Unilateral Upper Extremity Edema Associated with Sirolimus in a Heart Transplant Patient

Abstract

The use of sirolimus (SRL) as both a primary immunosuppressive medication and a substitute after the onset of calcineurin inhibitor-induced renal dysfunction has steadily increased. Reported complications of SRL include hyperlipidemia, lymphocele, acne, pneumonitis, eyelid edema, angioedema, and bone marrow toxicity (1, 2). Three recent reports of unilateral lymphedema in kidney transplant recipients on SRL have also been described (1–3). We report the case of a heart transplant patient taking SRL who developed unilateral edema. A 71-year-old man received a heart transplant in July 1991 for ischemic heart disease. His past medical history was significant for hypertension and sebaceous cell carcinoma of the eyelid treated with excision. His immunosuppressive regimen consisted of prednisone and SRL, started in January 2002 for renal dysfunction secondary to cyclosporine, with a maintenance dose of 2 mg daily. In December 2005, the patient presented with progressive facial and painful nonpitting edema of the right arm. He had no family history of lymphedema and there was no evidence of either malignancy or local infection. SRL levels were <2.5 ng/mL. The SRL dose was progressively reduced to 1 mg every three days with no effect on the upper extremity edema. Ultrasound imaging and venogram of the right upper extremity ruled out deep vein thrombosis. Two months after initial presentation, SRL was discontinued and the patient was started on mycophenolate mofetil (500 mg BID) and Zenapax (Hoffman La-Roche, Mississauga, Ontario, Canada) for the prophylaxis of acute rejection. Zenapax (1.5 mg/kg) was given every two to three months, aiming for CD25 expression <2% (4). Six weeks after stopping SRL, the right arm edema had resolved completely and control endomyocardial biopsy was normal. To the best of our knowledge, this is the first report of unilateral edema in a cardiac transplant patient treated with SRL. The major differences between previous reports and the present case are the type of transplant operation and the lack of hemodialysis access in the edematous arm. Past studies have suggested that a combination of increased lymphatic outflow secondary to SRL and disruption of normal lymphatic drainage channels by both hemodialysis access and the kidney transplant operations themselves were the causes of unilateral lymphedema in those patients (1, 3). The lack of lymphatic studies represents the major limitation of the present case. It remains unclear whether the unilateral upper-extremity edema resulted specifically from lymphedema or from another fluid type. However, the clinical features were more consistent with lymphedema. As previously reported, SRL may enhance lymphatic flow by inducing vasodilation and increasing vascular permeability (3). The combination of massive disruption of lymphatic flow associated with the cardiac transplant operation and the use of SRL may have lead to such an unusual clinical presentation. While previously recognized only in kidney transplant recipients, it seems that unilateral edema also may be seen in other solid organ transplant patients taking SRL. Additional studies are warranted to confirm the pathophysiology of this complication. Moreover, careful monitoring, early recognition and aggressive treatment are indicated to avoid permanent disfigurement and the development of further complications. Alfred Papali Nadia Giannetti Marcelo Cantarovich Department of Medicine Multi-Organ Transplant Program McGill University Health Center Montréal, Québec, Canada