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The kidney in different stages of the cardiovascular continuum
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.ORCID iD: 0000-0003-3880-2132
2013 (English)Doctoral 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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2013. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206; 946, 946
Keyword [en]
epidemiology, chronic kidney disease, cystatin C, glomerular filtration rate, albuminuria, euglycemic hyperinsulinemic clamp, insulin sensitivity, inflammation, oxidative stress, endothelial dysfunction and left ventricular dysfunction
National Category
Cardiac and Cardiovascular Systems Urology and Nephrology Gerontology, specializing in Medical and Health Sciences
Research subject
Health and Welfare, Nedsatt njurfunktion, insulinresistens, oxidativ stress och utvecklingen av hjärt-kärlsjukdomar
Identifiers
URN: urn:nbn:se:du-13489ISBN: 978-91-554-8792-8 (print)OAI: oai:DiVA.org:du-13489DiVA: diva2:677955
Public defence
2013-12-05, Universitetshuset Sal IX, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-12-12 Created: 2013-12-10 Last updated: 2015-12-07Bibliographically approved
List of papers
1. Insulin sensitivity, measured with euglycaemic-hyperinsulinaemic clamp is independently associated with glomerular filtration rate in elderly men
Open this publication in new window or tab >>Insulin sensitivity, measured with euglycaemic-hyperinsulinaemic clamp is independently associated with glomerular filtration rate in elderly men
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2008 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 31, no 8, 1550-5 p.Article in journal (Refereed) Published
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.

Research subject
Hälsa och välfärd, Nedsatt njurfunktion, insulinresistens, oxidativ stress och utvecklingen av hjärt-kärlsjukdomar
Identifiers
urn:nbn:se:du-3499 (URN)
Available from: 2008-11-24 Created: 2008-11-24 Last updated: 2015-06-15Bibliographically approved
2. Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study
Open this publication in new window or tab >>Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study
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2012 (English)In: BMC research notes, ISSN 1756-0500, Vol. 5, no 1, 537- p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keyword
Inflammation; Oxidative stress; Glomerular filtration rate and albuminuria
National Category
Urology and Nephrology
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-11503 (URN)10.1186/1756-0500-5-537 (DOI)23016573 (PubMedID)
Note

Open access

Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2016-05-31Bibliographically approved
3. Association between glomerular filtration rate and endothelial function in an elderly community cohort
Open this publication in new window or tab >>Association between glomerular filtration rate and endothelial function in an elderly community cohort
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2012 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 1, 242-246 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Chronic kidney disease; Endothelium-dependent vasodilatation; Endothelial dysfunction; Flow-mediated dilatation; Glomerular filtration rate; Epidemiology
National Category
Cardiac and Cardiovascular Systems
Research subject
Hälsa och välfärd
Identifiers
urn:nbn:se:du-10574 (URN)10.1016/j.atherosclerosis.2012.07.008 (DOI)000308078000038 ()22841608 (PubMedID)
Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2015-06-23Bibliographically approved
4. The association between glomerular filtration rate and left ventricular function in two independent community-based cohorts of elderly
Open this publication in new window or tab >>The association between glomerular filtration rate and left ventricular function in two independent community-based cohorts of elderly
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2014 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, no 11, 2069-2074 p.Article in journal (Refereed) Published
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.

National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-13504 (URN)10.1093/ndt/gfu199 (DOI)000344625400015 ()24916339 (PubMedID)
Available from: 2013-12-12 Created: 2013-12-12 Last updated: 2015-12-09Bibliographically approved
5. The combined contribution of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly men
Open this publication in new window or tab >>The combined contribution of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly men
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2011 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 26, no 9, 2820-2827 p.Article in journal (Refereed) Published
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.

Keyword
Albuminuria, eGFR and cardiovascular risk
National Category
Clinical Medicine
Research subject
Hälsa och välfärd
Identifiers
urn:nbn:se:du-10427 (URN)10.1093/ndt/gfq848 (DOI)000295231600017 ()21335440 (PubMedID)
Available from: 2012-08-03 Created: 2012-08-03 Last updated: 2015-06-16Bibliographically approved

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