, Ilan
    Maccabi Health Services, Southern District, Omer, Israel.
    Roller-Wirnsberger, Regina E
    Medical University of Graz, Graz, Austria.
    Wirnsberger, Gerhard H
    Medical University of Graz, Graz, Austria.
    Mattace-Raso, Francesco U S
    University Medical Center Rotterdam, Rotterdam, The Netherlands.
    Tap, Lisanne
    University Medical Center Rotterdam, Rotterdam, The Netherlands.
    Gil, Pedro G
    Hospital Clinico San Carlos, Madrid, Spain.
    Formiga, Francesc
    Bellvitge University Hospital-IDIBELL-L'Hospitalet de Llobregat, Barcelona, Spain.
    Moreno-González, Rafael
    Bellvitge University Hospital-IDIBELL-L'Hospitalet de Llobregat, Barcelona, Spain.
    Kostka, Tomasz
    Medical University of Lodz, Lodz, Poland.
    Guligowska, Agnieszka
    Medical University of Lodz, Lodz, Poland.
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Karolinska Institutet, Huddinge.
    Carlsson, Axel C
    Karolinska Institutet, Huddinge; Stockholm Region, Stockholm.
    Freiberger, Ellen
    Friedrich-Alexander-Universität Erlangen-Nürnberg, Nürnberg, Germany.
    Melzer, Itshak
    Ben-Gurion University of the Negev, Beer-Sheva, Israel.
    Quality of Life and Kidney Function in Older Adults: Prospective Data of the SCOPE Study2023In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 12, no 12, article id 3959Article in journal (Refereed)
    Abstract [en]

    A longitudinal alteration in health-related quality of life (HRQoL) over a two-year period and its association with early-stage chronic kidney disease (CKD) progression was investigated among 1748 older adults (>75 years). HRQoL was measured by the Euro-Quality of Life Visual Analog Scale (EQ-VAS) at baseline and at one and two years after recruitment. A full comprehensive geriatric assessment was performed, including sociodemographic and clinical characteristics, the Geriatric Depression Scale-Short Form (GDS-SF), Short Physical Performance Battery (SPPB), and estimated glomerular filtration rate (eGFR). The association between EQ-VAS decline and covariates was investigated by multivariable analyses. A total of 41% of the participants showed EQ-VAS decline, and 16.3% showed kidney function decline over the two-year follow-up period. Participants with EQ-VAS decline showed an increase in GDS-SF scores and a greater decline in SPPB scores. The logistic regression analyses showed no contribution of a decrease in kidney function on EQ-VAS decline in the early stages of CKD. However, older adults with a greater GDS-SF score were more likely to present EQ-VAS decline over time, whereas an increase in the SPPB scores was associated with less EQ-VAS decline. This finding should be considered in clinical practice and when HRQoL is used to evaluate health interventions among older adults.

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  • 9. Artzi-Medvedik, Rada
    et al.
    Kob, Robert
    Fabbietti, Paolo
    Lattanzio, Fabrizia
    Corsonello, Andrea
    Melzer, Yehudit
    Roller-Wirnsberger, Regina
    Wirnsberger, Gerhard
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala University; Karolinska Institutet.
    Melzer, Itshak
    Impaired kidney function is associated with lower quality of life among community-dwelling older adults: The screening for CKD among older people across Europe (SCOPE) study.2020In: BMC Geriatrics, E-ISSN 1471-2318, Vol. 20, no Suppl 1, article id 340Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Quality of life (QoL) refers to the physical, psychological, social and medical aspects of life that are influenced by health status and function. The purpose of this study was to measure the self-perceived health status among the elderly population across Europe in different stages of Chronic Kidney Disease (CKD).

    METHODS: Our series consisted of 2255 community-dwelling older adults enrolled in the Screening for Chronic Kidney Disease (CKD) among Older People across Europe (SCOPE) study. All patients underwent a comprehensive geriatric assessment (CGA), including included demographics, clinical and physical assessment, number of medications taken, family arrangement, Geriatric Depression Scale (GDS), Cumulative Illness Rating Scale, History of falls, Lower urinary tract symptoms, and Short Physical Performance Battery (SPPB). Estimated glomerular filtration rate (eGFR) was calculated by Berlin Initiative Study (BIS) equation. Quality of life was assessed by Euro Qol questionnaire (Euro-Qol 5D) and EQ-Visual Analogue Scale (EQ-VAS). The association between CKD (eGFR < 60, < 45 ml or < 30 ml/min/1.73m2) and low EQoL-VAS was investigated by multivariable logistic regression models.

    RESULTS: CKD was found to be significantly associated with low EQoL-VAS in crude analysis (OR = 1.47, 95%CI = 1.16-1.85 for eGFR< 60; OR = 1.38, 95%CI = 1.08-1.77 for eGFR< 45; OR = 1.57, 95%CI = 1.01-2.44). Such association was no longer significant only when adjusting for SPPB (OR = 1.20, 95%CI = 0.93-1.56 for eGFR< 60; OR = 0.87, 95%CI = 0.64-1.18 for eGFR< 45; OR = 0.84, 95%CI = 0.50-1.42), CIRS and polypharmacy (OR = 1.16, 95%CI = 0.90-1.50 for eGFR< 60; OR = 0.86, 95%CI = 0.64-1.16 for eGFR< 45; OR = 1.11, 95%CI = 0.69-1.80) or diabetes, hypertension and chronic obstructive pulmonary disease (OR = 1.28, 95%CI = 0.99-1.64 for eGFR< 60; OR = 1.16, 95%CI = 0.88-1.52 for eGFR< 45; OR = 1.47, 95%CI = 0.92-2.34). The association between CKD and low EQoL-VAS was confirmed in all remaining multivariable models.

    CONCLUSIONS: CKD may significantly affect QoL in community-dwelling older adults. Physical performance, polypharmacy, diabetes, hypertension and COPD may affect such association, which suggests that the impact of CKD on QoL is likely multifactorial and partly mediated by co-occurrent conditions/risk factors.

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  • 10. Baldanzi, Gabriel
    et al.
    Sayols-Baixeras, Sergi
    Ekblom-Bak, Elin
    Ekblom, Örjan
    Dekkers, Koen F
    Hammar, Ulf
    Nguyen, Diem
    Ahmad, Shafqat
    Ericson, Ulrika
    Arvidsson, Daniel
    Börjesson, Mats
    Johanson, Peter J
    Smith, J Gustav
    Bergström, Göran
    Lind, Lars
    Engström, Gunnar
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Karolinska Institutet, Huddinge.
    Kennedy, Beatrice
    Orho-Melander, Marju
    Fall, Tove
    Accelerometer-based physical activity is associated with the gut microbiota in 8416 individuals in SCAPIS.2024In: EBioMedicine, E-ISSN 2352-3964, Vol. 100, article id 104989Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous population-based studies investigating the relationship between physical activity and the gut microbiota have relied on self-reported activity, prone to reporting bias. Here, we investigated the associations of accelerometer-based sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity with the gut microbiota using cross-sectional data from the Swedish CArdioPulmonary bioImage Study.

    METHODS: In 8416 participants aged 50-65, time in SED, MPA, and VPA were estimated with hip-worn accelerometer. Gut microbiota was profiled using shotgun metagenomics of faecal samples. We applied multivariable regression models, adjusting for sociodemographic, lifestyle, and technical covariates, and accounted for multiple testing.

    FINDINGS: Overall, associations between time in SED and microbiota species abundance were in opposite direction to those for MPA or VPA. For example, MPA was associated with lower, while SED with higher abundance of Escherichia coli. MPA and VPA were associated with higher abundance of the butyrate-producers Faecalibacterium prausnitzii and Roseburia spp. We observed discrepancies between specific VPA and MPA associations, such as a positive association between MPA and Prevotella copri, while no association was detected for VPA. Additionally, SED, MPA and VPA were associated with the functional potential of the microbiome. For instance, MPA was associated with higher capacity for acetate synthesis and SED with lower carbohydrate degradation capacity.

    INTERPRETATION: Our findings suggest that sedentary and physical activity are associated with a similar set of gut microbiota species but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain gut microbiota species.

    FUNDING: European Research Council, Swedish Heart-Lung Foundation, Swedish Research Council, Knut and Alice Wallenberg Foundation.

