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  • 1. Helmersson-Karlqvist, Johanna
    et al.
    Riserus, Ulf
    Sundström, Johan
    Larsson, Anders
    Jobs, Elisabeth
    Dalarna University, School of Health and Social Studies, Medical Science.
    Basu, Samar
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Health and Social Studies, Medical Science.
    Cytokine mediated inflammation is involved in the early stages of kidney damage and dysfunction2011In: XIII Svenska Kardiovaskulära vårmötet, Örebro, 2011Conference paper (Other academic)
    Abstract [en]

    Background: Patients with severe chronic kidney disease (CKD) are characterized by increased inflammatory activity and higher oxidative stress, conditions that have been suggested to mediate the substantially increased risk for cardiovascular disease (CVD) in these patients. However, also individuals with mild signs of kidney damage and dysfunction have been shown to have an increased risk for CVD. Yet, data on the association between mild signs of kidney damage and dysfunction and markers of inflammation and oxidative stress in the community is scarce. Research Design and Methods: Accordingly, we investigated the cross-sectional associations between cystatin C based glomerular filtration rate (GFR), urinary albumin creatinine ratio (ACR), and markers of cytokine mediated inflammation (interleukin 6 [IL-6], high sensitivity C reactive protein [hsCRP], serum amyloid A [SAA]), cyclooxygenas-mediated inflammation (urinary prostaglandin F2-alpha [PGF2alpha]) and oxidative stress (urinary F2-isprostanes) in a sub-sample of a community based cohort (Uppsala Longitudinal Study of Adult Men, ULSAM, n=648, mean age 77 year) with normal eGFR (>60 ml/min/1.73m2 ) and normal ACR (<30 µmol/L) Results: In multivariable linear regression models adjusting for age, BMI, smoking, systolic and diastolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides and treatment with statin, ACE-inhibit-, ASA-, anti inflammation- , cortisone medication, eGFR was inversely associated with lower hsCRP (p<0.008), lower IL-6 (p<0.01), and ACR was positive associated with higher hsCRP (p=0.01), higher IL-6 (p=<0.004) and higher SAA (p=0.001). No significant association was seen between PGF2alpha, F2-isoprostanes and eGFR and ACR. Conclusion: Our community based data suggest that cytokine mediated inflammation is involved in the early stages of kidney damage and dysfunction, while cyclooxygenas-mediated inflammation and oxidative stress is not. Further studies are needed in order to evaluate to what extent cytokine mediated inflammation mediates the increased CVD risk seen in individuals with mild signs of kidney damage and dysfunction.

  • 2. Helmersson-Karlqvist, Johanna
    et al.
    Riserus, Ulf
    Sundström, Johan
    Larsson, Anders
    Jobs, Elisabeth
    Dalarna University, School of Health and Social Studies, Medical Science.
    Basu, Samar
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Health and Social Studies, Medical Science.
    Cytokine mediated inflammation is involved in the early stages of kidney damage and dysfunction – Possible link to cardiovascular disease2011In: European Society of Cardiology, Paris, 2011Conference paper (Other academic)
    Abstract [en]

    Purpose: Patients with severe chronic kidney disease (CKD) are characterized by increased inflammatory activity and higher oxidative stress, conditions that have been suggested to mediate the substantially increased risk for cardiovascular disease (CVD) in these patients. However, also individuals with mild signs of kidney damage and dysfunction have been shown to have an increased risk for CVD. Yet, data on the association between mild signs of kidney damage and dysfunction and markers of inflammation and oxidative stress in the community is scarce. Methods: Accordingly, we investigated the cross-sectional associations between cystatin C based glomerular filtration rate (GFR), urinary albumin creatinine ratio (ACR), and markers of cytokine mediated inflammation (interleukin 6 [IL-6], high sensitivity C reactive protein [hsCRP], serum amyloid A [SAA]), cyclooxygenas-mediated inflammation (urinary prostaglandin F2-alpha [PGF2alpha]) and oxidative stress (urinary F2-isprostanes) in a sub-sample of a community based cohort (Uppsala Longitudinal Study of Adult Men, ULSAM, n=648, mean age 77 year) with normal eGFR (>60 ml/min/1.73m2 ) and normal ACR (<30 µmol/L) Results: In multivariable linear regression models adjusting for age, BMI, smoking, systolic and diastolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides and treatment with statin, ACE-inhibit-, ASA-, anti inflammation- , cortisone medication, eGFR was inversely associated with lower hsCRP (p<0.008), lower IL-6 (p<0.01), and ACR was positive associated with higher hsCRP (p=0.01), higher IL-6 (p=<0.004) and higher SAA (p=0.001). No significant association was seen between PGF2alpha, F2-isoprostanes and eGFR and ACR. Conclusions: Our community based data suggest that cytokine mediated inflammation is involved in the early stages of kidney damage and dysfunction, while cyclooxygenas-mediated inflammation and oxidative stress is not. Further studies are needed in order to evaluate to what extent cytokine mediated inflammation mediates the increased CVD risk seen in individuals with mild signs of kidney damage and dysfunction.

