Circulating proteins as predictors of cardiovascular mortality in endstage renal disease
Author: Feldreich, Tobias; Nowak, Christoph; Fall, Tove; Carlsson, Axel C; Carrero, Juan-Jesus; Ripsweden, Jonaz; Qureshi, Abdul Rashid; Heimbürger, Olof; Barany, Peter; Stenvinkel, Peter; Vuilleumier, Nicolas; Kalra, Philip A; Green, Darren; Ärnlöf, Johan
Department: Inst för klinisk vetenskap, intervention och teknik / Dept of Clinical Science, Intervention and Technology
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Abstract
Introduction: Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years).
Results: In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26–2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03–2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort.
Conclusions Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.
Results: In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26–2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03–2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort.
Conclusions Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.
Institution:
- School of Health and Social Studies, Dalarna University, Falun, Sweden
- Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Genetics, Laboratory Medicine and Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Medical Specialties, Geneva Faculty of Medicine, Geneva, Switzerland
- Divison of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- Department of Renal, Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford, UK
Citation: J Nephrol. 2019 Feb;32(1):111-119.
Citation DOI: 10.1007/s40620-018-0556-5
Citation PMID: 30499038
Citation ISI: 000458699800013
Publishing journal: Journal of Nephrology
Eprint status: Peer Reviewed
Version: Published
Issue date: 2021-02-24
Sponsorship:
- Swedish Research Council
- Swedish Heart–Lung foundation
- European Union Horizon 2020, 634869
- Dalarna University
- Uppsala University
- Swedish Research Council
- Njurfonden
- European Union’s Horizon 2020 research and innovation programme, Marie Sklodowska-Curie, 722609
Rights:
CC BY 4.0
Publication year: 2019
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