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  • 11. Baldanzi, Gabriel
    et al.
    Sayols-Baixeras, Sergi
    Theorell-Haglöw, Jenny
    Dekkers, Koen F
    Hammar, Ulf
    Nguyen, Diem
    Lin, Yi-Ting
    Ahmad, Shafqat
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Karolinska Institutet, Huddinge.
    Fall, Tove
    Obstructive sleep apnea was associated with the human gut microbiota composition and functional potential in the population-based Swedish CardioPulmonary bioImage Study (SCAPIS)2023In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 164, no 2, p. 503-516Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep-breathing disorder linked to increased risk of cardiovascular disease. Intermittent hypoxia and intermittent airway obstruction, hallmarks of OSA, have been shown in animal models to induce substantial changes to the gut microbiota composition and subsequent transplantation of fecal matter to other animals induced changes in blood pressure and glucose metabolism.

    RESEARCH QUESTION: Does obstructive sleep apnea in adults associate with the composition and metabolic potential of the human gut microbiota?

    STUDY DESIGN AND METHODS: We used respiratory polygraphy data from up to 3,570 individuals aged 50-64 from the population-based Swedish CardioPulmonary bioImage Study combined with deep shotgun metagenomics of fecal samples to identify cross-sectional associations between three OSA parameters covering apneas and hypopneas, cumulative sleep time in hypoxia and number of oxygen desaturation events with gut microbiota composition. Data collection about potential confounders was based on questionnaires, on-site anthropometric measurements, plasma metabolomics, and linkage with the Swedish Prescribed Drug Register.

    RESULTS: We found that all three OSA parameters were associated with lower diversity of species in the gut. Further, the OSA-related hypoxia parameters were in multivariable-adjusted analysis associated with the relative abundance of 128 gut bacterial species, including higher abundance of Blautia obeum and Collinsela aerofaciens. The latter species was also independently associated with increased systolic blood pressure. Further, the cumulative time in hypoxia during sleep was associated with the abundance of genes involved in nine gut microbiota metabolic pathways, including propionate production from lactate. Lastly, we observed two heterogeneous sets of plasma metabolites with opposite association with species positively and negatively associated with hypoxia parameters, respectively.

    INTERPRETATION: OSA-related hypoxia, but not the number of apneas/hypopneas, is associated with specific gut microbiota species and functions. Our findings lay the foundation for future research on the gut microbiota-mediated health effects of OSA.

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  • 12.
    Balducci, Francesco
    et al.
    Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Ancona and Cosenza, Ancona, Italy, IT.
    Di Rosa, Mirko
    Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Ancona and Cosenza, Ancona, Italy, IT.
    Roller-Wirnsberger, Regina
    Department of Internal Medicine, Medical University of Graz, Graz, Austria, AT.
    Wirnsberger, Gerhard
    Department of Internal Medicine, Medical University of Graz, Graz, Austria, AT.
    Mattace-Raso, Francesco
    Section of Geriatric Medicine, Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands, NL.
    Tap, Lisanne
    Section of Geriatric Medicine, Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands, NL.
    Formiga, Francesc
    Geriatric Unit, Internal Medicine Department and Nephrology Department, Bellvitge University Hospital, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain, ES.
    Moreno-González, Rafael
    Geriatric Unit, Internal Medicine Department and Nephrology Department, Bellvitge University Hospital, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain, ES.
    Kostka, Tomasz
    Department of Geriatrics, Healthy Ageing Research Centre, Medical University of Lodz, Lodz, Poland, PL.
    Guligowska, Agnieszka
    Department of Geriatrics, Healthy Ageing Research Centre, Medical University of Lodz, Lodz, Poland, PL.
    Artzi-Medvedik, Rada
    The Recanati School for Community Health Professions at the Faculty of Health Sciences at Ben-Gurion University of the Negev, Beersheba, Israel, IL; Maccabi Healthcare Services, Southern Region, Tel Aviv, Israel, IL.
    Melzer, Itshak
    The Recanati School for Community Health Professions at the Faculty of Health Sciences at Ben-Gurion University of the Negev, Beersheba, Israel, IL.
    Weingart, Christian
    Department of General Internal Medicine and Geriatrics, Krankenhaus Barmherzige Brüder Regensburg and Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, DE.
    Sieber, Cornel
    Department of General Internal Medicine and Geriatrics, Krankenhaus Barmherzige Brüder Regensburg and Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, DE.
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm.
    Carlsson, Axel C
    Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm.
    Lattanzio, Fabrizia
    Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Ancona and Cosenza, Ancona, Italy, IT.
    Corsonello, Andrea
    Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Ancona and Cosenza, Ancona, Italy, IT; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza, Italy, IT.
    Healthcare costs in relation to kidney function among older people: the SCOPE study2024In: European Geriatric Medicine, ISSN 1878-7649, E-ISSN 1878-7657Article in journal (Refereed)
    Abstract [en]

    PURPOSE: In this study, a comprehensive analysis of costs of chronic kidney disease (CKD) was performed, to understand factors associated with the economic burden of the disease in a multicentre international framework.

    METHODS: The impact on costs of demographics, socio-economics, clinical, and functional variables was tested in 2204 subjects aged 75 years or more attending outpatient clinics in Europe using a multicentre 2-year prospective cohort study. By means of collected resources consumption and unit cost data a comprehensive cost database was built and then investigated using multilevel regression modeling.

    RESULTS: Overall, hospitalization, medications and specialist visits were the main cost items, with a notable variability among countries. Estimated yearly costs were 4478€ ± 9804€, rising up to 6683€ ± 10,953€ for subjects with estimated Glomerular Filtration Rate (eGFR) < 30. Costs increased significantly according to the severity of the disease, gender and age. Clinical and functional covariates were also significantly associated with CKD-related total costs, even after correcting for the inter-country variability.

    CONCLUSION: Findings corroborate the importance of multidimensional assessment of participants with CKD, as multimorbidity and functional disability produce a detrimental impact on participant's prognosis and cost of care. Preservation of functional impairment and adequate management of comorbidities may thus help decreasing the overall consumption on health care resources in CKD patients, especially in older people.

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  • 13. Bandak, Ghassan
    et al.
    Sang, Yingying
    Gasparini, Alessandro
    Chang, Alex R
    Ballew, Shoshana H
    Evans, Marie
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Lund, Lars H
    Inker, Lesley A
    Grams, Morgan E
    Hyperkalemia after initiating renin-angiotensin system blockade: The Stockholm creatinine measurements (SCREAM) project2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, E-ISSN 2047-9980, Vol. 6, no 7, article id e005428Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score.

    METHODS AND RESULTS: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new β-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m(2) were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration.

    CONCLUSIONS: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m(2), but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies.

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  • 14. Barber, Ryan M
    et al.
    Fullman, Nancy
    Sorensen, Reed J
    Bollyky, Thomas
    McKee, Martin
    Nolte, Ellen
    Abajobir, Amanuel Alemu
    Abete, Kalkidan Hassen
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska institutet.
    Murray, Christopher J L
    Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 20152017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10091, p. 231-266Article in journal (Refereed)
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  • 15. Basu, S
    et al.
    Zethelius, B
    Helmersson, J
    Berne, C
    Larsson, A
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men2011In: International Journal of Clinical and Experimental Medicine, E-ISSN 1940-5901, Vol. 4, no 2, p. 164-168Article in journal (Refereed)
    Abstract [en]

    Both clinical and experimental studies suggest a close relation between an inflammatory state and insulin resistance. We investigated the association between cytokine-mediated inflammation (high sensitivity C reactive protein [hsCRP] and interleukin [IL] 6) and insulin sensitivity (insulin-mediated glucose disposal rate, assessed by the euglycemic insulin clamp) in a community-based cohort, with subgroup analyses of normal weight individuals without diabetes mellitus and metabolic syndrome (NCEP). hsCRP and IL- 6 were inversely associated with insulin sensitivity (multivariable-adjusted regression coefficient for 1-SD increase of hsCRP -0.12 (-0.21-(-0.03), p=0.01) and of IL-6 - 0.11 (-0.21-(-0.02), p=0.01) in models adjusting for age and components of the metabolic syndrome (systolic and diastolic blood pressure, antihypertensive drugs, HDL-cholesterol, triglycerides, fasting plasma glucose, waist circumference). The multivariable-adjusted association between hsCRP, IL-6 and insulin sensitivity were of a similar magnitude in normal weight individuals without diabetes and without the metabolic syndrome. Our data show that cytokine -mediated subclinical inflammation is independently associated with decreased insulin sensitivity also in apparently metabolically healthy normal weight individuals, indicating that the interplay between inflammatory processes and insulin resistance is present already in the early stages of the development of glucometabolic disease. (IJCEM1012002).