  • 3.
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala University.
    Cathepsin S as a biomarker of low-grade inflammation, insulin resistance, and cardiometabolic disease risk2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.

       The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.

       This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.

       In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.

       Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations. 

  • 4.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitetet.
    Adamsson, Viola
    Larsson, Anders
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Risérus, Ulf
    Influence of a prudent diet on circulating cathepsin S in humans2014In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 13, no 84Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increased circulating cathepsin S levels have been linked to increased risk of cardiometabolic diseases and cancer. However, whether cathepsin S is a modifiable risk factor is unclear. We aimed to investigate the effects of a prudent diet on plasma cathepsin S levels in healthy individuals.

    FINDINGS: Explorative analyses of a randomized study were performed in 88 normal to slightly overweight and hyperlipidemic men and women (aged 25 to 65) that were randomly assigned to ad libitum prudent diet, i.e. healthy Nordic diet (ND) or a control group (habitual Western diet) for 6 weeks. Whereas all foods in the ND were provided, the control group was advised to consume their habitual diet throughout the study. The ND was in line with dietary recommendations, e.g. low in saturated fats, sugars and salt, but high in plant-based foods rich in fibre and unsaturated fats.The ND significantly decreased cathepsin S levels (from 20.1 (+/-4.0 SD) to 19.7 μg/L (+/-4.3 SD)) compared with control group (from 18.2 (+/-2.9 SD) to 19.1 μg/L (+/-3.8 SD)). This difference remained after adjusting for sex and change in insulin sensitivity (P = 0.03), and near significant after adjusting for baseline cathepsin S levels (P = 0.06), but not for change in weight or LDL-C. Changes in cathepsin S levels were directly correlated with change in LDL-C.

    CONCLUSIONS: Compared with a habitual control diet, a provided ad libitum healthy Nordic diet decreased cathepsin S levels in healthy individuals, possibly mediated by weight loss or lowered LDL-C. These differences between groups in cathepsin S were however not robust and therefore need further investigation.

  • 5.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Basu, Samar
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Association between serum cathepsin S and mortality in older adults2011In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, no 10, p. 1113-1121Article in journal (Refereed)
    Abstract [en]

    Context: Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking. Objective To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women.

    Design, Setting, and Participants: Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S.

    Main Outcome Measure Total mortality.

    Results: During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P = .009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P = .04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P = .01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P = .01).

    Conclusions Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

  • 6.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Serum cathepsin S levels independently predicts total- and cardiovascular mortality in elderly men2011In: European Society of Cardiology Congress 2011, Stockholm, 2011Conference paper (Other academic)
  • 7.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Serum cathepsin S levels independently predicts total- and cardiovascular mortality in elderly men2010In: Kardiovaskulära vårmötet, Göteborg, 2010Conference paper (Other academic)
  • 8.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Serum cathepsin S predicts the risk for mortality in elderly men and women2011In: Kardiovaskulära vårmötet, Örebro, 2011Conference paper (Other academic)
  • 9.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala university.
    Serum cathepsin S predicts the risk for mortality in elderly men and women2011Conference paper (Other academic)
  • 10.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala university.
    Risérus, U
    Ingelsson, E
    Helmersson, J
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, J
    Lind, L
    Larsson, A
    Basu, S
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Serum cathepsin S is associated with serum C-reactive protein and interleukin-6 independently of obesity in elderly men2010In: Journal of Clinical Epidemiology, ISSN 0895-4356, E-ISSN 1878-5921, Vol. 95, no 9, p. 4460-4464Article in journal (Refereed)
    Abstract [en]

    Objective: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants.

