Department of Internal Medicine and Pediatrics, Nephrology Section, Ghent University Hospital, Ghent, Belgium.
Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
Nephrol Dial Transplant. 2021 May 27;36(6):998-1005. doi: 10.1093/ndt/gfab004.
Several protein-bound uraemic toxins (PBUTs) have been associated with cardiovascular (CV) and all-cause mortality in chronic kidney disease (CKD) but the degree to which this is the case per individual PBUT and the pathophysiological mechanism have only partially been unraveled.
We compared the prognostic value of both total and free concentrations of five PBUTs [p-cresyl sulfate (pCS), p-cresyl glucuronide, indoxyl sulfate, indole acetic acid and hippuric acid] in a cohort of 523 patients with non-dialysis CKD Stages G1-G5. Patients were followed prospectively for the occurrence of a fatal or non-fatal CV event as the primary endpoint and a number of other major complications as secondary endpoints. In addition, association with and the prognostic value of nine markers of endothelial activation/damage was compared.
After a median follow-up of 5.5 years, 149 patients developed the primary endpoint. In multivariate Cox regression models adjusted for age, sex, systolic blood pressure, diabetes mellitus and estimated glomerular filtration rate, and corrected for multiple testing, only free pCS was associated with the primary endpoint {hazard ratio [HR]1.39 [95% confidence interval (CI) 1.14-1.71]; P = 0.0014}. Free pCS also correlated with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (r = -0.114, P < 0.05), angiopoietin-2 (ANGPT2) (r = 0.194, P < 0.001), matrix metallopeptidase 7 (MMP-7; (r = 0.238, P < 0.001) and syndecan 1 (r = 0.235, P < 0.001). Of these markers of endothelial activation/damage, ANGPT2 [HR 1.46 (95% CI 1.25-1.70); P < 0.0001] and MMP-7 [HR 1.31 (95% CI 1.08-1.59); P = 0.0056] were also predictive of the primary outcome.
Among PBUTs, free pCS shows the highest association with CV outcome in non-dialysed patients with CKD. Two markers of endothelial activation/damage that were significantly correlated with free pCS, ANGPT2 and MMP-7 were also associated with CV outcome. The hypothesis that free pCS exerts its CV toxic effects by an adverse effect on endothelial function deserves further exploration.
几种蛋白结合性尿毒症毒素（PBUT）与慢性肾脏病（CKD）患者的心血管（CV）和全因死亡率相关，但每种 PBUT 的程度以及病理生理机制仅部分得到阐明。
我们比较了 523 名非透析 CKD G1-G5 期患者中五种 PBUT[对甲酚硫酸酯（pCS）、对甲酚葡萄糖醛酸、吲哚硫酸、吲哚乙酸和马尿酸]的总浓度和游离浓度的预后价值。前瞻性随访患者以 CV 事件（主要终点）和其他一些主要并发症（次要终点）为终点。此外，比较了 9 种内皮激活/损伤标志物的相关性及其预后价值。
中位随访 5.5 年后，149 例患者发生主要终点事件。在多变量 Cox 回归模型中，调整了年龄、性别、收缩压、糖尿病和估计肾小球滤过率，并进行了多次检验校正，只有游离 pCS 与主要终点相关[危险比（HR）1.39（95%置信区间[CI]1.14-1.71）；P=0.0014]。游离 pCS 还与一种包含金属蛋白酶结构域的解整合素和金属蛋白酶 13（ADAM13）[r=-0.114，P<0.05]、血管生成素 2（ANGPT2）[r=0.194，P<0.001]、基质金属蛋白酶 7（MMP-7；r=0.238，P<0.001）和 syndecan 1（r=0.235，P<0.001）相关。在这些内皮激活/损伤标志物中，ANGPT2[HR 1.46（95% CI 1.25-1.70）；P<0.0001]和 MMP-7[HR 1.31（95% CI 1.08-1.59）；P=0.0056]也可预测主要结局。
在 PBUT 中，游离 pCS 与非透析性 CKD 患者的 CV 结局相关性最高。与游离 pCS 显著相关的两种内皮激活/损伤标志物，ANGPT2 和 MMP-7，也与 CV 结局相关。游离 pCS 通过对内皮功能的不良影响发挥其 CV 毒性作用的假说值得进一步探索。
