Comparisons of incidence are performed by calculation of relative rates and confidence interval between the different groups. 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, = 0.01). In patients receiving mycophenolate and ACEi (= 462), 10 instances of angioedema were found (2.1%, 0.8 per 100 treatment years, = 0.004). Conclusions: This systematic investigation exhibited 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. Depending on its magnitude and localization, the clinical picture of angioedema varies widely from moderate self-limiting facial edema up to life-threatening swelling of lips, tongue, or throat. Underlying etiologies include hereditary defects of complement inhibitor C1, drugs, and food allergies (1,2). Increased bradykinin levels may play a role in the development of angioedema; however, the exact pathophysiology of angioedema remains unclear (3). One of the most frequent causes of angioedema is use of angiotensin-converting enzyme inhibitors (ACEis), which are estimated to be responsible for 10% to 25% of all cases of angioedema (4). ACEis are widely used in patients with hypertension, heart failure, kidney diseases, or diabetes because of their convincing efficacy. It has been suggested that ACEi increases the risk of angioedema, most likely due to vasodilatation as a consequence of reduced bradykinin degradation (3). Initial data around the occurrence of angioedema under ACEi therapy came from registration trials and pharmacovigilance registries, but only recent large prospective trials provided reliable insight on the incidence of this rare side effect. In the randomized, double-blind OCTAVE trial with 12,000 patients, angioedema occurred in 0.68% of ACEi-treated patients (5). More recently, an overall incidence of 0.3% (= 25 of 8576) Ibrutinib-biotin angioedema was reported for ACEi during the ONTARGET study (6). In contrast, the use of angiotensin-receptor blockers (ARBs) was associated with a much lower risk of angioedema (0.1%; = 10 of Ibrutinib-biotin 8542 patients) in this trial. Thus, ARBs may be applied to patients with ACEi-induced angioedema, although 2 of 26 patients with angioedema due to ACEi therapy had also angioedema with ARBs (7). Approximately 60% of ACEi-induced angioedemas start within 1 week, but ACEi-induced angioedema may occur even after years (8). Higher incidence of angioedema under treatment with mTOR inhibitor (mTORi) in organ-transplanted patients has been implicated in case series and several case reports (9C13). Because we were confronted with comparable patients in our outpatient clinic, we initiated a systematic search in our database to investigate frequency and clinical course of angioedema in a larger cohort of kidney transplant recipients. Materials and Methods We conducted a retrospective, single-center analysis of all renal transplant recipients listed with their patient records in our electronic medical database Tbase (14). Starting in 1999, all medications, laboratory data, and the clinical course of all renal allograft recipients (= 1618) treated in our department (including all 763 transplantations performed in our hospital since 1999, 1000 waitlisted patients, all 754 patients undergoing transplantation in our hospital before 1999, and all patients undergoing transplantation who frequented our outpatient clinic at least Rabbit polyclonal to FOXQ1 once between 1999 and 2008) are compiled in the database with currently more than 2800 patient entries, corresponding to more than 3 billion lab values and 100,000 medication data. We set January 1, 2000 (the year of sirolimus approval in Germany), as the starting point of our analysis, which ended on December 31, 2008. During this period, a total of 1111 renal transplant patients were treated in our department with their data joined in the database. We first started to identify all patients under therapy with mTORi (= 309); either sirolimus (= 144) or everolimus (= 165), ACEis (= 617), ARBs (= 372), and mycophenolate (MPA; = 871). ACEis and ARBs were identified with the corresponding anatomical therapeutic chemical codes. Start and end dates of each medication were captured. Next, we selected all patients with combined therapy of mTORi plus ACEi (= 137); Ibrutinib-biotin mTORi plus ARBs (= 119); or MPA plus ACEi (= 460), including start and end dates of combination therapy. Of special interest were the date and medical reason for discontinuation of mTORi, ACEi, and ARBs, because we hypothesized that this development of angioedema could be one reason to discontinue therapy. Additionally, our database was queried for the following clinical terms: swelling, quincke-edema, angioedema, and laryngeal edema. Finally, we performed a systematic review of patient medical characteristics during each event of angioedema. Statistical Analyses The incidences of angioedema under different treatment modalities are calculated as the number of events divided by the time of respective therapy and expressed.