  • 16. Beijer, K.
    et al.
    Nowak, C.
    Sundström, J.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska Institutet.
    Fall, T.
    Lind, L.
    In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 11, p. 1998-2006Article in journal (Refereed)
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  • 17. Bikbov, Boris
    et al.
    Purcell, Carrie
    Levey, Andrew S.
    Smith, Mari
    Abdoli, Amir
    Abebe, Molla
    Adebayo, Oladimeji M.
    Afarideh, Mohsen
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Vos, Theo
    Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 20172020In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 395, no 10225, p. 709-733Article in journal (Refereed)
    Abstract [en]

    Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and induded incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017,1.2 million (95% uncertainty interval [UI] 1.2 to 1.3) people died from CKD. The global all-age mortality rate from CKD increased 41.5% (95% UI 35.2 to 46.5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2.8%, -1.5 to 6.3). In 2017,697.5 million (95% UI 649.2 to 752.0) cases of all-stage CKD were recorded, for a global prevalence of 9.1% (8.5 to 9.8). The global all-age prevalence of CKD increased 29.3% (95% UI 26.4 to 32.6) since 1990, whereas the age-standardised prevalence remained stable (1.2%, -1.1 to 3.5). CKD resulted in 35.8 million (95% UI 33.7 to 38.0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1.4 million (95% UI 1.2 to 1.6) cardiovascular disease-related deaths and 25.3 million (22.2 to 28.9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.

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  • 18. Bjerre, M.
    et al.
    Hilden, J.
    Winkel, P.
    Jensen, G. B.
    Kjøller, E.
    Sajadieh, A.
    Kastrup, J.
    Kolmos, H. J.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska Institute.
    Gluud, C.
    Serum osteoprotegerin as a long-term predictor for patients with stable coronary artery disease and its association with diabetes and statin treatment: A CLARICOR trial 10-year follow-up substudy2020In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 301, p. 8-14Article in journal (Refereed)
  • 19. Brauer, M.
    et al.
    Roth, G. A.
    Aravkin, A. Y.
    Zheng, P.
    Abate, K. H.
    Abate, Y. H.
    Abbafati, C.
    Abbasgholizadeh, R.
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm.
    Gakidou, E.
    Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 20212024In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 403, no 10440, p. 2162-2203Article in journal (Refereed)
    Abstract [en]

    Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions. Funding: Bill & Melinda Gates Foundation. © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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  • 20. Britting, Sabine
    et al.
    Artzi-Medvedik, Rada
    Fabbietti, Paolo
    Tap, Lisanne
    Mattace-Raso, Francesco
    Corsonello, Andrea
    Lattanzio, Fabrizia
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala University; Karolinska Institutet.
    Carlsson, Axel C
    Freiberger, Ellen
    Kidney function and other factors and their association with falls: The screening for CKD among older people across Europe (SCOPE) study.2020In: BMC Geriatrics, E-ISSN 1471-2318, Vol. 20, no Suppl 1, article id 320Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Reduced kidney function has become a major public health concern, especially among older people, as Chronic Kidney Disease (CKD) is associated with increased risk of end stage renal disease and mortality. Falls are a serious negative health outcome in older persons with one third of people aged 65 years experiencing a fall per year and increasing fall rates with increasing age. The impact of CKD on falls in older community-dwelling persons is not well investigated. Additionally, lower urinary tract symptoms (LUTS) may also increase the risk of falls. Therefore, our aim was to investigate the impact of CKD and LUTS on falls as well as on injurious falls.

    METHODS: The SCOPE study is an observational, multinational, multicenter, prospective cohort study involving community-dwelling older persons aged 75 years and more recruited from August 2016 to March 2018 in seven European countries. The main outcomes of the present study were any falls and any injurious falls during the 12 months before enrolment. The cross-sectional association of estimated glomerular filtration rate (eGFR) and LUTS with study outcomes was investigated by logistic regression analysis adjusted for baseline characteristics of enrolled subjects.

    RESULTS: Our series consisted of 2256 SCOPE participants (median age = 79.5 years, 55.7% female). Of them, 746 participants experienced a fall and 484 reported an injurious fall in the 12 months prior to baseline assessment. CKD was not significantly associated with falls (OR = 0.95, 95%CI = 0.79-1.14 for eGFR< 60; OR = 1.02, 95%CI = 0.81-1.28 for eGFR< 45; OR = 1.08, 95%CI = 0.74-1.57 for eGFR< 30) or injurious falls (OR = 0.91, 95%CI = 0.67-1.24 for eGFR< 60; OR = 0.93, 95%CI = 0.63-1.37 for eGFR< 45; OR = 1.19, 95%CI = 0.62-2.29 for eGFR< 30). LUTS were found significantly associated with both falls (OR = 1.56, 95%CI = 1.29-1.89) and injurious falls (OR = 1.58, 95%CI = 1.14-2.19), and such associations were confirmed in all multivariable models.

    CONCLUSIONS: Cross-sectional data suggest that CKD may not be associated with history of falls or injurious falls, whereas LUTS is significantly associated with the outcomes.

    TRIAL REGISTRATION: This study was registered on 25th February 2016 at clinicaltrials.gov ( NCT02691546 ).

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  • 21.
    Broberg, Olof
    et al.
    Skåne University Hospital, Lund; Lund University, Lund.
    Feldreich, Tobias
    Dalarna University, School of Health and Welfare, Medical Science.
    Weismann, Constance G
    Skåne University Hospital, Lund; Lund University, Lund; Ludwig-Maximilian University, Munich, DE, Germany.
    Øra, Ingrid
    Lund University, Lund; Skåne University Hospital, Lund.
    Wiebe, Thomas
    Lund University, Lund; Skåne University Hospital, Lund.
    Ärnlöv, Johan
    Dalarna University, School of Health and Welfare, Medical Science. Karolinska Institutet, Huddinge.
    Liuba, Petru
    Skåne University Hospital, Lund; Lund University, Lund.
    Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer2024In: Cardiology in the Young, ISSN 1047-9511, E-ISSN 1467-1107, Vol. 34, no 6, p. 1325-1333Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease.

    METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index).

    RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005).

    CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.

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  • 22. Brück, Katharina
    et al.
    Jager, Kitty J
    Dounousi, Evangelia
    Kainz, Alexander
    Nitsch, Dorothea
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala university.
    Rothenbacher, Dietrich
    Browne, Gemma
    Capuano, Vincenzo
    Ferraro, Pietro Manuel
    Methodology used in studies reporting chronic kidney disease prevalence: a systematic literature review2015In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30, no Supp. 4, p. iv6-iv16Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods.

    METHODS: For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers.

    RESULTS: We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) <60 mL/min/1.73 m(2) in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval.

    CONCLUSIONS: The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.

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  • 23. Brück, Katharina
    et al.
    Stel, Vianda S
    Gambaro, Giovanni
    Hallan, Stein
    Völzke, Henry
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Kastarinen, Mika
    Guessous, Idris
    Vinhas, José
    Stengel, Bénédicte
    CKD prevalence varies across the European general population2016In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, no 7, p. 2135-2147Article in journal (Refereed)
    Abstract [en]

    CKD prevalence estimation is central to CKD management and prevention planning at the population level. This study estimated CKD prevalence in the European adult general population and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity. We collected data from 19 general-population studies from 13 European countries. CKD stages 1-5 was defined as eGFR<60 ml/min per 1.73 m(2), as calculated by the CKD-Epidemiology Collaboration equation, or albuminuria >30 mg/g, and CKD stages 3-5 was defined as eGFR<60 ml/min per 1.73 m(2). CKD prevalence was age- and sex-standardized to the population of the 27 Member States of the European Union (EU27). We found considerable differences in both CKD stages 1-5 and CKD stages 3-5 prevalence across European study populations. The adjusted CKD stages 1-5 prevalence varied between 3.31% (95% confidence interval [95% CI], 3.30% to 3.33%) in Norway and 17.3% (95% CI, 16.5% to 18.1%) in northeast Germany. The adjusted CKD stages 3-5 prevalence varied between 1.0% (95% CI, 0.7% to 1.3%) in central Italy and 5.9% (95% CI, 5.2% to 6.6%) in northeast Germany. The variation in CKD prevalence stratified by diabetes, hypertension, and obesity status followed the same pattern as the overall prevalence. In conclusion, this large-scale attempt to carefully characterize CKD prevalence in Europe identified substantial variation in CKD prevalence that appears to be due to factors other than the prevalence of diabetes, hypertension, and obesity.

