¿PLASMA LEVELS OF BRADYKININ AND CLEAVED HIGH MOLECULAR WEIGHT KININOGEN IN PATIENTS WITH IDIOPATHIC ANGIOEDEMA DURING ACUTE ATTACK¿

Angioedema is a swelling of the subcutaneous and submucosal tissues that can involve lips, face, neck, extremities and/or submucosal tissues of the oral cavity, larynx and intestine. Patients with angioedema can be clinically critical and require urgent clinical evaluation, especially when angioedema affects the larynx (a life-threatening condition) or the gastrointestinal tract (mimicking an acute abdomen). Angioedema can be acquired or hereditary. The acquired forms may be histaminergic or non-histaminergic, drug-induced or due to an acquired C1-inhibitor deficiency; however, several cases remain idiopathic. The role of bradykinin in increasing vascular permeability has been demonstrated in angioedema due to C1-inhibitor deficiency and in angioedema due to the treatment with angiotensin converting enzyme (ACE) inhibitors, while its involvement in idiopathic angioedema is still unknown. Bradykinin derives from the cleavage of the high molecular weight kininogen and is catabolized mainly by ACE. During acute attacks of C1-inhibitor deficiency angioedema, high levels of cleaved high molecular weight kininogen (marker of bradykinin generation) were observed, thus indicating that the high concentrations of bradykinin detected in these patients are due to an excess of bradykinin production itself. Instead, during acute attacks of ACE inhibitor angioedema, the plasma levels of bradykinin are elevated without the presence of cleaved high molecular weight kininogen, thus indicating a reduction in bradykinin catabolism. Therefore, since in many cases of angioedema it is not possible to identify the underlying cause, a pathogenetic definition is necessary to adequately treat patients. Our preliminary data regarding 4 patients with non-histaminergic idiopathic angioedema demonstrated bradykinin production during acute attacks of the disease suggesting the potential role of this mediator in the pathogenesis of these forms of angioedema. Based on these observations, we planned a study on a larger cohort of subjects. We planned a study on a cohort of subjects consisting of 50 consecutive patients with angioedema attending the emergency room of our hospital. We will measure the vasoactive mediator bradykinin trying to understand the mechanism of its formation during acute attacks and during the remission phase. The measurement of cleaved high molecular weight kininogen will indicate the mechanism of bradykinin formation. Our group has been dealing with patients with angioedema for more than thirty years and the main problem has always been related to the difficulty in obtaining reliable biological samples during acute attacks. This problem can be solved with the presence of the researcher in the emergency context with the possibility therefore of collecting biological samples at the exact maximum moment of disease activity and during remission. Direct measurement of bradykinin in human plasma is extremely difficult owing to very low bradykinin concentration (pM), to its short half-life (seconds), its ready enzymatic generation and degradation during sampling and handling procedures and interference by precursor molecules, bradykinin catabolic products and other kinin peptides. Reliable data towards plasma bradykinin measurement have been obtained using the blockade of protease and peptidase activity during sampling and a high sensitive method for detection. By solving all these problems, we found increased levels of bradykinin and cleaved high molecular weight kininogen during acute attacks in patients with recurrent angioedema not due to allergies, C1-inhibitor deficiency, ACE inhibitor treatement and non steroidal-antiinflamatory drugs. All patients were treated with systemic steroids and antihistamine but the response to treatment was better in patients with lower levels of bradykinin. Our data suggest that the kinin system is involved at least in some cases of idiopathic angioedema and may influence the response to therapy, especially since effective drugs that block the kinin system are currently widely available. face, neck, extremities and/or submucosal tissues of the oral cavity, larynx and intestine. Patients with angioedema can be clinically critical and require urgent clinical evaluation, especially when angioedema affects the larynx (a life-threatening condition) or the gastrointestinal tract (mimicking an acute abdomen). Angioedema can be acquired or hereditary. The acquired forms may be histaminergic or non-histaminergic, drug-induced or due to an acquired C1-inhibitor deficiency; however, several cases remain idiopathic. The role of bradykinin in increasing vascular permeability has been demonstrated in angioedema due to C1-inhibitor deficiency and in angioedema due to the treatment with angiotensin converting enzyme (ACE) inhibitors, while its involvement in idiopathic angioedema is still unknown. Bradykinin derives from the cleavage of the high molecular weight kininogen and is catabolized mainly by ACE. During acute cleaved high molecular weight attacks of C1-inhibitor deficiency angioedema, high levels of kininogen (marker of bradykinin generation) were observed, thus indicating that the high concentrations of bradykinin detected in these patients are due to an excess of bradykinin production itself. Instead, during acute attacks of ACE inhibitor angioedema, the plasma levels of bradykinin are elevated without the presence of cleaved high molecular weight kininogen, thus indicating a reduction in bradykinin catabolism. Therefore, since in many cases of angioedema it is not possible to identify the underlying cause, a pathogenetic definition is necessary to adequately treat patients. Our preliminary data regarding 4 patients with non-histaminergic idiopathic angioedema demonstrated bradykinin production during acute attacks of the disease suggesting the potential role of this mediator in the pathogenesis of these forms of angioedema. Based on these observations, we planned a study on a larger cohort of subjects. We planned a study on a cohort of subjects consisting of 50 consecutive patients with angioedema attending the emergency room of our hospital. We will measure the vasoactive mediator bradykinin trying to understand the mechanism of its formation during acute attacks and during the remission phase. The measurement of cleaved high molecular weight kininogen will indicate the mechanism of bradykinin formation. Our group has been dealing with patients with angioedema for more than thirty years and the main problem has always been related to the difficulty in obtaining reliable biological samples during acute attacks. This problem can be solved with the presence of the researcher in the emergency context with the possibility therefore of collecting biological samples at the exact maximum moment of disease activity and during remission. Direct meas rement of bradykinin in human plasma is extremely short half-life (seconds), its re difficult owing to very low bradykinin concentration (pM), its dy enzymatic generation and degradation during sampling and handling procedures and interference by precursor molecules, bradykinin catabolic products and other kinin peptides. Reli ble data towards plasma bradykinin measurement have been obtained using the blockade of protease and peptidase activity during sampling and a high sensitive method for detection. By solving all these problems, we found increased levels of bradykinin and cleaved high molecular weight kininogen during acute attacks in patients with recurrent angioedema not due to allergies, C1-inhibitor deficiency, ACE inhibitor treatement and non steroidal-antiinflamatory drugs. All patients were treated with antihistamine but the response to treatment was better in patients sistemic steroids and with lower levels of bradykinin. Our data suggest that the kinin system is involved at least in some cases of idiopathic angioedema and may influence the response to therapy, especially since effective drugs that block the kinin system are currently widely available.