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Wuttke, M., Li, Y., Sieber, K. B., Feitosa, M. F., Gorski, M., Tin, A., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-30209 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)2-s2.0-85066607502 (Scopus ID)
Available from: 2019-06-13 Created: 2019-06-13 Last updated: 2019-06-20Bibliographically approved
Mok, Y., Ballew, S. H., Sang, Y., Grams, M. E., Coresh, J., Evans, M., . . . Matsushita, K. (2019). Albuminuria as a predictor of cardiovascular outcomes in patients with acute myocardial infarction. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 8(8), Article ID e010546.
Open this publication in new window or tab >>Albuminuria as a predictor of cardiovascular outcomes in patients with acute myocardial infarction
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2019 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 8, no 8, article id e010546Article in journal (Refereed) Published
Abstract [en]

Background. In patients with myocardial infarction ( MI ), reduced kidney function is recognized as an important predictor of poor prognosis, but the impact of albuminuria, a representative measure of kidney damage, has not been extensively evaluated.

Methods and Results. In the SCREAM (Stockholm Creatinine Measurements) project (2006-2012), we identified 2469 patients with incident MI with dipstick proteinuria measured within a year before MI (427 patients also had urine albumin to creatinine ratio [ ACR ] measured concurrently) and obtained estimates for ACR with multiple imputation in participants with data solely on dipstick proteinuria. We quantified the association of ACR with the post- MI composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI , ischemic stroke, or heart failure using Cox models and then evaluated the improvement in C statistic. During a median follow-up of 1.0 year after MI , 1607 participants (65.1%) developed the post- MI composite outcome. Higher ACR levels were independently associated with all outcomes except for ischemic stroke. Per 8-fold higher ACR (eg, 40 versus 5 mg/g), the hazard ratio of composite outcome was 1.21 (95% CI , 1.08-1.35). The addition of the ACR improved the C statistic of the post- MI composite by 0.040 (95% CI, 0.030-0.051). Largely similar results were obtained regardless of diabetic status and when ACR or dipstick was separately analyzed without imputation.

Conclusions. In patients with MI , albuminuria was a potent predictor of subsequent outcomes, suggesting the importance of paying attention to the information on albuminuria, in addition to kidney function, in this high-risk population.

Keywords
albuminuria, chronic kidney disease, myocardial infarction, prognosis
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29863 (URN)10.1161/JAHA.118.010546 (DOI)30947615 (PubMedID)2-s2.0-85064323096 (Scopus ID)
Available from: 2019-04-08 Created: 2019-04-08 Last updated: 2019-04-29Bibliographically approved
Wändell, P., Carlsson, A. C., Li, X., Gasevic, D., Ärnlöv, J., Holzmann, M. J., . . . Sundquist, K. (2019). Atrial fibrillation in immigrants under the age of 45 y in Sweden. International Health, 11(3), 193-202
Open this publication in new window or tab >>Atrial fibrillation in immigrants under the age of 45 y in Sweden
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2019 (English)In: International Health, ISSN 1876-3413, E-ISSN 1876-3405, Vol. 11, no 3, p. 193-202Article in journal (Refereed) Published
Abstract [en]

Aim: To study association between country of birth and risk of first-onset atrial fibrillation (AF) in first- and second-generation immigrants to Sweden under 45 y of age.

Methods: The study population included all individuals (n = 3 248 457) under the age of 45 y in Sweden, including immigrants (n = 722 249). AF was defined as first registered diagnosis in the National Patient Register. Association between country of birth and risk of AF was assessed by Cox regression, calculating HRs and 95% CIs, using Swedish-born individuals as referents. All models were stratified by sex, and in different models were adjusted for age, area of residence in Sweden, educational level, marital status, neighbourhood socioeconomic status and co-morbidity(ies).

Results: A higher fully adjusted HR of incident AF was found in the total sample of first-generation immigrants, 1.44 (95% CI 1.35 to 1.54), in males born in Denmark, Lebanon and Iraq, and in females born in Turkey and Iraq. Lower HRs were found in male and female immigrants from Latin America and Iran, and female immigrants from Finland. Among second-generation immigrants, the fully adjusted HR was significantly lower, 0.70 (95% CI 0.58 to 0.83).

