Sirolimus (SRL) is a macrolide immunosuppressant that has gained widespread use in organ transplantation. Its full spectrum of side-effects is yet to be defined. We describe herein three cases of SRL-induced angioedema (AE) in African-American (AA) primary renal allograft recipients who received SRL in combination with mycophenolate mofetil and steroids. In two cases, AE manifested after SRL was restarted after a period of discontinuation. The third case presented upon initial exposure to the drug. None of the patients was receiving any drug that has been previously associated with AE. Complete resolution occurred only after SRL was withdrawn. AE has not recurred in any of the patients during a follow-up period of up to 21 months. We conclude that AE is a previously unrecognized adverse event associated with SRL use. Close monitoring for this side-effect, especially in AA patients, is warranted.
Sirolimus (SRL) is a macrolide antibiotic with anti-proliferative properties that has proven effective in reducing the risk of acute rejection in solid-organ transplantation. Although the hyperlipidemic and myelosuppressive effects of SRL are well-established, its full side-effect profile is yet to be elucidated. In this report, we present three cases of angioedema (AE) associated with SRL use. To our knowledge, this is the first description of such an association.
A 49-year-old African-American (AA) male with a history of hypertension and end-stage renal disease (ESRD) secondary to focal segmental glomerulosclerosis received a deceased-donor renal transplant in January 2002. His immunosuppressive regimen included Thymoglobulin for induction, and mycophenolate mofetil (MMF), SRL, and tapering doses of steroid for maintenance therapy. SRL was started on post-operative day (POD) 3, with target trough levels 12–15 ng/mL. His course was complicated by delayed graft function (DGF) secondary to acute tubular necrosis, necessitating dialysis for the first month post-transplant. His renal function subsequently stabilized, with serum creatinine levels in the 3.0–4.0 mg/dL range. SRL was held for 1 week beginning on POD 20 secondary to thrombocytopenia. Four weeks after it was restarted, the patient presented with diffuse facial swelling, periorbital edema, and dysphonia. His medications at that time included SRL 19 mg qd, prednisone 15 mg qd, MMF 500 mg bid, amlodipine 10 mg qd, minoxidil 5 mg bid, metoprolol 100 mg bid, clonidine 0.2 mg bid, trimethoprim/sulfamethoxazole 1 single-strength tablet qd, and valganciclovir 450 mg qd. There was no previous history of drug allergy. Examination showed diffuse swelling of the face, tongue, and floor of the mouth. He did not have lower extremity edema or skin rash. Indirect laryngoscopy revealed swelling of the epiglottis and floor of the mouth. At the time of presentation, SRL trough level and serum creatinine were 10.3 ng/mL and 3.5 mg/dL, respectively, and there was no eosinophilia. Parenteral steroids together with oral diphenhydramine and ranitidine were started with improvement of the patient's symptoms, but the AE did not completely resolve until after SRL was discontinued, 2 d after his initial presentation. Tacrolimus was started as an outpatient with no other changes made in his drug regimen. AE did not recur during the subsequent 21 months of follow-up.
A 54-year-old AA male with ESRD secondary to diabetic nephropathy received a deceased-donor renal transplant in June 2002. Basiliximab was used for induction, and he was started on MMF and prednisone. His post-operative course was complicated by DGF due to acute tubular necrosis, and the patient was dialysis-dependent for 3 weeks post-transplant. SRL was started on POD 4, with target trough levels of 12–15 ng/mL. Three weeks after starting SRL, the patient was switched to tacrolimus because of thrombocytopenia. However, his diabetes became more difficult to control, and 7 weeks later, he was converted from tacrolimus back to SRL. After receiving 3 daily doses of SRL (5 mg, 10 mg, and 5 mg), the patient presented with fever, change in tone of voice, and diffuse facial and periorbital swelling. He did not have pruritis or hives. His medications included prednisone 7.5 mg qd, MMF 250 mg bid, rosiglitazone 4 mg bid, insulin 70/30, furosemide 80 mg bid, minoxidil 5 mg bid, and metoprolol 50 mg bid. There was no history of drug allergy. Physical examination revealed diffuse swelling of the eyelids, floor of the mouth, tongue, and soft palate. Indirect laryngoscopy revealed diffuse laryngeal swelling with epiglottic edema and without critical airway obstruction. SRL trough level and serum creatinine were 3.1 ng/mL and 2.1 mg/dL, respectively, and complete blood count did not reveal eosinophilia. Chest X-ray showed a left perihilar and basilar infiltrate, and oral antibiotic therapy was begun. SRL was discontinued, and the patient was treated with parenteral steroids, diphenhydramine, and ranitidine. AE resolved completely within 2 d, and the patient was converted to cyclosporin A-based immunosuppression. AE has not recurred in the subsequent 12 months.
