Increased Incidence of Angioedema with ACE Inhibitors in Combination with mTOR Inhibitors in Kidney Transplant Recipients

Abstract

Background and objective: The clinical manifestation of angioedema ranges from minor facial edema up to life-threatening swelling of mouth and throat. Hereditary defects, drugs, and food allergies may play a role in the development of angioedema. We systematically investigated the incidence of angioedema in renal allograft recipients treated with mTOR inhibitors (mTORis).Design, setting, participants, & measurements: All patients in the authors' electronic database who had received mTORis (n ‫؍‬ 309) between 2000 and 2008 were identified. Of these, 137 were additionally treated with angiotensin-converting enzyme inhibitors (ACEis).Results: Nine patients (6.6%, 3.8 per 100 treatment years) developed angioedema after a mean period of 123 days under combined therapy with mTORi and ACEi. Among the remaining 172 patients on mTORi, including 119 patients treated with angiotensin-receptor blockers, only two developed angioedema (1.2%, 0.5 per 100 treatment years, P ‫؍‬ 0.01). In patients receiving mycophenolate and ACEi (n ‫؍‬ 462), 10 instances of angioedema were found (2.1%, 0.8 per 100 treatment years, P ‫؍‬ 0.004).Conclusions: This systematic investigation demonstrated a noticeable incidence of 6.6% angioedema under combined therapy with mTORi and ACEi in kidney transplant recipients. Treatment with either ACEi or mTORi alone resulted in a significantly lower incidence of angioedema, suggesting that this combination should be avoided.

Tuberous sclerosis complex: the past and the future

“…No data are available regarding the treatment of choice for hypertension, regarding neither the incidence of proteinuria nor the effect of long-term use of ACEi in TSC. However, we would like to highlight the increased incidence of angioedema in patients treated with the combination of ACEi and mTORi [50]. This needs to be further elucidated in a large TSC cohort.…”

“…However, the combination of treatment with ACEi and mTORi should be avoided. Duerr et al reported a higher incidence of angioedema under combined therapy with mTORi and ACEi in kidney transplant recipients [50]. There is no recommendation on the evaluation of proteinuria.…”

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

“…The excess risk of angioedema (ranging from minor facial edema up to lifethreatening throat and mouth swelling) associated with mTOR and ACE inhibitor combination therapy could be explained by defective degradation of the vasoactive peptides bradykinin or substance P when ACE is inhibited (20,21). Bradykinin is inactivated by aminopeptidase P (22), whereas substance P is inactivated by dipeptidyl peptidase IV (23).…”

ACE inhibitor‐associated intestinal angioedema in orthotopic heart transplantation

“…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.…”