Conclusions: Clinicians may show a greater awareness of AF in some groups of younger immigrants to enable early diagnosis.

Keywords
Atrial fibrillation, co-morbidity, gender, younger immigrants
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-28849 (URN)10.1093/inthealth/ihy075 (DOI)30364949 (PubMedID)2-s2.0-85064837373 (Scopus ID)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2019-05-14Bibliographically approved
Coresh, J., Heerspink, H. J., Sang, Y., Matsushita, K., Ärnlöv, J., Astor, B. C., . . . Gansevoort, R. T. (2019). Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.. The Lancet Diabetes and Endocrinology, 7(2), 115-127
Open this publication in new window or tab >>Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.
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2019 (English)In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 7, no 2, p. 115-127Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies.

METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC.

FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed.

INTERPRETATION: Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria.

FUNDING: US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.

National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29275 (URN)10.1016/S2213-8587(18)30313-9 (DOI)000456442200017 ()30635225 (PubMedID)2-s2.0-85060314551 (Scopus ID)
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-06-27Bibliographically approved
Ruge, T., Carlsson, A. C., Kjøller, E., Hilden, J., Kolmos, H. J., Sajadieh, A., . . . Ärnlöv, J. (2019). Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study. Atherosclerosis, 284, 202-208
Open this publication in new window or tab >>Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study
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2019 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 284, p. 202-208Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain.

METHODS: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979).

RESULTS: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%).

CONCLUSIONS: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

Keywords
Cardiovascular, Endostatin, Epidemiology, Extracellular matrix, Mortality
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29873 (URN)10.1016/j.atherosclerosis.2019.02.031 (DOI)000466155400027 ()30959314 (PubMedID)2-s2.0-85063916828 (Scopus ID)
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-06-03Bibliographically approved
Wändell, P., Carlsson, A. C., Li, X., Gasevic, D., Ärnlöv, J., Sundquist, J. & Sundquist, K. (2019). End-stage kidney diseases in immigrant groups: a nationwide cohort study in Sweden. American Journal of Nephrology, 49(3), 186-192
Open this publication in new window or tab >>End-stage kidney diseases in immigrant groups: a nationwide cohort study in Sweden
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2019 (English)In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 49, no 3, p. 186-192Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Our aim was to study the association between the country of birth and incident end-stage kidney disease (ESKD) in several immigrant groups in Sweden, using individuals born in Sweden or with Swedish-born parents as referents.

METHODS: A cohort study of first- and second-generation immigrants residing in Sweden between January 1, 1998 and December 31, 2012 was performed. Outcomes were defined as having at least one registered diagnosis of ESKD in the National Patient Register. The incidence of ESKD in different immigrant groups was used in the Cox regression models to estimate hazard ratios (HRs) and 95% CIs. All models were stratified by sex and adjusted for age, geographical residence, educational level, marital status, and neighbourhood socioeconomic status.

RESULTS: Compared to their referents, higher incidence rates and HRs of ESKD (HR; 95% CI) were observed in general among foreign-born men (1.10; 1.04-1.16) and women (1.12; 1.04-1.21) but not among second-generation immigrants (persons born in Sweden with foreign-born parents). A particularly high -incidence was noted among men and women from -East-European countries, as well as from non-European regions. A lower incidence of ESKD was noted among men from Finland.

CONCLUSIONS: We observed substantial differences in incidence of ESKD between immigrant groups and the Swedish-born population, which may be clinically relevant when monitoring preventive measures in patient subgroups with a higher risk of deteriorating kidney disease, and suggest higher attention to hypertension and diabetes control in immigrants. Mechanisms attributable to the migration process or ethnic differences may lead to an increased risk of ESKD.

