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Sirolimus and ACE-Inhibitors: A Note of Caution

2005; Wolters Kluwer; Volume: 79; Issue: 2 Linguagem: Inglês

10.1097/01.tp.0000140966.13047.85

1534-6080

Manuel Burdese, Maura Rossetti, Cesare Guarena, Valentina Consiglio, Elisabetta Mezza, Giorgio Soragna, Massimo Gai, Giuseppe Segoloni, Giorgina Barbara Piccoli,

Drug-Induced Adverse Reactions

Sirolimus is a promising immunosuppressive drug, whose use in renal transplantation is particularly advantageous because of the lack of nephrotoxicity. Like most potent drugs, it has peculiar and occasionally severe side effects (common: thrombocytopenia, dyslipemia, retarded wound healing, hypertension; rare: bone pain, abacterial pneumonia, persistent acute tubular necrosis) (1–3). ACE-inhibitors have three major indications in renal transplantation (antihypertensive, nephro-protective, and active in posttransplant erythrocytosis). An important side effect is the pro-allergic profile, but ACE-inhibitors are not considered to interfere with sirolimus (4). Of note, anaphylactoid reactions are very uncommonly reported and the cases so far published mainly deal with specific types of dialysis membrane, LDL apheresis, or rare situations such as Venom immunotherapy (5–6). Here we report on two renal graft patients who developed an acute, severe allergic reaction when sirolimus and ACE-inhibitors were combined. Case 1: 54-year-old woman, on RRT for 29 years (glomerulonephritis), recipient of a second kidney graft (initial immunosuppression with tacrolimus and steroid, followed by a reduction of tacrolimus levels to 4–7 ng/mL, and the addition of mycophenolate). Renal function was suboptimal (at hospital discharge, serum creatinine 1.8 mg/dL) and blood pressure control difficult. ACE-inhibitors were started at low doses (enalapril 2.5 mg/day) 2 years after the graft, with improvement in blood pressure control and without a creatinine increase (2.5–2.8 mg/dL at the time). Two months later, a renal biopsy showed severe vascular damage, with signs of tacrolimus nephrotoxicity. Sirolimus was added to allow tacrolimus withdrawal. At that time, therapy consisted in sirolimus 2 mg, MMF 1,000 mg, prednisone 10 mg, furosemide 50 mg, atenolol 50 mg, felodipine 15 mg, aspirin 50 mg, and erythropoietin beta 12,000 units/week. Nine days after the start of sirolimus, she developed an urticaria-like erythematous skin lesion, with localized non-pitting oedema, involving the face, neck, and upper thorax. Enalapril was stopped. Prednisone was up-titrated (25 mg/day, tapered to the previous levels within 1 week), with prompt resolution of the clinical picture. Case 2: a 61-year-old man, on RRT since the age of 56 years (APKD). He received a kidney graft in August 2002 (immunosuppression with sirolimus, mycophenolate, and steroid; serum creatinine 2.2 mg/dL at 4 months). Ramipril was added at the fifth month after the graft, for antihypertensive and nephro-protective purposes. The patient did not take the drug regularly until May 2003; chronic therapy consisted in: sirolimus 9 mg, MMF 1,000 mg, methylprednisolone 4 mg, atenolol 100 mg, calcitriol 25 mcg, pantoprazole 20 mg, and erythropoietin beta 18,000 units/week. After few days of regular ramipril therapy, he suddenly developed non-pitting edema, involving the left cheek, eyelid, and lips, with paresthesia and respiratory distress. Sirolimus and ramipril were both withdrawn, mycophenolate was increased to 2 g, and methylprednisolone to 8 mg. A daily intravenous infusion with methylprednisolone 100 mg was performed for the following 3 days. Respiratory symptoms rapidly improved and the facial oedema resolved over the next 10 days. Sirolimus was immediately restarted (1 mg, slowly up-titrated to 6 mg/day) without problems. While only a potentially harmful pharmacologic challenge would definitely prove the presence of an allergic reaction triggered by either sirolimus or ACE-inhibitors, these two cases suggest caution when either drug is added to a chronic regimen. Manuel Burdese Maura Rossetti Cesare Guarena Valentina Consiglio Elisabetta Mezza Giorgio Soragna Massimo Gai Giuseppe Paolo Segoloni Giorgina Barbara Piccoli Department of Nephrology University of Torino Torino, Italy