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  • 1. 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.

  • 2.
    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.

  • 3.
    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.

  • 4.
    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)
  • 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
    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)
  • 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 predicts the risk for mortality in elderly men and women2011In: Kardiovaskulära vårmötet, Örebro, 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. Uppsala university.
    Serum cathepsin S predicts the risk for mortality in elderly men and women2011Conference paper (Other academic)
  • 8.
    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.

  • 9.
    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.

  • 10.
    Nerpin, Elisabet
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    The combined effect of low-grade albuminuria and a reduced glomerular filtration rate for the prediction of cardiovascular disease2009In: XI Kardiovasculära Vårmötet 2009, Uppsala, 2009Conference paper (Other academic)
    Abstract [sv]

    Abstract Background: The combined impact of reduced glomerular filtration rate (GFR) and microalbuminuria on the risk for cardiovascular disease is scarcely studied. Thus, we aimed to identify optimal cut-offs for albuminuria and GFR for the prediction of cardiovascular mortality in a community-based cohort of elderly men and to investigate whether the combined addition of these kidney markers adds independent prognostic information. Material and methods: In a sub-sample, without cardiovascular disease at baseline, of the community-based Uppsala Longitudinal Study of Adult Men (ULSAM, n=649, mean age 71 years, median follow-up 12.9 years; 86 cardiovascular deaths during follow-up), GFR (cystatin C-based) and urinary albumin excretion rate (UAER, overnight urine collection) were calculated. Results: The following cut-off points were identified in order to achieve optimal model discrimination based on the integrated discriminative improvement: UAER 6.25 µg/min and GFR 45 ml/min/1.73m2. In Cox-proportional hazard models adjusted for established risk factors (age, systolic blood pressure, antihypertensive treatment, total cholesterol, HDL cholesterol, lipid lowering treatment, diabetes, smoking, body-mass-index and previous cardiovascular disease), participants with low-grade albuminuria only (>6.25 µg/min, HR 1.75, 95 % CI 1.05-2.89), participants with reduced GFR only (<45 ml/min/1.73m2, HR 2.56, 95 % CI 1.05-6.28) and participants with both low-grade albuminuria and reduced GFR (HR 5.91, 95% CI 2.87-12.18) were at higher risk for cardiovascular mortality compared to participants with normoalbuminuria and normal GFR.

  • 11.
    Nerpin, Elisabet
    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 kidney in different stages of the cardiovascular continuum2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum.

    The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death.

    This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).

    The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress.

    In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease.

    Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

  • 12.
    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.

  • 13.
    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.

  • 14.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Ingelsson, Erik
    Riserus, Ulf
    Sundström, Johan
    Larsson, Anders
    Hallan, Stein
    Zethelius, Björn
    Berglund, Lars
    Basu, Samar
    Ärnlöv, Johan
    A Cystatin C-based glomerular filtration rate equation is a stronger predictor of cardiovascular mortality compared to creatinine-based equations2010In: Svenska Kardiovasculära vårmötet, Göteborg, 2010Conference paper (Other academic)
    Abstract [sv]

    Background: Several prior studies report that decreased estimated glomerular filtration rate (eGFR) predicts cardiovascular disease in the general population, but this is less studied in a primary preventive setting. Currently, various methods are available to assess eGFR. In the present study, we aimed to evaluate different eGFR-equations (creatinine-based or cystatin C-based), for the prediction of cardiovascular death. Material and methods: In men without cardiovascular disease, participating in the community-based Uppsala Longitudinal Study of Adult Men (ULSAM, n=649, mean age 71 years, median follow-up 12.9 years; 86 cardiovascular deaths during follow-up), eGFR was calculated from circulating creatinine by using the Modification of Diet in Renal Disease formula (eGFRMDRD) and the Chronic Kidney Disease Epidemiology Collaboration formula (eGFRCKD-EPI) and from circulating cystatin C using the following formula: 77.24x-1.2623 (eGFRcyst). Results: In Cox-proportional hazard models, 1-SD increase in eGFRcyst was associated with lower risk of cardiovascular mortality after adjustment for established cardiovascular risk factors and urinary albumin excretion rate (hazard ratio 0.74, 95% CI 0.59-0.92 (p=0.007). However, the creatinine-based GFR equations were not significantly associated with cardiovascular death (for eGFRMDRD: hazard ratio 0.84, 95% CI 0.67-1.06, (p=0.14), for eGFRCKD-EP : hazard ratio 0.86, 95% CI 0.69-1.07 (p=0.17)) in multivariable models. Moreover, when eGFRcyst was incorporated to a model with established risk factors, the integrated discrimination improvement was significantly increased 0.015, (p=0.02). Also eGFRcyst, provided improved discrimination beyond established risk factors and urinary albumine excretion rate (0.012, p=0.03). No improvement in integrated discrimination were seen with eGFRMDRD (p=0.25) or eGFRCKD-EPI (p=0.36). Conclusion: In our community-based cohort of elderly men free from cardiovascular disease at baseline, eGFRcyst significantly predicted cardiovascular death while the creatinine-based eGFR-equations did not. The fact that eGFRcyst improved model discrimination beyond established cardiovascular risk factors suggest that it may be a relevant risk marker for cardiovascular death in the elderly.

