凝血因子XIIa-激肽介导对慢性肾脏病高血压的作用

Coagulation factor XIIa-kinin-mediated contribution to hypertension of chronic kidney disease.

作者信息

Papageorgiou Peter C, Chan Christopher T, Yeo Erik L, Backx Peter H, Floras John S

机构信息

aHeart and Stroke/Richard Lewar Centre of Excellence bDepartment of Medicine, University Health Network and Mount Sinai Hospital cDepartment of Physiology, University of Toronto, Toronto, Ontario, Canada.

出版信息

J Hypertens. 2014 Jul;32(7):1523-33; discussion 1533. doi: 10.1097/HJH.0000000000000192.

DOI:10.1097/HJH.0000000000000192

PMID:24733030

Abstract

BACKGROUND

Activated coagulation Factor XII (FXIIa) infusion increases peripheral resistance (TPR) and mean arterial pressure (MAP) of Brown Norway but not plasma kininogen deficient Brown Norway Katholiek (BNK) rats. FXIIa concentrations are elevated in hypertensive end-stage renal disease patients receiving conventional haemodialysis (CHD). Conversion to nocturnal haemodialysis (NHD) lowers peripheral resistance and MAP.

OBJECTIVE

To determine whether the plasma coagulation FXIIa-kallikrein-kinin axis contributes to the hypertension of chronic kidney disease (CKD).

METHODS

Plasma FXIIa and haemodynamic data were acquired in 11 CHD patients before and after 2 months of NHD. Cardiac and systemic haemodynamics of Brown Norway and BNK rats rendered hypertensive and uremic by 5/6 nephrectomy (NX) were determined before and after acute FXIIa inhibition.

RESULTS

FXIIa was increased three-fold in CHD patients relative to control plasma (P < 0.05). After conversion to NHD, both ΔMAP and ΔTPR correlated with ΔFXIIa. In rats, plasma FXIIa was three-fold higher in both NX groups than respective SHAM controls (all P < 0.05), but MAP (147 ± 4 vs. 133 ± 2 mmHg; P < 0.05) and TPR (2.8 ± 0.2 vs. 2.3 ± 0.2 units; P < 0.05) were greater in Brown Norway NX (n = 16) than in BNK (n = 15) NX rats. FXIIa correlated with MAP only in Brown Norway NX, and plasma catecholamines were increased relative to SHAM only in Brown Norway NX (P < 0.05). In Brown Norway NX rats, FXIIa inhibitor infusion decreased MAP (-12 mmHg) and TPR (-0.5 Units) (both P < 0.05), and halved catecholamines (P < 0.05). No such changes occurred in BNK NX rats.

CONCLUSION

FXIIa-kininogen mediated vasoconstriction contributes significantly to CKD hypertension in Brown Norway rats; this novel mechanism may be active in humans with CKD.

摘要

背景

输注活化凝血因子 XII（FXIIa）可增加挪威棕色大鼠的外周阻力（TPR）和平均动脉压（MAP），但对血浆激肽原缺乏的挪威棕色天主教大鼠（BNK）无效。接受常规血液透析（CHD）的高血压终末期肾病患者的 FXIIa 浓度升高。改为夜间血液透析（NHD）可降低外周阻力和 MAP。

目的

确定血浆凝血 FXIIa-激肽释放酶-激肽轴是否与慢性肾脏病（CKD）高血压有关。

方法

在 11 例 CHD 患者接受 NHD 治疗 2 个月前后获取血浆 FXIIa 和血流动力学数据。测定 5/6 肾切除术（NX）致高血压和尿毒症的挪威棕色大鼠和 BNK 大鼠在急性抑制 FXIIa 前后的心脏和全身血流动力学。

结果

与对照血浆相比，CHD 患者的 FXIIa 增加了两倍（P < 0.05）。改为 NHD 后，ΔMAP 和 ΔTPR 均与 ΔFXIIa 相关。在大鼠中，两个 NX 组的血浆 FXIIa 均比各自的假手术对照组高两倍（均 P < 0.05），但挪威棕色 NX 大鼠（n = 16）的 MAP（147 ± 4 对 133 ± 2 mmHg；P < 0.05）和 TPR（2.8 ± 0.2 对 2.3 ± 0.2 单位；P < 0.05）高于 BNK（n = 15）NX 大鼠。FXIIa 仅与挪威棕色 NX 大鼠的 MAP 相关，且仅挪威棕色 NX 大鼠相对于假手术组血浆儿茶酚胺增加（P < 0.05）。在挪威棕色 NX 大鼠中，输注 FXIIa 抑制剂可降低 MAP（-12 mmHg）和 TPR（-0.5 单位）（均 P < 0.05），并使儿茶酚胺减半（P < 0.05）。BNK NX 大鼠未出现此类变化。