MO009ROLE OF GDF-15, YKL-40, AND MMP-9 IN PATIENTS WITH ESKD: FOCUS ON SEX SPECIFIC ASSOCIATIONS WITH VASCULAR OUTCOMES AND ALL-CAUSE MORTALITY
Authors: Laucyte-Cibulskiene Agne , Ward Liam , Ebert Thomas , Tosti Guilia , Tucci Claudia , Hernandez Leah , Stenvinkel Peter , Raparelli Valeria , Kublickiene Karolina 
Published: May 2021

Abstract

Background and Aims
This study was performed on behalf of the GOING-FWD Consortium.
The importance of sex difference in the development of cardiovascular complications is well appreciated, however, further studies are warranted to assess if sex specific pathophysiological changes occur under uremic environment. Little is known about the relationship between the uremic phenotype and novel cardiovascular biomarkers like growth differentiation factor 15 (GDF-15), cartilage glycoprotein 39 (YKL-40), and matrix metalloproteinase 9 (MMP9), and if they have a sex specific effects in relation to inflammation, vascular remodelling, cardiovascular outcomes and all-cause mortality. Therefore, we hypothesise that there is a sex specific relationship between GDF-15, YKL-40, MMP9 and vascular outcomes defined as athero-/arteriosclerosis and vascular calcification.

Method
ESKD patients (n = 231), males (n = 152) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective CKD cohorts from the Division of Renal Medicine, Karolinska University Hospital, Sweden. Three putative CVD biomarkers, GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay (ELISA) kits. Biomarker level/activity was analysed in the context of gut microbiota derived TMAO, vascular calcification (determined as CAC score on CT scans, aortic valve calcification (AVC) and medial calcification on epigastric artery biopsies), inflammatory response, oxidative stress and all-cause mortality.

Results
The levels of investigated biomarkers have not differed between female and male patients with ESKD. However, GDF-15 correlated with TMAO in females from more severe cohort that are not receiving renal replacement therapy yet, whereas in males increased GDF-15 level was associated with higher Agatston score on CT-scans, inflammatory biomarker (IL-6) and oxidative stress biomarker 8-OHdG. None of biomarkers was related to intimal medial calcification assessed in epigastric artery biopsies. Comorbidity analysis revealed elevated GDF-15 levels in both females and males, while increased MMP-9 levels were observed only in females with diabetes mellitus, but not with CVD. When assessing death of any cause in our cohorts, both deceased males and females had higher GDF-15 concentration (p = 0.01 and p &lt; 0.001, respectively), meanwhile only YKL-40 level was increased in deceased males (p = 0.02).

Conclusion
In summary, here we report that in males GDF-15 and YKL-40 were related to vascular calcification, inflammageing and oxidative stress, while in females the relationship of GDF-15 with TMAO was observed. Higher MMP-9 level was seen in males without diabetes and in females with confirmed diabetes mellitus. YKL-40 increase in males and GDF-15 in both males and females were associated with all-cause mortality. Our findings suggest that sex specific associations exist and those could have a potential to affect development of cardiovascular complications in patients with ESKD.