  • 24. Burgaz, A.
    et al.
    Byberg, L.
    Rautiainen, S.
    Orsini, N.
    Hakansson, N.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundstrom, J.
    Lind, L.
    Melhus, H.
    Michaelsson, K.
    Wolk, A.
    Confirmed hypertension and plasma 25(OH)D concentrations amongst elderly men2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 269, no 2, p. 211-218Article in journal (Refereed)
    Abstract [en]

    Objectives. The results of experimental studies suggest that vitamin D deficiency activates the renin-angiotensin system and predisposes to hypertension. Results of previous epidemiological studies investigating the association between 25-hydroxyvitamin D [25(OH)D] status and hypertension have not been consistent, perhaps because of their sole reliance on office blood pressure (BP) measurements leading to some misclassification of hypertension status. No previous studies have examined the association between 25(OH)D status and confirmed hypertension assessed with both office and 24-h BP measurements.

    Design. In this cross-sectional study, we investigated 833 Caucasian men, aged 71 +/- 0.6 years, to determine the association between plasma 25(OH)D concentrations, measured with high-pressure liquid chromatography mass spectrometry, and the prevalence of hypertension. We used both supine office and 24-h BP measurements for classifying participants as normotensive or confirmed hypertensive; participants with inconsistent classifications were excluded.

    Results. In a multivariable adjusted logistic regression model, men with 25(OH)D concentrations < 37.5 nmol L-1 had a 3-fold higher prevalence of confirmed hypertension compared to those with >= 37.5 nmol L-1 25(OH)D (odds ratio = 3.3, 95% CI: 1.0-11.0).

    Conclusions. Our results show that low plasma 25(OH)D concentration is associated with a higher prevalence of confirmed hypertension.

  • 25. Böger, Carsten A
    et al.
    Chen, Ming-Huei
    Tin, Adrienne
    Olden, Matthias
    Köttgen, Anna
    de Boer, Ian H
    Fuchsberger, Christian
    O'Seaghdha, Conall M
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Kao, W. H. L
    CUBN is a gene locus for albuminuria2011In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 22, no 3, p. 555-70Article in journal (Refereed)
    Abstract [en]

    Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10−11) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes

  • 26. Carlsson, A. C.
    et al.
    Riserus, U.
    Engstrom, G.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Melander, O.
    Leander, K.
    Gigante, B.
    Hellenius, M-L
    de Faire, U.
    Novel and established anthropometric measures and the prediction of incident cardiovascular disease: a cohort study2013In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 37, no 12, p. 1579-1585Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of this study was to compare novel and established anthropometrical measures in their ability to predict cardiovascular disease (CVD), and to determine whether they improve risk prediction beyond classical risk factors in a cohort study of 60-year-old men and women. We also stratified the results according to gender to identify possible differences between men and women. Furthermore, we aimed to replicate our findings in a large independent cohort (The Malmo Diet and Cancer study-cardiovascular cohort).

    METHODS: This was a population-based study of 1751 men and 1990 women, aged 60 years and without CVD at baseline, with 375 incident cases of CVD during 11 years of follow-up. Weight, height, waist circumference (WC), hip circumference and sagittal abdominal diameter (SAD) were measured at baseline. Body mass index (BMI), waist-hip ratio (WHR), waist-hip-height ratio (WHHR), WC-to-height ratio (WCHR) and SAD-to-height ratio (SADHR) were calculated.

    RESULTS: All anthropometric measures predicted CVD in unadjusted Cox regression models per s.d. increment (hazard ratios, 95% confidence interval), while significant associations after adjustments for established risk CVD factors were noted for WHHR 1.20 (1.08-1.33), WHR 1.14 (1.02-1.28), SAD 1.13 (1.02-1.25) and SADHR 1.17 (1.06-1.28). WHHR had higher increases in C-statistics, and model improvements (likelihood ratio tests (P<0.001)). In the replication study (MDC-CC, n = 5180), WHHR was the only measure that improved Cox regression models in men (P = 0.01).

    CONCLUSION: WHHR, a new measure reflecting body fat distribution, showed the highest risk estimates after adjustments for established CVD risk factors. These findings were verified in men but not women in an independent cohort.

  • 27.
    Carlsson, A C
    et al.
    Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden ; Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Riserus, Ulf
    Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Department of Public Health and Caring Sciences/Section of Geriatrics Uppsala University, Uppsala, Sweden.
    Borné, Y
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Leander, K
    Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gigante, B
    Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden ; Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Hellénius, M-L
    Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Bottai, M
    Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institute, Sweden.
    de Faire, U
    Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden ; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
    Prediction of cardiovascular disease by abdominal obesity measures is dependent on body weight and sex: results from two community based cohort studies2014In: NMCD. Nutrition Metabolism and Cardiovascular Diseases, ISSN 0939-4753, E-ISSN 1590-3729, Vol. 24, no 8, p. 891-899Article in journal (Refereed)
    Abstract [en]

    AIM: To study waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), and waist-hip-height ratio (WHHR) as predictors of CVD, in men and women stratified by BMI (cut-off ≥25).

    METHODS AND RESULTS: A cohort of n = 3741 (53% women) 60-year old individuals without CVD was followed for 11-years (375 CVD cases). To replicate the results, we also assessed another large independent cohort; The Malmö Diet and Cancer study - cardiovascular cohort (MDCC, (n = 5180, 60% women, 602 CVD cases during 16-years). After adjustment for established risk factors in normal-weight women, the hazard ratio (HR) per one standard deviation (SD) were; WHR; 1.91 (95% confidence interval (CI) 1.35-2.70), WC; 1.81 (95% CI 1.02-3.20), SAD; 1.25 (95% CI 0.74-2.11), and WHHR; 1.97 (95% CI 1.40-2.78). In men the association with WHR, WHHR and WC were not significant, whereas SAD was the only measure that significantly predicted CVD in men (HR 1.19 (95% CI 1.04-1.35). After adjustments for established risk factors in overweight/obese women, none of the measures were significantly associated with CVD risk. In men, however, all measures were significant predictors; WHR; 1.24 (955 CI 1.04-1.47), WC 1.19 (95% CI 1.00-1.42), SAD 1.21 (95% CI 1.00-1.46), and WHHR; 1.23 (95% CI 1.05-1.44). Only the findings in men with BMI ≥ 25 were verified in MDCC.

    CONCLUSION: In normal weight individuals, WHHR and WHR were the best predictors in women, whereas SAD was the only independent predictor in men. Among overweight/obese individuals all measures failed to predict CVD in women, whereas WHHR was the strongest predictor after adjustments for CVD risk factors in men.

  • 28. Carlsson, A. C.
    et al.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Sundström, J.
    Michaëlsson, K.
    Byberg, L.
    Lind, L.
    Physical activity, obesity and risk of cardiovascular disease in middle-aged men during a median of 30 years of follow-up2016In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 4, p. 359-365Article in journal (Refereed)
    Abstract [en]

    Background: We aimed to investigate associations between combinations of body mass index (BMI)-categories, levels of physical activity and long-term risk of cardiovascular disease.

    Method and results: At age 50 years, cardiovascular risk factors were assessed in 2196 participating men of the ULSAM-study. This investigation was repeated at age 60, 70, 77 and 82 years. Being physically active (PA) was defined as three hours of recreational or hard physical training per week. The men were categorized according to BMI/PA-status, as PA/normal weight (n = 593 at baseline), non-PA/normal weight (BMI &lt; 25 kg/m2, n = 580), PA/overweight (n = 418), non-PA/overweight (BMI 25-30 kg/m2, n = 462), PA/obese (n = 62), non-PA/obese (BMI &gt;30 kg/m2, n = 81). We used updated data on BMI and physical activity obtained at all examinations. During follow-up (median 30 years) 850 individuals suffered a cardiovascular disease (myocardial infarction, stroke or heart failure). Using updated data on BMI/PA categories, an increased risk for cardiovascular disease was seen with increasing BMI, but a high physical activity was associated with a lower risk of cardiovascular disease within each BMI category: non-PA/normal weight (hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.04-1.66), PA/overweight (HR 1.52, 95% CI 1.20-1.94), non-PA/overweight (HR 1.65, 95% CI 1.31-2.07) PA/obese (HR 2.05, 95% CI 1.44-2.92) and non-PA/obese (HR 2.39, 95% CI 1.74-3.29), using PA/normal weight men as referent.

    Conclusions: Although physical activity was beneficial at all levels of BMI regarding the risk of future cardiovascular disease, there was still a substantial increased risk associated with being overweight or obese during 30 years of follow-up. 

