Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
J Diabetes Investig. 2021 Dec;12(12):2172-2182. doi: 10.1111/jdi.13602. Epub 2021 Jun 23.
AIMS/INTRODUCTION: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria.
Plasma HCII activity and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP), were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females).
The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate-regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log-transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL-FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log-transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively).
The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria.
目的/引言：凝血酶通过激活蛋白酶激活受体（PARs）发挥各种病理生理功能。最近的数据表明，PARs 通过调节炎症影响包括糖尿病肾病（DKD）在内的肾小球疾病的发展。肝素辅因子 II（HCII）特异性失活凝血酶；因此，我们假设低血浆 HCII 活性与 DKD 发展相关，表现为蛋白尿。
在 310 名日本糖尿病患者（176 名男性和 134 名女性）中测定了血浆 HCII 活性和点尿生物标志物，包括白蛋白和肝型脂肪酸结合蛋白（L-FABP），作为尿白蛋白与肌酐比（uACR）和尿 L-FABP 与肌酐比（uL-FABPCR）。统计评估了血浆 HCII 活性与这些 DKD 尿液生物标志物之间的关系。此外，统计评估了 201/310 例患者（115 名男性和 86 名女性）中血浆 HCII 活性与年 uACR 变化的关系。
所有参与者的平均血浆 HCII 活性为 93.8±17.7%。包括混杂因素的多元回归分析表明，血浆 HCII 活性独立于抑制 uACR 和对数转换的 uACR 值（P=0.036 和 P=0.006），但不影响 uL-FABPCR（P=0.541）。此外，在调整混杂因素后，血浆 HCII 活性与年 uACR 和对数转换的 uACR 增量呈显著负相关（P=0.001 和 P=0.014）。
血浆 HCII 活性与糖尿病患者的肾小球损伤呈负相关且具有特异性。结果表明，HCII 可作为白蛋白尿代表的早期 DKD 发展的新型预测因子。
