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. 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. 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). 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.

中文翻译：

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GDF-15、YKL-40 和 MMP 9 在终末期肾病患者中的作用：重点关注与血管结局和全因死亡率的性别特异性相关性

目前对心血管疾病 (CVD) 与慢性肾脏病 (CKD) 相关性的认识并未充分认识到性别差异。CKD 的一个标志是血管老化，其特征包括：全身炎症、微生物群失衡、氧化应激和血管钙化——与动脉粥样硬化/动脉硬化发展相关的特征。因此，有必要引入与动脉粥样硬化/动脉粥样硬化损伤相关的新型生物标志物，以更好地评估 CKD 患者的血管老化。然而，人们对尿毒症与新型 CVD 生物标志物（如生长分化因子 15 (GDF-15)、软骨糖蛋白 39 (YKL-40) 和基质金属蛋白酶 9 (MMP-9)）之间的关系知之甚少。因此，我们假设终末期肾病 (ESKD) 患者的 GDF-15、YKL-40、MMP-9 水平与肠道菌群、血管钙化、炎症、合并症和所有疾病之间存在性别特异性关系。导致死亡。从两个正在进行的前瞻性 ESKD 队列中选择未接受肾脏替代治疗的 ESKD 患者，男性（n = 151）和女性（n = 79）。使用酶联免疫吸附测定试剂盒分析 GDF-15、YKL-40 和 MMP9。在肠道微生物群衍生的三甲胺 N-氧化物 (TMAO)、血管钙化、炎症反应、氧化应激、合并症和全因死亡率的背景下分析生物标志物水平。仅在女性中，GDF-15 的增加与较高的 TMAO 相关，并且与较高的冠状动脉钙化和 IL-6 相关。在女性中，糖尿病与 GDF-15 和 MMP-9 升高相关，而男性糖尿病患者仅与 GDF-15 升高相关。未发现生物标志物与 CVD 合并症之间存在关联。已故男性和女性的 GDF-15 浓度较高（分别为 p = 0.01 和 p < 0.001），同时，已故男性中仅 YKL-40 增加（p = 0.02）。总之，在男性中，GDF-15 和 YKL-40 与血管钙化、炎症和氧化应激有关，而在女性中，GDF-15 与 TMAO 相关。男性 YKL-40 和 GDF-15 水平升高，而女性仅 GDF-15 水平升高，与全因死亡率相关。我们的研究结果表明，新型 CVD 生物标志物的性别特异性关联有可能影响 ESKD 患者心血管并发症的发展。