    Methods: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr.

    Results: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 SD increase, 0.13; 95% confidence interval 0.07–0.19; P < 0.001) and higher serum IL-6 (regression coefficient for 1 SD increase, 0.08; 95% confidence interval 0.01–0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index <25 kg/m2, n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr.

    Conclusions: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.

  • 11.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Risérus, Ulf
    Ingelsson, Erik
    Helmersson, Johanna
    Nerpin, Elisabet
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Cathepsin S is independently associated with cytokine mediated inflammation in elderly men2009In: European Society of Cardiology Congress, Uppsala, 2009Conference paper (Other academic)
    Abstract [en]

    Cathepsin S is independently associated with cytokine mediated inflammation in elderly men Conclusion: Higher serum levels of Cathepsin S were independently associated with higher CRP and IL-6 in a community– based sample of elderly men. Our data provides support for the notion that Cathepsin S is involved in inflammatory processes, possibly leading to atherosclerosis and cardiovascular disease. Background: Cathepsin S is a lysosomal protease that has been suggested to play a key role in the development of atherosclerosis and cardiovascular disease by degradation of vascular extracellular matrix. Previous studies have suggested that cathepsin S provides a molecular link between obesity and atherosclerosis, possibly via increased inflammatory activity. Yet, the association between circulating cathepsin S and inflammation markers has not previously been reported in the community. Aim: To investigate the association between plasma levels of cathepsin- S, C-reactive protein (CRP) and Interleukin 6 (IL-6), in the community. Methods: Serum levels of cathepsin S, CRP, IL-6 were measured in frozen samples from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (n=999, mean age 71 years). Results: Cross-sectional association between Cathepsin S, CRP and IL-6 at age 70 showed that one standard deviation (SD) higher serum Cathepsin S was significantly associated with 0.14 SD higher serum CRP and 0.07-0.08 SD higher serum IL-6 when adjusting for age, life style factors (body mass index, physic activity and smoking), cardiovascular risk factors (hypertension, dyslipidemia, previous cardiovascular disease and diabetes and smoking), and the combination of all covariates

  • 12.
    Jobs, Elisabeth
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Risérus, Ulf
    Ingelsson, Erik
    Sundström, Johan
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Iggman, David
    Basu, Samar
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men2012In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 1, p. 163-165Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE. To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

    RESEARCH DESIGN AND METHODS. Serum cathepsin S, insulin sensitivity (euglycaemic-hyperinsulinaemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

    RESULTS. After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).

    CONCLUSIONS. Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.

  • 13.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Helmersson-Karlqvist, Johanna
    Riserus, Ulf
    Sundström, Johan
    Larsson, Anders
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Basu, Samar
    Ingelsson, Erik
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study2012In: BMC research notes, ISSN 1756-0500, Vol. 5, no 1, p. 537-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of inflammation and oxidative stress in mild renal impairment in the elderly is not well studied. Accordingly, we aimed at investigating the associations between estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR), and markers of different inflammatory pathways and oxidative stress in a community based cohort of elderly men. FINDINGS: Cystatin C-based GFR, ACR, and biomarkers of cytokine-mediated inflammation (interleukin-6, high-sensitivity C-reactive protein[CRP], serum amyloid A[SAA]), cyclooxygenase-mediated inflammation (urinary prostaglandin F2alpha [PGF2alpha]), and oxidative stress (urinary F2 isoprostanes) were assessed in the Uppsala Longitudinal Study of Adult Men(n = 647, mean age 77 years). RESULTS: In linear regression models adjusting for age, BMI, smoking, blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, and treatment with statins, ACE-inhibitors, ASA, and anti-inflammatory agents, eGFR was inversely associated with CRP, interleukin-6, and SAA (beta-coefficient -0.13 to -0.19, p < 0.001 for all), and positively associated with urinary F2-isoprostanes (beta-coefficient 0.09, p = 0.02). In line with this, ACR was positively associated with CRP, interleukin-6, and SAA (beta- coefficient 0.09-0.12, p < 0.02 for all), and negatively associated with urinary F2-isoprostanes (beta-coefficient -0.12, p = 0.002). The associations were similar but with lower regression coefficients in a sub-sample with normal eGFR (>60 ml/min/1.73 m2, n = 514), with the exception that F2-isoprostane and SAA were no longer associated with eGFR. CONCLUSION: Our data indicate that cytokine-mediated inflammation is involved in the early stages of impaired kidney function in the elderly, but that cyclooxygenase-mediated inflammation does not play a role at this stage. The unexpected association between higher eGFR/lower albuminuria and increased F2-isoprostanes in urine merits further studies.