  • 29. Carlsson, A C
    et al.
    Östgren, C J
    Länne, T
    Larsson, A
    Nystrom, F H
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    The association between endostatin and kidney disease and mortality in patients with type 2 diabetes2016In: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 42, no 5, p. 351-357Article in journal (Refereed)
    Abstract [en]

    AIM: Circulating endostatin, a biologically active derivate of collagen XVIII, is considered to be a marker of kidney disease and a risk factor for its related mortality. However, less is known of the role of endostatin in diabetes and the development of diabetic nephropathy. For this reason, our study investigated the associations between circulating endostatin and the prevalence and progression of kidney disease, and its mortality risk in patients with type 2 diabetes (T2D).

    METHODS: This was a cohort study of 607 patients with T2D (mean age: 61 years, 44% women). Estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was used to assess the patients' kidney function decline and mortality.

    RESULTS: Of the total study cohort, 20 patients declined by ≥20% in eGFR over 4 years, and 44 died during the follow-up (mean duration: 6.7 years). At baseline, participants with diabetic nephropathy (defined as eGFR<60mL/min/1.73m(2)) and/or microalbuminuria [defined as a urinary albumin-to-creatinine ratio (ACR)>3g/mol] had higher median levels of endostatin than those without nephropathy (62.7μg/L vs 57.4μg/L, respectively; P=0.031). In longitudinal analyses adjusted for age, gender, baseline eGFR and ACR, higher endostatin levels were associated with a higher risk of decline (≥20% in eGFR, OR per 1 SD increase: 1.73, 95% CI: 1.13-2.65) and a higher risk of mortality (HR per 1 SD increase: 1.57, 95% CI: 1.19-2.07).

    CONCLUSION: In patients with T2D, circulating endostatin levels can predict the progression of kidney disease and mortality independently of established kidney disease markers. The clinical usefulness of endostatin as a risk marker in such patients merits further studies.

  • 30.
    Carlsson, Axel C
    et al.
    Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden ; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Calamia, Michael
    Landstinget Dalarna, Falun, Sweden.
    Risérus, Ulf
    Department of Public Health and Caring Sciences/Section of Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Helmersson-Karlqvist, Johanna
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Kidney injury molecule (KIM)-1 is associated with insulin resistance: results from two community-based studies of elderly individuals2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 103, no 3, p. 516-21Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Insulin resistance has been shown to be closely associated with glomerular filtration rate and urinary albumin/creatinine ratio, even prior to the development of diabetes. Urinary kidney injury molecule 1 (KIM-1) is a novel, highly specific marker of kidney tubular damage. The role of insulin resistance in the development of kidney tubular damage is not previously reported. Thus, we aimed to investigate the associations between insulin sensitivity (assessed by HOMA) and urinary KIM-1.

    DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Two community-based cohorts of elderly individuals were investigated: Prospective Investigation of the vasculature in Uppsala seniors (PIVUS, n=701; mean age 75 years, 52% women); and Uppsala Longitudinal Study of adult men (ULSAM, n=533; mean age 78 years).

    RESULTS: Lower insulin sensitivity was associated with higher urinary KIM-1 in both cohorts after adjustments for age, BMI, blood pressure, antihypertensive treatment, glomerular filtration rate, and urinary albumin-creatinine ratio (PIVUS: regression coefficient for 1-SD higher HOMA-IR 0.11, 95% CI 0.03-0.20, p=0.009, and ULSAM: 0.13, 95% CI 0.04-0.22, p=0.007). Results were similar in individuals without diabetes, with normal kidney function and normo-albuminuria.

    CONCLUSIONS: Our findings in elderly individuals support the notion that the interplay between an impaired glucose metabolism and renal tubular damage is evident even prior to the development of diabetes and overt kidney disease.

  • 31. Carlsson, Axel C.
    et al.
    Carrero, Juan-Jesus
    Stenvinkel, Peter
    Bottai, Matteo
    Barany, Peter
    Larsson, Anders
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Endostatin, cathepsin S, and cathepsin L, and their association with inflammatory markers and mortality in patients undergoing hemodialysis2015In: Blood Purification, ISSN 0253-5068, E-ISSN 1421-9735, Vol. 39, no 4, p. 259-265Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Although both endostatin and cathepsins S have been associated with higher mortality, data in patients with end-stage renal disease (ESRD) are scarce.

    Methods: A longitudinal cohort study of 207 prevalent patients undergoing hemodialysis.

    Results: Cathepsins S and L were associated with soluble receptors for tumor necrosis factor (sTNFR1 and sTNFR2, rho between 0.28 and 0.43, p < 0.001 for all). Weaker or absent associations between endostatin, cathepsins S and L were seen with other inflammatory biomarkers, that is, CRP, interleukin 6, pentraxin 3, and TNF. In Cox and Laplace regression models adjusted for age, sex, dialysis vintage, and diabetes: standard deviation increments of endostatin was associated with a lower mortality (hazard ratio 0.75, 95% confidence interval (CI) 0.57-0.98), and with 6.8 months longer median survival.

    Conclusions: The high levels of endostatin, cathepsins S and L, and their associations with sTNFR1 and sTNFR2 warrant further studies exploring mortality, and the angiogenic and inflammatory pathways in ESRD. (C) 2015 S. Karger AG, Basel

  • 32. Carlsson, Axel C.
    et al.
    Carrero, Juan-Jesus
    Stenvinkel, Peter
    Bottai, Matteo
    Barany, Peter
    Larsson, Anders
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    High levels of soluble tumor necrosis factor receptors 1 and 2 and their association with mortality in patients undergoing hemodialysis2015In: CardioRenal Medicine, ISSN 1664-3828, Vol. 5, no 2, p. 89-95Article in journal (Refereed)
    Abstract [en]

    Objective: Circulating soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and 5TNFR2) are associated with chronic kidney disease (CKD) progression in patients with CKD or diabetes, and with higher mortality. However, data in patients with end-stage renal disease are scarce. Therefore, we analyzed serum levels of sTNFR1 and sTNFR2 and investigated their association with inflammatory markers and mortality in dialysis patients. Research Design and Methods: This was a longitudinal cohort study of 207 prevalent patients (median age 66 years, 56% men) undergoing hemodialysis in Stockholm, Sweden. Demographics, clinical characteristics, including comorbidities and laboratory data, were obtained at baseline, together with prospective follow-up for mortality.

    Results: The median sTNFR1 and sTNFR2 levels were 17,680 ng/l [95% confidence interval (CI) 17,023-18,337] and 24,450 ng/l (95% CI 23,721-25,179), respectively. During a follow-up of 31 months (interquartile range, 21-38), 77 patients died. There was no association between the levels of sTNFRs and mortality in Cox regression models, and no consistent trend towards higher or lower mortality was seen in Laplace regression models. sTNFR1 and sTNFR2 levels were highly associated with other inflammatory markers including interleukin-6, pentraxin 3 and TNF-alpha. Conclusions:Prevalent hemodialysis patients have several-fold higher levels of sTNFRs compared to previous studies in CKD stage 4 patients. As no consistent association between TNFR and mortality was observed, clinical implications of measuring these receptors to predict outcome end-stage renal disease patients provide limited results.

  • 33. Carlsson, Axel C
    et al.
    Ingelsson, Erik
    Sundström, Johan
    Carrero, Juan Jesus
    Gustafsson, Stefan
    Feldreich, Tobias
    Stenemo, Markus
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Use of proteomics to investigate kidney function decline over 5 years2017In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 12, no 8, p. 1226-1235Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Using a discovery/replication approach, we investigated associations between a multiplex panel of 80 circulating proteins associated with cardiovascular pathology or inflammation, and eGFR decline per year and CKD incidence.

    DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used two cohorts, the Prospective Investigation of the Vasculature in Uppsala Seniors Study (PIVUS; n=687, mean age of 70 years, 51% women) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=360 men, mean age of 78 years), with 5-year follow-up data on eGFR. There were 231 and 206 incident cases of CKD during follow-up in the PIVUS and ULSAM studies, respectively. Proteomic profiling of 80 proteins was assessed by a multiplex assay (proximity extension assay). The assay uses two antibodies for each protein and a PCR step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations.

    RESULTS: In the discovery cohort from the PIVUS Study, 28 plasma proteins were significantly associated with eGFR decline per year, taking into account the multiple testing. Twenty of these proteins were significantly associated with eGFR decline per year in the replication cohort from the ULSAM Study after adjustment for age, sex, cardiovascular risk factors, medications, and urinary albumin-to-creatinine ratio (in order of significance: TNF-related apoptosis-inducing ligand receptor 2*, CD40L receptor, TNF receptor 1*, placenta growth factor*, thrombomodulin*, urokinase plasminogen activator surface receptor*, growth/differentiation factor 15*, macrophage colony-stimulating factor 1, fatty acid-binding protein*, cathepsin D, resistin, kallikrein 11*, C-C motif chemokine 3, proteinase-activated receptor 1*, cathepsin L, chitinase 3-like protein 1, TNF receptor 2*, fibroblast growth factor 23*, monocyte chemotactic protein 1, and kallikrein 6). Moreover, 11 of the proteins predicted CKD incidence (marked with * above). No protein consistently predicted eGFR decline per year independently of baseline eGFR in both cohorts.

