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Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease : focus on sex-specific associations with vascular outcomes and all-cause mortality

Laucyte-Cibulskiene, Agne LU orcid ; Ward, Liam J. ; Ebert, Thomas ; Tosti, Giulia ; Tucci, Claudia ; Hernandez, Leah ; Kautzky-Willer, Alexandra ; Herrero, Maria Trinidad ; Norris, Colleen M. and Pilote, Louise , et al. (2021) In Biology of Sex Differences 12(1).
Abstract

Background: Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification—features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix... (More)

Background: Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification—features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. Methods: ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. Results: Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p < 0.001, respectively), meanwhile only YKL-40 was increased in deceased males (p = 0.02). Conclusions: In conclusion, in males GDF-15 and YKL-40 were related to vascular calcification, inflammation, and oxidative stress, whilst in females GDF-15 was related to TMAO. Increased levels of YKL-40 and GDF-15 in males, and only GDF-15 in females, were associated with all-cause mortality. Our findings suggest that sex-specific associations of novel CVD biomarkers have a potential to affect development of cardiovascular complications in patients with ESKD.

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type
Contribution to journal
publication status
published
subject
keywords
Biomarkers, Calcification, Cardiovascular disease, Chronic kidney disease, End stage kidney disease, TMAO, Uraemia
in
Biology of Sex Differences
volume
12
issue
1
article number
50
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85115261469
  • pmid:34526107
ISSN
2042-6410
DOI
10.1186/s13293-021-00393-0
language
English
LU publication?
yes
id
3c518608-5f9c-4b6c-a55a-2e65f8d400bc
date added to LUP
2021-09-29 15:44:51
date last changed
2024-06-15 17:09:39
@article{3c518608-5f9c-4b6c-a55a-2e65f8d400bc,
  abstract     = {{<p>Background: Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification—features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. Methods: ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. Results: Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p &lt; 0.001, respectively), meanwhile only YKL-40 was increased in deceased males (p = 0.02). Conclusions: In conclusion, in males GDF-15 and YKL-40 were related to vascular calcification, inflammation, and oxidative stress, whilst in females GDF-15 was related to TMAO. Increased levels of YKL-40 and GDF-15 in males, and only GDF-15 in females, were associated with all-cause mortality. Our findings suggest that sex-specific associations of novel CVD biomarkers have a potential to affect development of cardiovascular complications in patients with ESKD.</p>}},
  author       = {{Laucyte-Cibulskiene, Agne and Ward, Liam J. and Ebert, Thomas and Tosti, Giulia and Tucci, Claudia and Hernandez, Leah and Kautzky-Willer, Alexandra and Herrero, Maria Trinidad and Norris, Colleen M. and Pilote, Louise and Söderberg, Magnus and Brismar, Torkel B. and Ripsweden, Jonaz and Stenvinkel, Peter and Raparelli, Valeria and Kublickiene, Karolina}},
  issn         = {{2042-6410}},
  keywords     = {{Biomarkers; Calcification; Cardiovascular disease; Chronic kidney disease; End stage kidney disease; TMAO; Uraemia}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Biology of Sex Differences}},
  title        = {{Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease : focus on sex-specific associations with vascular outcomes and all-cause mortality}},
  url          = {{http://dx.doi.org/10.1186/s13293-021-00393-0}},
  doi          = {{10.1186/s13293-021-00393-0}},
  volume       = {{12}},
  year         = {{2021}},
}