#363 Altered filtration of middle-sized molecules is related to cardiovascular disease-related proteins

Abstract

Abstract Background and Aims Cardiovascular (CV) complications, driven by complex vascular-metabolic interactions, are the leading cause of frailty in chronic kidney disease (CKD) complications. Advancing knowledge on cardio-renal interactions is a key to preventive and treatment strategies. Still, the cost-effective tools and biomarkers for early detection of altered glomerular filtration that subsequently leads to accelerated cardiovascular aging and, thus, higher CV mortality are lacking. Our objective was to investigate how molecules of varying masses, specifically cystatin C and creatinine, are filtered in kidney in relation to variations of plasma protein levels that might accelerate vascular changes, ultimately leading to early vascular aging and chronic kidney disease (CKD). Method From the Malmo Diet Cancer cohort, 4426 out of the 5061 participants had cardiovascular and renal biomarkers measured (mean age of 57 ± 6 years). These biomarkers included factors related to tissue growth and repair (EGFR), matrix metalloproteinases (MMP-12), proinflammatory cytokines (TNF-R1, TNF-R2, CXCL13, CXCL5), markers of vascular repair (SCF), homeostatic cytokines (CCL19), anti-apoptotic proteins (REG-4), adipokines (FABP4, LEP), as well as other cardiovascular proteins (NT-pro-BNP, MB) and indicators of kidney function. These 13 proteins were analyzed using multiplex proximity extension assay (Olink Cardiovascular II and Oncology panels), and have molecular masses either like creatinine (0.113 kDa) or cystatin C (13.3 kDa). These proteins were previously shown to be associated with measured glomerular filtration rate (mGFR) by Christensson A et al. (Proteomics Clin App, 2018). Kidney function was estimated by using cystatin C (CAPA, CKD-EPIcys) and creatinine (Lund-Malmo revised, CKD-EPIcr) equations. The filtration ratio was presented as CAPA/LMrev and CKD-EPIcys/CKD-EPIcr. The subgroups of this ratio were <0.70. Results Mean kidney function was as follows: 65 (±15)/ 69 (±16)/ 78 (±13) and 76 (±14) mL/min/1.73 m2 (CAPA/ CKD-EPIcys/ LMrev and CKD-EPIcr, respectively). The CAPA/LMrev filtration ratio was 0.84 (±0.18), whereas CKD-EPIcys/cr was 0.91 (±0.19). The filtration ratio negatively correlated with TNF-R1, TNF-R2, SCF, MMP-12, FABP4, LEP, NT-pro-BNP, CCL19, CXCL5, CXCL13 and REG-4; positively to EGFR and MB (all p < 0.001). In the whole cohort, participants with filtration ratio below 0.7 had significantly higher levels of TNF-R1, TNF-R2, MMP12, FABP4, LEP, NT-pro-BNP, CCL19, REG-4, and CXCL13, but similar levels of EGFR. CXCL5 and SCF levels were higher at <0.70 compared to 0.84-0.99 and >1.0 (Fig. 1). Interestingly, in women, MB was highest at <0.70; SCF level was higher at <0.70 compared to 0.84-0.99 and >1.00; EGFR level was highest at 0.70-0.84 compared to 0.84-0.99. In men, higher FABP4, LEP, CCL19, and MB were observed at <0.70 compared to 0.84-0.99 and >1.00. Conclusion Altered glomerular filtration for middle-sized molecules is related to the accumulation of plasma proteins that have similar molecular mass to creatinine and cystatin C and have sex-specific patterns. The proteins studied have been previously shown to contribute to vascular aging, cardiac damage and remodeling, and chronic kidney disease, and thus enlighten complex mechanisms behind cardio-renal interactions.