    CONCLUSIONS: Several circulating proteins involved in phosphate homeostasis, inflammation, apoptosis, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction were associated with worsening kidney function. Multiplex proteomics appears to be a promising way of discovering novel aspects of kidney disease pathology.

  • 34. Carlsson, Axel C
    et al.
    Jansson, Jan-Håkan
    Söderberg, Stefan
    Ruge, Toralph
    Larsson, Anders
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 272, p. 41-46Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Soluble receptors for tumor necrosis factor alpha (sTNFR1 and sTNFR2) have been associated with cardiovascular diseases, and some evidence points towards a difference in associated risk between men and women. We aimed to study the association between sTNFR1 and sTNFR2 and incident myocardial infarctions (MI) and to explore the influence of established cardiovascular risk factors in men and women.

    METHODS: We conducted a nested case control study in three large Swedish cohorts, including 533 myocardial infarction cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated.

    RESULTS: An association between circulating sTNFR1 and sTNFR2 and an increased risk for MI was found when comparing cases and controls. The odds ratios were significant after adjustment for established cardiovascular risk factors and C-reactive protein in women (OR 1.44, 95% CI 1.08-1.93 for TNFR1, and 1.61, 95% CI 1.11-2.34 for TNFR2), but was abolished in men. Women with a combination of elevated CRP and values in the upper quartile of TNFR1 or TNFR2 had a 5-fold higher risk of myocardial infarction versus those with normal CRP and values in the lower three quartiles of TNFR1 or TNFR2.

    CONCLUSIONS: As the risk estimates for TNFR1 and TNFR2 were higher and remained significant after adjustments for established cardiovascular risk factors in women but not in men, a potential role for TNFR1 and TNFR2 in identifying women with a higher MI risk is possible. The future clinical role of TNFR1 and TNFR2 in combination with CRP to identify high risk patients for coronary heart disease has yet to be determined.

  • 35. Carlsson, Axel C
    et al.
    Juhlin, C Christofer
    Larsson, Tobias E
    Larsson, Anders
    Ingelsson, Erik
    Sundström, Johan
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Soluble tumor necrosis factor receptor 1 (sTNFR1) is associated with increased total mortality due to cancer and cardiovascular causes: findings from two community based cohorts of elderly2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 237, no 1, p. 236-242Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Experimental evidence support soluble receptors for tumor necrosis factor alpha as important mediators of the underlying pathology leading to cardiovascular disease and cancer. However, prospective data concerning the relation between circulating soluble tumor necrosis factor receptor-1 (sTNFR1) and mortality in humans are lacking. We aimed to explore and validate the association between sTNFR1 and mortality, and to explore the influence of other established risk factors for mortality, including other inflammatory markers.

    METHODS: The association between serum sTNFR1and the risk for mortality was investigated in two community-based cohorts of elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n = 1005, mean age 70 years, median follow-up 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 775, mean age 77 years, median follow-up 8.1 years).

    RESULTS: In total, 101 participants in PIVUS and 274 in ULSAM died during follow-up. In multivariable Cox regression models adjusted for inflammation, lifestyle and established cardiovascular risk factors, one standard deviation (SD) higher sTNFR1 was associated with a hazard ratio (HR) for mortality of 1.37, 95% confidence interval (CI) 1.17-1.60, in PIVUS and HR 1.22, 95% CI 1.10-1.37 in ULSAM. Moreover, circulatingsTNFR1 was associated with cardiovascular mortality (HR per SD of sTNFR1, 1.24, 95% CI 1.07-1.44) and cancer mortality (HR per SD of sTNFR1, 1.32, 95% CI 1.11-1.57) in the ULSAM cohort. High levels of sTNFR1 identified individuals with increased risk of mortality among those with high as well as low levels of systemic inflammation.

    CONCLUSIONS: An association between circulating sTNFR1 and an increased risk for mortality was found and validated in two independent community-based cohorts. The future clinical role of sTNFR1 to identify high risk patients for adverse outcomes and mortality has yet to be determined.

  • 36.
    Carlsson, Axel C
    et al.
    Centre for Family Medicine, Department of Neurobiology, Care Sciences, and Society, Karolinska Institute, Huddinge, Sweden; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Helmersson-Karlqvist, Johanna
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Ingelsson, Erik
    Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Larsson, Tobias E
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Bottai, Matteo
    Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Sundström, Johan
    Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Urinary kidney injury molecule-1 and the risk of cardiovascular mortality in elderly men2014In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 9, no 8, p. 1393-1401Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Kidney injury molecule-1 (KIM-1) has been suggested as a clinically relevant highly specific biomarker of acute kidney tubular damage. However, community-based data on the association between urinary levels of KIM-1 and the risk for cardiovascular mortality are lacking. This study aimed to investigate the association between urinary KIM-1 and cardiovascular mortality.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective study, using the community-based Uppsala Longitudinal Study of Adult Men (N=590; mean age 77 years; baseline period, 1997-2001; median follow-up 8.1 years; end of follow-up, 2008).RESULTS: During follow-up, 89 participants died of cardiovascular causes (incidence rate, 2.07 per 100 person-years at risk). Models were adjusted for cardiovascular risk factors (age, systolic BP, diabetes, smoking, body mass index, total cholesterol, HDL cholesterol, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, and history of cardiovascular disease) and for markers of kidney dysfunction and damage (cystatin C-based eGFR and urinary albumin/creatinine ratio). Higher urinary KIM-1/creatinine (from 24-hour urine collections) was associated with a higher risk for cardiovascular mortality (hazard ratio per SD increase, 1.27; 95% confidence interval [95% CI], 1.05 to 1.54; P=0.01). Participants with a combination of high KIM-1/creatinine (upper quintile, ≥175 ng/mmol), low eGFR (≤60 ml/min per 1.73 m(2)), and microalbuminuria/macroalbuminuria (albumin/creatinine ratio≥3 g/mol) had a >8-fold increased risk compared with participants with low KIM-1/creatinine (<175 ng/mmol), normal eGFR (>60 ml/min per 1.73 m(2)), and normoalbuminuria (albumin/creatinine ratio<3 g/mol) (hazard ratio, 8.56; 95% CI, 4.17 to 17.56; P<0.001).CONCLUSIONS: These findings suggest that higher urinary KIM-1 may predispose to a higher risk of cardiovascular mortality independently of established cardiovascular risk factors, eGFR, and albuminuria. Additional studies are needed to further assess the utility of measuring KIM-1 in the clinical setting.

  • 37. Carlsson, Axel C
    et al.
    Larsson, Anders
    Helmersson-Karlqvist, Johanna
    Lind, Lars
    Ingelsson, Erik
    Larsson, Tobias E
    Sundström, Johan
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Urinary kidney injury molecule 1 and incidence of heart failure in elderly men2013In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 15, no 4, p. 447-446Article in journal (Refereed)
    Abstract [en]

    AIMS: There is growing recognition of the clinical importance of cardiorenal syndrome-the bidirectional interplay between kidney and cardiac dysfunction. Yet, the role of kidney tubular damage in the development of heart failure is less studied. The objective of this study was to investigate whether urinary kidney injury molecule (KIM)-1, a specific marker of tubular damage, predisposes to an increased heart failure risk.

    METHODS AND RESULTS: This was a community-based cohort study [Uppsala Longitudinal study of Adult Men (ULSAM)] of 565, 77-year-old men free from heart failure at baseline. Heart failure hospitalizations were used as outcome. During follow-up (median 8.0 years), 73 participants were hospitalized for heart failure. In models adjusted for cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, LDL/HDL ratio, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, LV hypertrophy, and prevalent cardiovascular disease) and markers of kidney dysfunction and damage [cystatin C-based glomerular filtration rate (GFR) and urinary albumin/creatinine ratio], a higher urinary KIM-1/creatinine ratio was associated with higher risk for heart failure (hazard ratio upper vs. lower tertile, 1.81; 95% confidence interval 1.01-3.29; P < 0.05). Participants with a combination of low GFR (<60 mL/min/1.72 m(2)) and high KIM-1/creatinine (>128 ng/mmol) had a 3-fold increase in heart failure risk compared with participants with normal GFR and KIM-1 (P < 0.001).