  • 14.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Riserus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Andren, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    The association between glomerular filtration rate and left ventricular function in two independent community-based cohorts of elderly2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, no 11, p. 2069-2074Article in journal (Refereed)
    Abstract [en]

    The cardiorenal syndrome, the detrimental bi-directional interplay between symptomatic heart failure and chronic kidney disease, is a major clinical challenge. Nonetheless, it is unknown if this interplay begins already at an asymptomatic stage. Therefore we investigated whether the glomerular filtration rate (GFR) is associated with left ventricular function in participants free from clinical heart failure and with a left ventricular ejection fraction (LVEF) > 40% and with pre-specified sub-group analyses in individuals with a GFR > 60 mL/min/m(2). Two independent community-based cohorts were used; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 911; 50% women; mean age: 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 538; mean age: 71 years). We investigated cross-sectional association between cystatin C-based GFR (estimated glomerular function [eGFR]) and systolic (LVEF), diastolic- (isovolumic relaxation time [IVRT]) and global left ventricular function (myocardial performance index [MPI]) determined by echocardiography. In both PIVUS and ULSAM, higher eGFR was significantly associated with higher LVEF (P = 0.004 [PIVUS] and P = 0.005 [ULSAM]). In PIVUS, higher eGFR was significantly associated with lower IVRT (P = 0.001) and MPI (P = 0.006), in age- and sex-adjusted models. After further adjustment for cardiovascular risk factors, the association between higher eGFR and higher LVEF was still statistically significant (P = 0.008 [PIVUS] and P = 0.02 [ULSAM]). In PIVUS, the age- and sex-adjusted association between eGFR and left ventricular function was similar in participants with eGFR > 60 mL/min/m(2). Our data suggest that the interplay between kidney and heart function begins prior to the development of symptomatic heart failure and kidney disease.

  • 15.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Riserus, Ulf
    Sundström, Johan
    Larsson, Anders
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Hallan, Stein
    Ärnlöv, Johan
    The combined contribution of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly men2011In: EuroPrevent, Geneve, 2011Conference paper (Other academic)
    Abstract [en]

    Purpose: Patients with severe chronic kidney disease are at substantially higher risk to develop cardiovascular disease, but an increased risk is also evident in individuals with only mild signs of kidney damage in the community. Cardiovascular risk prediction is particularly important in the primary prevention of cardiovascular disease. Nevertheless, data on whether the combined addition of albuminuria and estimated glomerular filtration rate (eGFR) improves cardiovascular risk prediction in individuals without cardiovascular disease in the community is scarce. Methods and results: We investigated associations between urinary albumin excretion rate (UAER), cystatin C-based eGFR and cardiovascular mortality in a community-based cohort of elderly men (ULSAM-study; n=1113, mean age 71 years, 208 cardiovascular deaths, median follow-up 12.9 years) with pre-specified analyses in participants without cardiovascular disease (n=649, 86 cardiovascular deaths). Using multivariable Cox regression, higher UAER and lower eGFR were associated with increased risk for cardiovascular mortality independently of established cardiovascular risk factors in the whole sample and in men without cardiovascular disease at baseline (sub-sample without cardiovascular disease: UAER; hazard ratio per 1-SD 1.26, 95% CI 1.05-1.51, p=0.01; eGFR: hazard ratio per 1-SD 0.74, 95% CI 0.59-0.92, p=0.007). Analyses of model discrimination, calibration, reclassification and global fit suggested that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors also in participants without prevalent cardiovascular disease. Interestingly, established cut-offs used to diagnose microalbuminuria (UAER>20µg/min) and chronic kidney disease stage 3 (eGFR<60ml/min/1.73m2), appeared less suitable for cardiovascular risk prediction (integrated discrimination improvement (IDI) 0.006, p=0.11, while cut-offs UAER>6µg/min and eGFR<45ml/min/1.73m2 significantly improved IDI (0.047, p<0.001) Conclusion: UAER and eGFR improved cardiovascular risk prediction beyond established cardiovascular risk factors, suggesting that these kidney biomarkers may be useful in predicting cardiovascular death in the elderly.