A 56-year-old AA male with a history of congestive heart failure, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea and ESRD secondary to hypertension underwent deceased-donor renal allografting in December 2002. He received basiliximab for induction, and was maintained on tacrolimus, MMF, and prednisone post-operatively. His serum creatinine was 2.1 mg/dL at the time of hospital discharge on POD 6. The patient subsequently developed post-transplant diabetes mellitus, and required hospital admissions for exacerbation of congestive heart failure and upper gastrointestinal tract bleeding from erosive esophagitis. Three months after transplantation, the patient's serum creatinine increased to 3.2 mg/dL, and a transplant kidney biopsy showed evidence of calcineurin inhibitor toxicity. Tacrolimus was then switched to SRL, with a target trough level of 10–12 ng/mL. Two weeks after starting SRL, the patient reported a change in tone of voice, followed by diffuse facial swelling and worsening dyspnea. He denied any itching or hives. There was no history of drug allergy. His medications at that time included prednisone 7.5 mg qd, MMF 500 mg bid, SRL 4 mg qd, amlodipine 10 mg qd, minoxidil 10 mg bid, metoprolol 50 mg qd, atorvastatin 10 mg qd, aspirin 81 mg qd, clopidogrel bisulfate 75 mg qd, and pantoprazole 40 mg bid. On physical examination, the patient had diffuse facial swelling, especially affecting the eyelids, and swelling of the tongue and floor of the mouth. Indirect laryngoscopy revealed edema and erythema of the epiglottis and arytenoids without critical airway compromise. At presentation, SRL trough level and serum creatinine were 19.4 ng/mL and 2.1 mg/dL, respectively, and there was no eosinophilia. With the diagnosis of AE, parenteral steroids, diphenhydramine, and ranitidine were started and SRL was held. A repeat indirect laryngoscopy 2 d later showed resolution of the epiglottic and arytenoid edema. At that time, parenteral steroid was switched to oral prednisone, and the SRL trough level was down to 7 ng/mL. However, the patient inadvertently received two more daily 4 mg doses of SRL, and the AE recurred with significant facial swelling, difficulty breathing, and nasal tone of voice. SRL was then switched to cyclosporin A, and the AE again responded to adjunctive parenteral followed by oral steroid therapy. No other medication changes were made. There has been no recurrence of AE in the subsequent 11 months.
SRL is a macrolide antibiotic with potent immunosuppressive and anti-proliferative effects. Because of its proven efficacy, once-daily dosing, lack of nephrotoxicity, and potential for use in calcineurin-inhibitor free and dose-reduction protocols (1,2), SRL is being used more widely by many transplant centers. Increasing use of SRL would be expected to reveal more of its adverse effects.
In clinical studies, thrombocytopenia and dyslipidemia were the major side-effects associated with SRL use. Other common adverse effects include anemia, leukopenia, elevated liver enzymes, and acne. Post-marketing experience with SRL has demonstrated an increased incidence of lymphoceles and wound complications, including delayed wound healing, hematomas, and hernias (3,4). Moreover, there are also reports relating SRL administration to development of interstitial pneumonitis, leukocytoclastic vasculitis, and thrombotic microangiopathy (5–7). Mohaupt et al. (8) described the development of eyelid edema in five renal allograft recipients on SRL. To our knowledge, this is the first report of AE secondary to use of SRL.