    CONCLUSION: Our findings suggest that kidney tubular damage predisposes to an increased risk for heart failure in the community. Further studies are needed to clarify the causal role of KIM-1 in the development of heart failure, and to evaluate the clinical utility of urinary KIM-1 measurements.

  • 38.
    Carlsson, Axel C
    et al.
    Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden ; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Larsson, Tobias E
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Helmersson-Karlqvist, Johanna
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Soluble TNF receptors and kidney dysfunction in the elderly2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 6, p. 1313-1320Article in journal (Refereed)
    Abstract [en]

    The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=-0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.

  • 39. Carlsson, Axel C
    et al.
    Li, Xinjun
    Holzmann, Martin J
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska Institute.
    Wändell, Per
    Gasevic, Danijela
    Sundquist, Jan
    Sundquist, Kristina
    Neighborhood socioeconomic status at the age of 40 years and ischemic stroke before the age of 50 years: A nationwide cohort study from Sweden.2017In: International Journal of Stroke, ISSN 1747-4930, E-ISSN 1747-4949, Vol. 12, no 8, p. 815-826Article in journal (Refereed)
    Abstract [en]

    Objective: We aimed to study the association between neighborhood socioeconomic status at the age of 40 years and risk of ischemic stroke before the age of 50 years.

    Methods: All individuals in Sweden were included if their 40th birthday occurred between 1998 and 2010. National registers were used to categorize neighborhood socioeconomic status into high, middle, and low and to retrieve information on incident ischemic strokes. Hazard ratios and their 95% confidence intervals were estimated.

    Results: A total of 1,153,451 adults (women 48.9%) were followed for a mean of 5.5 years (SD 3.5 years), during which 1777 (0.30%) strokes among men and 1374 (0.24%) strokes among women were recorded. After adjustment for sex, marital status, education level, immigrant status, region of residence, and neighborhood services, there was a lower risk of stroke in residents from high-socioeconomic status neighborhoods (hazard ratio 0.87, 95% confidence interval 0.78-0.96), and an increased risk of stroke in adults from low-socioeconomic status neighborhoods (hazard ratio 1.16, 95% confidence interval 1.06-1.27), compared to their counterparts living in middle-socioeconomic status neighborhoods. After further adjustment for hospital diagnoses of hypertension, diabetes, heart failure, and atrial fibrillation prior to the age of 40, the higher risk in neighborhoods with low socioeconomic status was attenuated, but remained significant (hazard ratio 1.12, 95% confidence interval 1.02-1.23).

    Conclusions: In a nationwide study of individuals between 40 and 50 years, we found that the risk of ischemic stroke differed depending on neighborhood socioeconomic status, which calls for increased efforts to prevent cardiovascular diseases in low socioeconomic status neighborhoods.

  • 40.
    Carlsson, Axel C.
    et al.
    Karolinska Institutet.
    Nordquist, Lina
    Uppsala Universitet.
    Larsson, Tobias E.
    Karolinska Institutet.
    Carrero, Juan-Jesus
    Karolinska Institutet.
    Larsson, Anders
    Uppsala Universitet.
    Lind, Lars
    Uppsala university hospital.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Soluble tumor necrosis factor receptor 1 is associated with glomerular filtration rate progression and incidence of chronic kidney disease in two community-based cohorts of elderly individuals2015In: CardioRenal Medicine, ISSN 1664-3828, Vol. 5, no 4, p. 278-288Article in journal (Refereed)
    Abstract [en]

    Objective: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes.

    Research design and methods: Two community-based cohorts of elderly individuals were used with 5-year follow-up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as >= 60, 30-60, and <30 ml/min/1.73 m(2).

    Results: In longitudinal multivariable logistic regression models adjusted for inflammatory markers and established cardiovascular risk factors, higher serum sTNFR1 was significantly associated with an increased risk to progress to a lower GFR category in both ULSAM and PIVUS [odds ratio (OR) per standard deviation (SD) increase 1.28 (95% CI 1.03-1.60) and OR 1.56 (95% CI 1.30-1.87), respectively]. Also, in subgroup analyses in individuals with a GFR >= 60 ml/min/1.73 m(2) at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes.

    Conclusions: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings. 

  • 41. Carlsson, Axel C
    et al.
    Nowak, Christoph
    Lind, Lars
    Östgren, Carl Johan
    Nyström, Fredrik H
    Sundström, Johan
    Carrero, Juan Jesus
    Riserus, Ulf
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska Institutet.
    Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach2020In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 25, no 1, p. 37-43Article in journal (Refereed)
    Abstract [en]

    Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful.Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes.Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m2 and/or urinary albumin-creatinine ratio ≥3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline.Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors.Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.

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  • 42. Carlsson, Axel C.
    et al.
    Riserus, Ulf
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Hypertriglyceridemic waist phenotype is associated with decreased insulin sensitivity and incident diabetes in elderly men2014In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 22, no 2, p. 526-529Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the association between hypertriglyceridemic waist (HTGW) and insulin sensitivity (assessed by euglycemic clamp method), and the development of diabetes in a longitudinal community-based cohort of elderly men without diabetes at baseline.

    Design and Methods: The present cross-sectional study comprised 1,026, 70-year-old men without diabetes. The gold standard euglycaemic-hyperinsulinaemic clamp technique was used. Six-year follow-up on diabetes status were available in n = 667. The HTGW phenotype was defined as having waist circumference >= 90 cm, and triglycerides >= 2 mmol L-1. The men were stratified into those having normal WC and TG (n = 299), one HTGW component (n = 606), and HTGW (n = 121).

    Results: The association between insulin sensitivity and one HTGW component as well as HTGW was highly significant (P < 0.001) in the whole sample, as well as in individuals with high/low BMI (stratified at >= 25). In longitudinal analyses, participants with HTGW was associated with a more than fourfold increased risk for diabetes (Odds ratio 4.64, 95% CI 1.61-13.4, P = 0.004) compared to those with normal WC and TG.

    Conclusion: The present study both confirm and extend previous research suggesting that the HTGW-phenotype portrays an increased glucometabolic risk, also in lean individuals.

  • 43. Carlsson, Axel C
    et al.
    Ruge, Toralph
    Kjøller, Erik
    Hilden, Jørgen
    Kolmos, Hans Jørn
    Sajadieh, Ahmad
    Kastrup, Jens
    Jensen, Gorm Boje
    Larsson, Anders
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska institutet.
    10-year associations between tumor necrosis factor receptors 1 and 2 and cardiovascular events in patients with stable coronary heart disease: a CLARICOR (effect of clarithromycin on mortality and morbidity in patients with ischemic heart disease) trial substudy2018In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, E-ISSN 2047-9980, Vol. 7, no 9, article id e008299Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.

    METHODS AND RESULTS: <0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).

    CONCLUSIONS: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.

    CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

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  • 44. Carlsson, Axel C
    et al.
    Ruge, Toralph
    Sundström, Johan
    Ingelsson, Erik
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Association between circulating endostatin, hypertension duration, and hypertensive target-organ damage2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 6, p. 1146-1151Article in journal (Refereed)
    Abstract [en]

    Our aim is to study associations between circulating endostatin, hypertension duration, and hypertensive target-organ damage. Long-term hypertension induces cardiovascular and renal remodeling. Circulating endostatin, a biologically active derivate of collagen XVIII, has been suggested to be a relevant marker for extracellular matrix turnover and remodeling in various diseases. However, the role of endostatin in hypertension and hypertensive target-organ damage is unclear. Serum endostatin was measured in 2 independent community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 51%; n=812; mean age, 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=785; mean age, 77.6 years). Retrospective data on blood pressure measurements and antihypertensive medication (PIVUS >5 years, ULSAM >27 years), and cross-sectional data on echocardiographic left ventricular mass, endothelial function (endothelium-dependent vasodilation assessed by the invasive forearm model), and urinary albumin/creatinine ratio were available. In PIVUS, participants with ≥5 years of history of hypertension portrayed 0.42 SD (95% confidence interval, 0.23-0.61; P<0.001) higher serum endostatin, compared with that of normotensives. This association was replicated in ULSAM, in which participants with 27 years hypertension duration had the highest endostatin (0.57 SD higher; 95% confidence interval, 0.35-0.80; P<0.001). In addition, higher endostatin was associated with higher left ventricular mass, worsened endothelial function, and higher urinary albumin/creatinine ratio (P<0.03 for all) in participants with prevalent hypertension. Circulating endostatin is associated with the duration of hypertension, and vascular, myocardial, and renal indices of hypertensive target-organ damage. Further studies are warranted to assess the prognostic role of endostatin in individuals with hypertension.