  • 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.

  • 18.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala University.
    Jacinto, Tiago
    Fonseca, João A.
    Alving, Kjell
    Janson, Christer
    Malinovschi, Andrei
    Systemic inflammatory markers in relation to lung function in NHANES. 2007–20102018In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 142, p. 94-100Article in journal (Refereed)
    Abstract [en]

    Background Low-grade systemic inflammation, mainly assessed by C-reactive protein (CRP), has been associated with impaired lung function. Few studies have studied if CRP, blood eosinophils, and blood neutrophils offer additive information in relation to lung function. Objectives To analyse associations between lung function and CRP, blood eosinophils, and blood neutrophils, with special regard to additive information of combining the inflammatory markers. Methods Cross-sectional study on 7753 participants, 20–80 years of age, in the National Health and Nutrition Examination Survey. Gender-based tertiles for CRP, blood eosinophils, and blood neutrophils were analysed in relation to the following lung function parameters: forced expiratory volume in 1 s (FEV1% predicted), forced vital capacity (FVC % predicted), and FEV1/FVC ratio. Results CRP, blood eosinophils, and blood neutrophils levels were inversely related to FEV1 and FVC. Only blood eosinophils and blood neutrophils were inversely related to FEV1/FVC ratio. Further, lower lung function was found with increased number of elevated inflammatory markers in the highest tertile (one, two or three vs. non elevated) for FEV1 (β-coeff., −2.20, −4.43, and −6.43, p < 0.001) and FVC (β-coeff., −1.70, −3.15 and −5.33, p < 0.001), respectively. Conclusions & clinical relevance CRP, blood eosinophils, and blood neutrophils offer independent and additive information in relation to lower FEV1 and FVC in the general population. This indicates that a combination of biomarkers yields more information than the biomarkers assessed individually.

  • 19.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Jarvis, Debbie
    Olivieri, M
    Gislason, T
    Olin, AC
    Jansson, Christer
    Malinovschi, Andrei
    Different relation between exhaled nitric oxide and lung function with regard to current smoking2018Conference paper (Other academic)
    Abstract [en]

    Background: Exhaled nitric oxide (FeNO) is a non-invasive marker of airway inflammation. Smokingreduces FeNO by 30-60%. Weak positive relation between lung function and FeNO has been inconsistently described. This has not been separately for smokers. Therefore we investigated the relation between lung function and FeNO with regard to smoking.

    Methods: FeNO and lung function post-bronchodilation (BD) were measured in 4813 subjects from the European Community Respiratory Health Survey III. GLI reference values were used. Smoking habits were self-reported.

    Results: Current smokers with FEV1 <lower limit of normal (LLN) had lower FeNO levels (ppb, geometric mean (95%CI)) than subjects with FEV1 ≥LLN: 10.1 (9.1, 11.1) vs 11.7 (11.3, 12.2), p=0.005, while the opposite was found in non-smokers: 20.0 (18.4, 21.6) vs 18.5 (18.2, 18.8), p=0.03. This interaction with current smoking was significant both before and after adjustments for study centres, age, BMI and gender (p=0.001 and p=0.004). Current smokers with FEV1/FVC <LLN had lower FeNO than current smokers with FEV1/FVC ≥LLN: 10.5 (9.4, 11.6) vs 11.6 (11.2, 12.1), p=0.04, and the opposite was found in non-smokers: 20.8 (19.1, 22.7) vs 18.4 (18.1, 18.8), p<0.001. There was a significant interaction with current smoking both in unadjusted and adjusted models (both p<0.001).

    Conclusion: Higher FeNO relates with lower FEV1 and FEV1/FVC-ratio among non-smoking individuals, suggesting that the obstruction is related with airways inflammation. In current smokers, higher FeNO relates with better preserved lung function and this finding warrants further studies to understand the underlying mechanisms. Presented on behalf of ECRHS III (www.ecrhs.org)

  • 20.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Joao, F. A
    Alving, Kjell
    Jansson, Christer
    Malinovschi, Andrei
    Blood cell counts and C-reactive protein inrelation to lung function in NHANES 2007-20102018Conference paper (Other academic)
    Abstract [en]

    Background:

    Low-grade systemic inflammation is associated with impaired lung function. Few studies have examined if C-reactive protein (CRP), blood eosinophil (B-Eos), and blood neutrophil (B-Neu) counts offer additive information in relation to lung function. The aim of this study was to analyse associations between CRP, BEos, and B-Neu and effects on lung function, with special regards to additive information.

    Methods:

    Cross-sectional study on 7,753 participants, 20-80 years of age, in the National Health and Nutrition Examination Survey. Gender-based tertiles for CRP, B-Eos, and B-Neu were analyzed in relation to forced expiratory volume in 1 second (FEV1 % predicted), forced vital capacity (FVC % predicted), and FEV1/FVC ratio.

