Elsevier

Peptides

Volume 20, Issue 4, May 1999, Pages 421-430
Peptides

Original Articles
Des-Arg9-bradykinin metabolism in patients who presented hypersensitivity reactions during hemodialysis: role of serum ACE and aminopeptidase P

https://doi.org/10.1016/S0196-9781(99)00020-0Get rights and content

Abstract

Bradykinin (BK) has been proposed as the principal mediator of hypersensitivity reactions (HSR) in patients dialyzed using negatively charged membranes and concomitantly treated with angiotensin-converting enzyme (ACE) inhibitors. We investigated the metabolism of exogenous BK added to the sera of 13 patients dialyzed on an AN69 membrane with a history of HSR (HSR+ patients) and 10 others who did not present such a reaction (HSR–patients) while dialyzed under the same conditions. No significant difference in the t1/2 of BK was found between the patient groups. However, the t1/2 of generated des-Arg9-BK was significantly increased (2.2-fold) in HSR+ patients compared to HSR–subjects. Preincubation of the sera with an ACE inhibitor (enalaprilat) significantly increased the t1/2 of both BK and des-Arg9-BK in both groups. There was no significant difference between the groups with respect to the t1/2 of BK, but there was a significantly greater increase (3.8-fold) in the t1/2 of des-Arg9-BK in HSR+ patients compared to HSR–subjects. The level of serum aminopeptidase P (APP) activity showed a significant decrease in the HSR+ sera when compared to HSR–samples. In HSR–and HSR+ patients, a significant inverse relation (r2 = 0.6271; P < 0.00005) could be calculated between APP activity and des-Arg9-BK t1/2. In conclusion, HSR in hemodialyzed patients who are concomitantly treated with a negatively charged membrane and an ACE inhibitor can be considered as a multifactorial disease in that a decreased APP activity resulting in reduced degradation of des-Arg9-BK may lead to the accumulation of this B1 agonist that could be responsible, at least in part, for the signs and symptoms of HSR.

Introduction

KININS are a family of powerful proinflammatory peptides. In human, bradykinin (BK), the principal member of this class of autacoids, is mainly released from high molecular weight kininogen by plasma kallikrein after activation of the contact system of plasma [1], [37]. BK exerts its pharmacological effect via the activation of B2 receptors [19]. Various peptidases are able to metabolize BK including angiotensin-converting enzyme (ACE, kininase II, EC 3.4.15.1) that was originally shown to be a major kininase in blood by Erdös and coworkers [reviewed in Ref. [49]]. We have also shown that ACE plays a major role in the inactivation of this B2 agonist in serum [9]. In addition to ACE, BK can be inactivated by different endopeptidases, depending on the biologic milieu [13], [14]. BK is also metabolized by different carboxypeptidases (N, M and U), that are collectively named kininase I, into des-Arg9-BK that is the active metabolite of BK [14], [47], [48]. In contrast to BK that activates B2 receptors, des-Arg9-BK activates B1 receptors, the expression that is upregulated by cytokines and growth factors [19], [28]. Des-Arg9-BK is also inactivated by ACE [9], [22], [34], [44] and by another metabolic pathway whose nature remains to be determined. Aminopeptidase P (APP, X-Pro aminopeptidase, EC 3.4.11.9) is potentially involved in the inactivation of BK and des-Arg9-BK [31] and has been shown to be physiologically relevant in the rat pulmonary and coronary vascular beds [16], [36], [39].

Hypersensitivity reactions (HSR) during hemodialysis are rare, but potentially life-threatening adverse reactions [57]. It is generally accepted that in many cases ethylene oxide gas may have induced these HSR [10], [25]. The activation of complement and the release of histamine are other factors that were claimed to contribute to these reactions [18]. HSR have been also associated with the simultaneous use of negatively charged dialysis membranes and ACE inhibitor therapy [51], [56]. BK was proposed to be responsible for the main symptoms characterizing this latter kind of HSR [43], [51], [56]. However, none of these studies characterized the metabolism of BK or des-Arg9-BK in the serum of patients, nor the effect of ACE inhibition on that metabolism.

The aim of the present study was to define the metabolism of BK and des-Arg9-BK in the sera of patients who had previously presented with HSR at the beginning of dialysis using AN69 membranes and concomitant treatment with an ACE inhibitor. With the same experimental approach as we previously used to define kinin metabolism in normal serum [9] and in sera of patients who had presented with angioedema or severe hypotensive reactions during blood transfusion associated with ACE inhibitor therapy [4], [6], we compared serum BK and des-Arg9-BK metabolism, in the absence and the presence of an ACE inhibitor, between patients who had previously presented with HSR and those who had not. Finally, the kinetic parameters characterizing the metabolism of des-Arg9-BK have been related to the serum APP activity measured in both groups of patients.

Section snippets

2.1. Patients

Serum samples from 23 hemodialyzed patients were obtained, before dialysis and before the administration of the anticoagulant heparin to avoid an activation of the contact system [45]. Patients were from 8 dialysis centers (Hôpital du Sacré–Coeur, Hôpital Saint–Luc and Hôpital Notre–Dame, Montréal, QC, Canada; Centre Hospitalier de Sainte– Ode, Sainte-Ode, Cliniques Universitaires Saint–Luc, Bruxelles and Universitaire Zeikenhuizen Leuven, Leuven, Belgium; Centre Hospitalier Louis-Pasteur,

3.1. Half-life (t1/2) of BK and des-Arg9-BK in the absence of an ACE inhibitor

As shown in Fig. 1 A, the mean BK t1/2 calculated for the HSR+ group (34 ± 3 s, n = 10) was not statistically different from that calculated for the HSR–patients (30 ± 3 s, n = 3) (P = 0.491). In absence of ACE inhibition, des-Arg9-BK t1/2 was significantly higher in the HSR+ group (878 ± 104 s, n = 10) when compared to HSR–patients (392 ± 157 s, n = 3) (P = 0.041; Fig. 1B).

3.2. Effect of ACE inhibitor on t1/2 of BK and des-Arg9-BK

Inhibition of ACE by preincubation of the serum sample with enalaprilat greatly reduced the degradation of BK and des-Arg9

4. Discussion

In the present study, we defined for the first time the metabolism not only of BK, but also of des-Arg9-BK in the sera of patients who had previously presented with HSR when dialyzed with an AN69 membrane while receiving an ACE inhibitor. Des-Arg9-BK t1/2, but not BK t1/2, allowed us to differentiate between the 2 groups of patients, the t1/2 of the B1 agonist being significantly higher in the sera of patients who presented with HSR than in the sera of HSR–patients. For that purpose, we

Acknowledgements

This work was partially supported by a grant of Hospal R&D Int. (Meyzieu, France) to A. Adam. C. Blais, Jr. is the recipient of a scholarship from the Fonds de la recherche en santé du Québec (FRSQ).

We are grateful to Dr L. Dufresne (Hôpital St-Luc, Montréal, QC, Canada), Dr M. Prud’homme (Hôpital Notre–Dame, Montréal, QC, Canada), Dr M. Jadoul (Cliniques Universitaires Saint–Luc, Bruxelles, Belgium), Dr J. Donck (Universitaire Zeikenhuizen Leuven, Leuven, Belgium), Dr J. Potier (Centre

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