  • 45. Carlsson, Axel C
    et al.
    Sundström, Johan
    Carrero, Juan Jesus
    Gustafsson, Stefan
    Stenemo, Markus
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala University.
    Use of a proximity extension assay proteomics chip to discover new biomarkers associated with albuminuria.2017In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 24, no 4, p. 340-348Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The underlying mechanisms for the development of albuminuria and the increased cardiovascular risk in patients with elevated albuminuria levels are incompletely understood. We therefore investigated the associations between 80 cardiovascular proteins and the urinary albumin to creatinine ratio (ACR).

    METHODS: We used a discovery/replication approach in two independent community-based cohorts of elderly patients: the Uppsala Longitudinal Study of Adult Men (n = 662; mean age 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (n = 757; mean age 75 years; 51% women). A proteomic chip with a panel of 80 plasma proteins associated with different aspects of cardiovascular disease was analysed. In the discovery cohort, we used a false discovery rate of 5% to take into account the multiple statistical testing. Nominal p values were used in the replication.

    RESULTS: Higher levels of T-cell immunoglobulin mucin-1, placenta growth factor, growth/differentiation factor-15, urokinase plasminogen activator surface receptor and kallikrein-11 were robustly associated with a higher ACR in both cohorts in multivariable linear regression models adjusted for sex, established cardiovascular risk factors, antihypertensive treatment, prevalent cardiovascular disease and glomerular filtration rate (p < 0.02 for all). All associations were also significant in separate analyses of patients without diabetes.

    CONCLUSIONS: We discovered and replicated associations between ACR and five cardiovascular proteins involved in tubular injury, atherosclerosis, endothelial function, heart failure, inflammation, glomerulosclerosis and podocyte injury. Our findings put forward multiplex proteomics as a promising approach to explore novel aspects of the complex detrimental interplay between kidney function and the cardiovascular system.

  • 46. Carlsson, Axel C
    et al.
    Wessman, T
    Larsson, A
    Leijonberg, G
    Tofik, R
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska Institutet.
    Melander, O
    Ruge, T
    Endostatin predicts mortality in patients with acute dyspnea - a cohort study of patients seeking care in emergency departments.2019In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 75, article id S0009-9120(19)30514-4Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increased levels of circulating endostatin predicts cardiovascular morbidity and impaired kidney function in the general population. The utility of endostatin as a risk marker for mortality in the emergency department (ED) has not been reported.

    AIM: Our main aim was to study the association between plasma endostatin and 90-day mortality in an unselected cohort of patients admitted to the ED for acute dyspnea. Design Circulating endostatin was analyzed in plasma from 1710 adults and related to 90-day mortality in Cox proportional hazard models adjusted for age, sex, body mass index, oxygen saturation, respiratory rate, body temperature, C-reactive protein, lactate, creatinine and medical priority according to the Medical Emergency Triage and Treatment System-Adult score (METTS-A). The predictive value of endostatin for mortality was evaluated with receiver operating characteristic (ROC) analysis and compared with the clinical triage scoring system and age.

    RESULTS: Each one standard deviation increment of endostatin was associated with a HR of 2.12 (95 % CI 1.31-3.44 p< 0.01) for 90-day mortality after full adjustment. Levels of endostatin were significantly increased in the group of patients with highest METTS-A (p<0.001). When tested for the outcome 90-day mortality, the area under the ROC curve (AUC) was 0.616 for METTS-A, 0.701 for endostatin, 0.708 for METTS -A and age and 0.738 for METTS-A, age and levels of endostatin.

    CONCLUSIONS: In an unselected cohort of patients admitted to the ED with acute dyspnea, endostatin had a string association to 90-day mortality and improved prediction of 90-day mortality in the ED beyond the clinical triage scoring system and age with 3 %.

  • 47. Carlsson, Axel C
    et al.
    Wändell, Per
    Riserus, Ulf
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Borné, Yan
    Engström, Gunnar
    Leander, Karin
    Gigante, Bruna
    Hellénius, Mai-Lis
    de Faire, Ulf
    Differences in anthropometric measures in immigrants and Swedish-born individuals: results from two community-based cohort studies2014In: Preventive Medicine, ISSN 0091-7435, E-ISSN 1096-0260, Vol. 69, p. 151-156Article in journal (Refereed)
    Abstract [en]

    AIM: To study differences in body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), waist-hip-height ratio (WHHR) and percent body fat in immigrants and Swedish-born men and women in two large population-based samples.

    METHODS: A cross-sectional analysis of 60-year-old individuals, n=4 232. To replicate the results, we also assessed another large independent cohort cross-sectionally, the Malmö Diet and Cancer Study (MDC, n=26 777). The data from both cohorts were collected in the 1990s in Sweden.

    RESULTS: Significant differences between Finnish-born, Middle Eastern and women from the rest of the world were seen for all anthropometric measures, using Swedish-born women as referent. However, WHHR was the only anthropometric measure that identified all these three groups of immigrant women as different from Swedish-born women with high statistical certainty (p<0.001). Apart from WHHR that identified differences in anthropometry in all immigrant groups of men using Swedish-born men as referent, few significant differences were seen in anthropometry among groups of immigrant men. These finding were observed in both cohorts, and remained after adjustments for smoking, physical activity and educational level.

    CONCLUSION: The present study confirms previous findings of more obesity among immigrants and is the first to report that WHHR measurements may detect anthropometric differences between different ethnic groups better than other anthropometrical measures.

  • 48. Carlsson, Axel C
    et al.
    Östgren, Carl Johan
    Nystrom, Fredrik H
    Länne, Toste
    Jennersjö, Pär
    Larsson, Anders
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes2016In: Cardiovascular Diabetology, E-ISSN 1475-2840, Vol. 15, article id 40Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease.

    METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used.

    RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality.

    CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

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  • 49. Carrero, Juan Jesús
    et al.
    Grams, Morgan E
    Sang, Yingying
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Gasparini, Alessandro
    Matsushita, Kunihiro
    Qureshi, Abdul R
    Evans, Marie
    Barany, Peter
    Coresh, Josef
    Albuminuria changes are associated with subsequent risk of end-stage renal disease and mortality2017In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 91, no 1, p. 244-251Article in journal (Refereed)
    Abstract [en]

    Current guidelines for chronic kidney disease (CKD) recommend using albuminuria as well as estimated glomerular filtration rate (eGFR) to stage CKD. However, CKD progression is solely defined by change in eGFR with little regard to the risk implications of change in albuminuria. This is an observational study from the Stockholm CREAtinine Measurements (SCREAM) project, a health care utilization cohort from Stockholm, Sweden, with laboratory measures from 2006-2011 and follow-up through December 2012. Included were 31,732 individuals with two or more ambulatory urine albumin to creatinine ratio (ACR) tests. We assessed the association between change in ACR during a baseline period of 1, 2, or 3 years and end-stage renal disease (ESRD) or death. Using a 2-year baseline period, there were 378 ESRD events and 1712 deaths during a median of 3 years of follow-up. Compared to stable ACR, a 4-fold increase in ACR was associated with a 3.08-times (95% confidence interval 2.59 to 3.67) higher risk of ESRD while a 4-fold decrease in ACR was associated with a 0.34-times (0.26 to 0.45) lower risk of ESRD. Similar associations were found in people with and without diabetes mellitus, with and without hypertension, and also when adjusted for the change in eGFR during the same period. The association between change in ACR and mortality was weaker: ACR increase was associated with mortality, but the relationship was largely flat for ACR decline. Results were consistent for 1-, 2-, and 3-year ACR changes. Thus, changes in albuminuria are strongly and consistently associated with the risk of ESRD and death.

  • 50.
    Cedervall, Jessica
    et al.
    Uppsala Univ, Biomed Ctr, Sci Life Lab, Dept Med Biochem & Microbiol, Box 582, SE-75123 Uppsala, Sweden..
    Dragomir, Anca
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Saupe, Falk
    Uppsala Univ, Biomed Ctr, Sci Life Lab, Dept Med Biochem & Microbiol, Box 582, SE-75123 Uppsala, Sweden..
    Zhang, Yanyu
    Uppsala Univ, Biomed Ctr, Sci Life Lab, Dept Med Biochem & Microbiol, Box 582, SE-75123 Uppsala, Sweden..
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska institutet.
    Larsson, Erik
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Dimberg, Anna
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Larsson, Anders
    Uppsala Univ, Dept Med Sci, Uppsala, Sweden..
    Olsson, Anna-Karin
    Uppsala Univ, Biomed Ctr, Sci Life Lab, Dept Med Biochem & Microbiol, Box 582, SE-75123 Uppsala, Sweden..
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

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