Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD. Individuals with CKD stages 3-5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample. In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 ± 2.9 years (range 0.005-12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean ± SD change of 2.9 ± 1.2 years (range 0.1-4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07-1.75), p = 0.013). Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.

Osteopontin is a member of the proinflammatory cytokine network, a complex system that involves many chemokines, cytokines, and growth factors. The aim of the present study was to study the associations between osteopontin and a large number of chemokines, cytokines, and growth factors. We analyzed plasma and urine osteopontin in 652 men from the Uppsala Longitudinal Study of Adult Men (ULSAM) study cohort and compared the levels with the levels of eighty-five chemokines, cytokines, and growth factors. We found significant associations between plasma osteopontin and 37 plasma biomarkers in a model adjusted for age, and 28 of those plasma biomarkers were significant in a model also adjusting for cardiovascular risk factors. There were no significant associations after Bonferroni adjustment between urine osteopontin and any of the studied plasma cytokine biomarkers. This study shows that circulating osteopontin participates in a protein–protein interaction network of chemokines, cytokines, and growth factors. The network contains responses, pathways, and receptor binding interactions relating to cytokines, regulation of the immune system, and also regulation of apoptosis and intracellular signal transduction.

Background: Associations between high physical activity (PA) levels and incident atrial fibrillation (AF) is found in some earlier studies. We aim to study the association between levels of PA and AF in two cohorts. Methods: We used data from the Uppsala Longitudinal Study of Adult Men (ULSAM) study, initiated in 1970, included men aged 50 years, with 2202 included in the study. Examinations were reiterated three times, with follow-up after in median 33 years, with 3.8–6.0% on the highest PA level. We also used data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; with women 50%); mean age 70 years, baseline 2001–2004, median follow-up 15 years, with 961 included in the study, with 4.8% on the highest PA level. Cox regression analysis with hazard ratios (HRs) was used to study association between PA levels and incident AF, adjusted for CV risk factors: systolic blood pressure, LDL- and HDL-cholesterol, BMI, diabetes, and smoking. Results: Totally, in ULSAM 504 men during 59,958 person-years at risk, and in PIVUS 204 individuals during a follow-up of 11,293 person-years experienced an AF. Neither in ULSAM, PIVUS, nor in the meta-analysis of both cohorts, individuals with the highest PA level showed an increased AF risk, compared to individuals with lowest level of PA. Conclusions: The benefits of PA in community dwelling individuals for its benefits to mental, metabolic, and cardiovascular health should guide public recommendations, rather than a possible risk of AF. Lay Summary: We studied the risk of incident atrial fibrillation at various levels of physical activity in two cohorts and found no statistically significant increased risk after adjusting for cardiovascular risk factors (systolic blood pressure, LDL- and HDL-cholesterol, BMI, diabetes, and smoking).