  • 16.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Helmersson-Karlqvist, Johanna
    Sundström, Johan
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Association between glomerular filtration rate and endothelial function in an elderly community cohort2012In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 1, p. 242-246Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Endothelial dysfunction is prevalent among individuals with chronic kidney disease. However, the association between glomerular filtration rate and endothelial function in the community is unclear and needs to be investigated in the general population.

    METHODS: In the community-based Prospective Investigation of the Vasculature of Uppsala Seniors study (PIVUS, n = 952, mean age 70, women 49.3%), we investigated cross-sectional associations between estimated cystatin C-based glomerular filtration rate (eGFR), and 3 measures representing different aspects of endothelial function (endothelial-dependent vasodilation [EDV], endothelial independent vasodilatation [EIDV], and flow-mediated dilatation [FMD]). We also performed pre-specified sub-group analyses in participants with normal eGFR (>60 ml/min/1.73 m(2)).

    RESULTS: In the whole cohort, 10 ml/min/1.73 m(2) higher eGFR was associated with 3% higher EDV (p = 0.001) and 2% higher EIDV (p = 0.007), adjusted for age and sex. The associations were attenuated and no longer statistically significant after adjusting for established cardiovascular risk factors. In participants with eGFR >60 ml/min/1.73 m(2), 10 ml higher eGFR was associated with 2% higher EDV (p = 0.04) after adjusting for sex and age. eGFR was not associated to FMD in any model or sub-sample.

    CONCLUSION: This community-based study suggests that eGFR is associated with endothelial function also in persons with normal kidney function, but that this association is largely explained by confounding by established cardiovascular risk factors. Thus, our data do not support the notion of a direct causal interplay between renal and vascular function prior to the development of CKD.

  • 17.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Risérus, Ulf
    Sundström, Johan
    Larsson, Anders
    Jobs, Elisabeth
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Hallan, Stein
    Zethelius, Björn
    Berglund, Lars
    Basu, Samar
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    The combined contribution of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly men2011In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 26, no 9, p. 2820-2827Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiovascular risk prediction is particularly important in the primary prevention of cardiovascular disease (CVD). Yet, data on whether the combined addition of albuminuria and estimated glomerular filtration rate (eGFR) improves cardiovascular risk prediction in individuals without CVD in the community is scarce.

    METHODS: We investigated associations between urinary albumin excretion rate (UAER), cystatin C-based eGFR and cardiovascular mortality in a community-based cohort of elderly men (ULSAM study; n = 1113, mean age 71 years, 208 cardiovascular deaths, median follow-up 12.9 years) with prespecified analyses in participants without CVD (n = 649, 86 cardiovascular deaths).

    RESULTS: Using multivariable Cox regression, higher UAER and lower eGFR were associated with increased risk for cardiovascular mortality independently of established cardiovascular risk factors in the whole sample and in men without CVD at baseline [subsample without CVD: UAER; hazard ratio (HR) per 1 SD 1.26, 95% confidence interval (CI) 1.05-1.51, P = 0.01; eGFR: HR per 1 SD 0.74, 95% CI 0.59-0.92, P = 0.007]. Analyses of model discrimination, calibration, reclassification and global fit suggested that UAER and eGFR also add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent CVD. Interestingly, established cutoffs used to diagnose microalbuminuria (UAER > 20 μg/min) and chronic kidney disease Stage 3 (eGFR < 60 mL/min/1.73 m(2)), appeared less suitable for cardiovascular risk prediction [integrated discrimination improvement (IDI) 0.006, P = 0.11], while cutoffs UAER > 6 μg/min and eGFR < 45 mL/min/1.73 m(2) significantly improved IDI (0.047, P < 0.001).

    CONCLUSIONS: UAER and eGFR improved cardiovascular risk prediction beyond established cardiovascular risk factors, suggesting that these kidney biomarkers may be useful in predicting cardiovascular death in elderly men.

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