Keywords
End-stage kidney disease, First generation immigrants, Gender, Neighbourhood, Socioeconomic status
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29422 (URN)10.1159/000497063 (DOI)000462034300002 ()30712037 (PubMedID)2-s2.0-85061304574 (Scopus ID)
Available from: 2019-02-05 Created: 2019-02-05 Last updated: 2019-04-04Bibliographically approved
Xu, H., Matsushita, K., Su, G., Trevisan, M., Ärnlöv, J., Barany, P., . . . Carrero, J.-J. (2019). Estimated glomerular filtration rate and the risk of cancer. American Society of Nephrology. Clinical Journal, 14(4), 530-539
Open this publication in new window or tab >>Estimated glomerular filtration rate and the risk of cancer
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2019 (English)In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 14, no 4, p. 530-539Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND OBJECTIVES: Community-based reports regarding eGFR and the risk of cancer are conflicting. We here explore plausible links between kidney function and cancer incidence in a large Scandinavian population-based cohort.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the Stockholm Creatinine Measurements project, we quantified the associations of baseline eGFR with the incidence of cancer among 719,033 Swedes ages ≥40 years old with no prior history of cancer. Study outcomes were any type and site-specific cancer incidence rates on the basis of International Classification of Diseases-10 codes over a median follow-up of 5 years. To explore the possibility of detection bias and reverse causation, we divided the follow-up time into different time periods (≤12 and >12 months) and estimated risks for each of these intervals.

RESULTS: In total, 64,319 cases of cancer (affecting 9% of participants) were detected throughout 3,338,226 person-years. The relationship between eGFR and cancer incidence was U shaped. Compared with eGFR of 90-104 ml/min, lower eGFR strata associated with higher cancer risk (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05 to 1.11 for eGFR=30-59 ml/min and adjusted hazard ratio, 1.24; 95% confidence interval, 1.15 to 1.35 for eGFR<30 ml/min). Lower eGFR strata were significantly associated with higher risk of skin, urogenital, prostate, and hematologic cancers. Any cancer risk as well as skin (nonmelanoma) and urogenital cancer risks were significantly elevated throughout follow-up time, but they were higher in the first 12 months postregistration. Associations with hematologic and prostate cancers abrogated after the first 12 months of observation, suggesting the presence of detection bias and/or reverse causation.

CONCLUSIONS: There is a modestly higher cancer risk in individuals with mild to severe CKD driven primarily by skin and urogenital cancers, and this is only partially explained by bias.

Keywords
Bias, Cancer, Confidence Intervals, Follow-Up Studies, Hematologic Neoplasms, Incidence, International Classification of Diseases, Proportional Hazards Models, Prostatic Neoplasms, Renal Insufficiency, Chronic, Risk, Urogenital Neoplasms, chronic kidney disease, detection bias, estimated glomerular filtration rate, glomerular filtration rate, reverse causation
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29666 (URN)10.2215/CJN.10820918 (DOI)000463891100010 ()30872279 (PubMedID)2-s2.0-85064491897 (Scopus ID)
Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-05-06Bibliographically approved
Feigin, V., Nichols, E., Alam, T., Bannick, M., Beghi, E., Blake, N., . . . Vos, T. (2019). Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology, 18(5), 459-480
Open this publication in new window or tab >>Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016
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2019 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 5, p. 459-480Article in journal (Refereed) Published
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29933 (URN)10.1016/S1474-4422(18)30499-X (DOI)000464140400014 ()
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-04-26Bibliographically approved
Johnson, C., Nguyen, M., Roth, G., Nichols, E., Alam, T., Abate, D., . . . Murray, C. (2019). Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology, 18(5), 439-458
Open this publication in new window or tab >>Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016
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2019 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 5, p. 439-458Article in journal (Refereed) Published
National Category
Clinical Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29934 (URN)10.1016/S1474-4422(19)30034-1 (DOI)000464140400013 ()
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-05-09Bibliographically approved
Lind, L., Sundström, J., Larsson, A., Lampa, E., Ärnlöv, J. & Ingelsson, E. (2019). Longitudinal effects of aging on plasma proteins levels in older adults: associations with kidney function and hemoglobin levels. PLoS ONE, 14(2), Article ID e0212060.
Open this publication in new window or tab >>Longitudinal effects of aging on plasma proteins levels in older adults: associations with kidney function and hemoglobin levels
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0212060Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels.

MATERIAL AND METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured.

RESULTS: Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships.

CONCLUSION: The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.

National Category
Clinical Laboratory Medicine
Research subject
Health and Welfare
Identifiers
urn:nbn:se:du-29617 (URN)10.1371/journal.pone.0212060 (DOI)000459710700009 ()30802263 (PubMedID)2-s2.0-85062001083 (Scopus ID)
Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-03-14Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6933-4637

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