AE is an episodic allergic condition that commonly manifests as isolated or diffuse nonpitting edema of the face, the floor of the mouth, and larynx. Most cases of AE result from a reaction to food or drugs, but some episodes have no identifiable trigger. Penicillins, ACE inhibitors, sulfonamides, aspirin, and nonsteroidal anti-inflammatory drugs are the most common drug classes related to AE. AE can be induced by various mechanisms, including IgE-mediated pathways, inhibition of the cyclooxygenase pathway of arachidonic acid metabolism, activation of the kinin-forming system, and complement activation. All these mechanisms induce AE via the release of vasoactive mediators, such as bradykinin, that increase vascular permeability with subsequent fluid accumulation in the subcutaneous tissues. Most cases of AE are associated with urticaria. However, in AE caused by excessive activation of the complement or kinin systems urticaria is characteristically absent (9). Moreover, AE can also result from either hereditary or acquired disorders of the complement system, associated with deficient C1 esterase inhibitor activity. This can lead to activation of C4 and release of vasoactive anaphylatoxins (10).
Interestingly, AE is more commonly seen in the AA population (11). In a study by Chiu et al. (12), AAs accounted for 90% of cases with AE treated in two tertiary care centers. Cohen et al. (13) noted that 94% of patients who presented with AE, including 92% of those with ACE inhibitor-induced disease, were AA. In another study, the adjusted relative risk of AE among AAs taking ACE inhibitors was found to be 4.5 when compared with Caucasians (14). Along these lines, Gainer et al. (15) have hypothesized that AAs may be more sensitive to the effects of endogenous or exogenous bradykinin.
Little is known about the occurrence of AE in transplant patients. Abbosh et al. (16) reported a 24-fold and fivefold higher incidence of AE in cardiac and renal transplant recipients, respectively, who were maintained on cyclosporin A, azathioprine, and prednisone when compared with the general population. Five of the six cases occurred in AA patients on maintenance ACE inhibitor treatment.
In our cases, the temporal relationship of AE to the start and discontinuation of SRL, as well as the absence of other AE-associated medications, made SRL the most likely cause for inducing the AE. Although minoxidil may produce salt retention, none of our patients presented with peripheral edema, and it has not been associated with AE. Our cases differ markedly from the patients described in the previous report of Mohaupt et al. (8), who noted unilateral and bilateral eyelid edema in 5 out of 11 patients treated with SRL. Development of eyelid edema was gradual, occurring over 1–5 months after starting SRL. The edema was mild in three cases, and reduction of SRL dose was not warranted. In the other two patients, discontinuation of SRL was followed by delayed resolution of the swelling, with full recovery taking as long as 7 months in one case.
Among our three patients, AE occurred in the first two following re-exposure to SRL, while in the third case it manifested during the initial drug exposure, and recurred upon re-initiation of the drug. At presentation, the first two patients had a SRL trough level at or below the target level, while the third patient had a trough level in the toxic range. The time period from starting SRL to the occurrence of AE ranged from 3 d to 4 weeks. In all cases, the condition responded promptly to parenteral steroids, H1 and H2 blockers, and discontinuation of SRL.
The underlying mechanism of SRL-induced AE in these patients is unknown. The absence of urticaria makes a complement- or bradykinin-mediated mechanism more likely. Because AE occurred only after the drug was reintroduced in two of our three cases, an antibody-mediated mechanism can be postulated. This antibody could be directed against C1 esterase inhibitor, with subsequent activation of C4 and an increase in vasoactive anaphylatoxins. The higher dose of maintenance steroids at the time of re-initiation of the drug (15 mg compared with 7.5 mg) could be the reason that the first case presented after 4 weeks of SRL therapy, in contrast to the second patient, who presented after only 3 d. The occurrence of AE after initial exposure to the drug in the third case could be due to previous exposure to a cross-reactive antigen, or possibly to a direct effect of SRL on the kinin system or other vasoactive mediator(s). The occurrence of AE in association with a toxic drug level in this case may suggest a threshold effect for activation of such mediators. One could also speculate that the much higher steroid doses utilized in the immediate post-transplant period might have masked the effects of SRL in inducing AE at that early time point, and that the AE only became evident after the steroid dose was reduced. Notably, all three patients in our series were AAs; an observation that supports the reported propensity of this group to develop AE.
In summary, SRL is a potent immunosuppressant and anti-proliferative agent whose full spectrum of adverse effects is yet to be defined. In this report, we described three cases of SRL-induced AE. The precise mechanism by which this side-effect occurs remains unclear. Early diagnosis and discontinuation of the drug in conjunction with a short course of high-dose steroids and histamine receptor blockers will result in prompt resolution of the syndrome. Close monitoring of patients who receive SRL, especially AAs, for development of this side-effect is warranted.