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

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 &Dgr;MAP and &Dgr;TPR correlated with &Dgr;FXIIa. 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.

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