    Results:

    CRP, B-Eos, and B-Neu were inversely related to FEV1 and FVC. Only B-Eos and B-Neu were inversely related to FEV1/FVC ratio. Further, lower lung function was found with increased number of elevated

    inflammatory markers in the highest tertile (one, two or three vs. non elevated) for FEV1 (% predicted): β-coefficients (95% CI) -2.20(-2.98, -1.41), -4.43 (-5.39, -3.45), and -6.43(-8.07, -4.79), all P=0.001; FVC (% predicted): -1.70 (-2.42, -0.98), -3.17 (-4.06, -2.29), and -5.34 (-6.85, -3.84), all P=0.001.

    Conclusion:

    CRP, B-Eos, and B-Neu offer independent and additive information in relation to lower FEV1 and FVC in the general population. This indicates that a combination of biomarkers yields more information than the biomarkers assessed individually. The mechanisms appear to be different, as B-Neu and B-Eos seem to relate more closely to obstructive impairment, e.g., lower FEV1/FVC ratio, which was not found for CRP.

  • 21.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Risérus, U
    Ingelsson, E
    Sundström, J
    Jobs, Magnus
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Larsson, A
    Basu, S
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Insulin sensitivity, measured with euglycaemic-hyperinsulinaemic clamp is independently associated with glomerular filtration rate in elderly men2008In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 31, no 8, p. 1550-5Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE—To investigate the association between insulin sensitivity and glomerular filtration rate (GFR) in the community, with prespecified subgroup analyses in normoglycemic individuals with normal GFR. RESEARCH DESIGN AND METHODS—We investigated the cross-sectional association between insulin sensitivity (M/I, assessed using euglycemic clamp) and cystatin C–based GFR in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1,070). We also investigated whether insulin sensitivity predicted the incidence of renal dysfunction at a follow-up examination after 7 years. RESULTS—Insulin sensitivity was directly related to GFR (multivariable-adjusted regression coefficient for 1-unit higher M/I 1.19 [95% CI 0.69–1.68]; P < 0.001) after adjusting for age, glucometabolic variables (fasting plasma glucose, fasting plasma insulin, and 2-h glucose after an oral glucose tolerance test), cardiovascular risk factors (hypertension, dyslipidemia, and smoking), and lifestyle factors (BMI, physical activity, and consumption of tea, coffee, and alcohol). The positive multivariable-adjusted association between insulin sensitivity and GFR also remained statistically significant in participants with normal fasting plasma glucose, normal glucose tolerance, and normal GFR (n = 443; P < 0.02). In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function (GFR <50 ml/min per 1.73 m2) during follow-up independently of glucometabolic variables (multivariable-adjusted odds ratio for 1-unit higher of M/I 0.58 [95% CI 0.40–0.84]; P < 0.004). CONCLUSIONS—Our data suggest that impaired insulin sensitivity may be involved in the development of renal dysfunction at an early stage, before the onset of diabetes or prediabetic glucose elevations. Further studies are needed in order to establish causality.

  • 22.
    Nerpin, Elisabet
    et al.
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Risérus, Ulf
    Ingelsson, Erik
    Sundström, Johan
    Jobs, Magnus
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Insulin sensitivity measured with euglycemic clamp is independently associated with glomerular filtration rate in a community-based cohort2008Conference paper (Refereed)
    Abstract [en]

    Objective: To investigate the association between insulin sensitivity and glomerular filtration rate (GFR) in the community, with pre-specified subgroup analyses in normoglycemic individuals with normal GFR. Research Design and Methods: We investigated the cross-sectional association between insulin sensitivity (M/I, assessed using euglycemic clamp) and cystatin C-based GFR in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men, ULSAM; n=1070). We also investigated whether insulin sensitivity predicted the incidence of renal dysfunction at a follow-up examination after 7 years. Results: Insulin sensitivity was directly related to GFR (multivariable-adjusted regression coefficient for 1-unit higher M/I 1.19, 95% CI 0.69-1.68, p<0.001) after adjusting for age, glucometabolic variables (fasting plasma glucose, fasting plasma insulin, 2-hour glucose after an oral glucose tolerance test), cardiovascular risk factors (hypertension, dyslipidemia, smoking), and lifestyle factors (BMI, physical activity, consumption of tea, coffee and alcohol). The positive multivariable-adjusted association between insulin sensitivity and GFR remained statistically significant also in participants with normal fasting plasma glucose, normal glucose tolerance and normal GFR (n=443, p<0.02). In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function (GFR<50ml/min/1.73 m2) during follow-up independently of glucometabolic variables (multivariable-adjusted odds ratio for 1-unit higher of M/I 0.58, 95 % CI 0.40-0.84, p<0.004). Conclusion: Our data suggest that impaired insulin sensitivity may be involved in the development of renal dysfunction at an early stage, prior to the onset of diabetes or pre-diabetic glucose elevations. Further studies are needed in order to establish causality.

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