Association of angiotensin‐converting enzyme inhibitor‐associated angioedema with transplant and immunosuppressant use

Abstract

Background Immunosuppressants decrease circulating dipeptidyl peptidase IV (DPPIV) activity in transplant patients, and decreased DPPIV activity has been associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. One study has reported an increased incidence of ACE inhibitor-associated angioedema among transplant patients compared to published rates, while several case series report angioedema in patients taking specific immunosuppressant agents. Objective To test the hypothesis that transplant patients are at increased risk of ACE inhibitor-associated angioedema. Methods We assessed the proportion of transplant patients in 145 cases with ACE inhibitor-associated angioedema and 280 ACE inhibitor-exposed controls. We measured the relationship between case–control status, transplant status, and immunosuppressant use and circulating DPPIV activity. We also assessed the incidence of angioedema among consecutive patients who underwent renal or cardiac transplant and were treated with an ACE inhibitor. Results Transplant patients were significantly overrepresented among ACE inhibitor-associated angioedema cases compared to controls (odds ratio 18.5, 95% CI 2.3–147.2, P = 0.0004). Immunosuppressant use, chronic renal failure, seasonal allergies and smoking were also associated with ACE inhibitor-associated angioedema in univariate analysis. The association of transplant status with ACE inhibitor-associated angioedema was no longer significant after inclusion of immunosuppressant therapy in a multivariate analysis. Dipeptidyl peptidase IV activity was significantly decreased in sera from cases compared to ACE inhibitor-exposed controls, as well as in individuals taking immunosuppressants. Two of 47 ACE inhibitor-treated renal transplant patients and one of 36 ACE inhibitor-treated cardiac transplant patients developed angioedema. Conclusion Transplant patients are at increased risk of ACE inhibitor-associated angioedema possibly because of the effects of immunosuppressants on the activity of DPPIV.

ACE inhibitor‐associated intestinal angioedema in orthotopic heart transplantation

“…Use of immunosuppressive medications with ACE inhibitors is a risk factor for angioedema among patients on immunosuppression, including the heart transplant population 2, 3, 4, 5, 6, 7. Isolated involvement of the gastrointestinal tract is a rare presentation of ACE inhibitor induced angioedema.…”

“…Although not definitively demonstrated in humans, one hypothesis is that immunosuppressive agents increase this risk by decreasing the activity of circulating dipeptidyl peptidase IV (both dipeptidyl peptidase IV and ACE inactivate vasodilatory bradykinin and substance P). This effect is seen with both calcineurin and mTOR inhibitors but is greater with the latter 2, 8. Reports have demonstrated episodes of facial and sublingual angioedema in kidney transplant patients on mTOR inhibitors without concomitant use of an ACE‐inhibitor 4, 9.…”

“…Despite the increasing incidence of ACE inhibitor‐induced angioedema in patients taking calcineurin inhibitors,2, 3, 4, 5, 6, 7, 8, 9 extrapolation of basic science studies suggests that mTOR inhibitors pose a greater risk to interact with ACE inhibitors. Physicians prescribing mTOR inhibitors should have knowledge of the potential interaction.…”

Arzneimittelassoziierte Angioödeme

“…Es wurde spekuliert, dass Immunsuppressiva das Risiko für ACE-Hemmerinduzierte Angioödeme erhöhen, indem sie die Aktivität von DPP-IV reduzieren [67]. Dieser Überlegung liegen die Beobachtungen zugrunde, dass DPP-IV (auch als Oberflächenmarker CD26 bekannt) eine Rolle bei der Aktivierung und Proliferation von T-Lymphozyten spielt [61,67].…”

“…Dieser Überlegung liegen die Beobachtungen zugrunde, dass DPP-IV (auch als Oberflächenmarker CD26 bekannt) eine Rolle bei der Aktivierung und Proliferation von T-Lymphozyten spielt [61,67]. Immunsuppressiva erniedrigen die Expression von CD26 auf T-Lymphozyten und die Aktivität des zirkulierenden DPP-IV [67].…”