Pericardial Effusion Associated With Sirolimus Use After Renal Transplantation: A Single-Center Case Series Reynold I. Lopez-Solera,*, Sunil K. Patela, Ramila Lyubarovab, Eugene Pashkovetskyb, Stephani Wangc, Daniel Schusterd, Nikolaos Chandoliase, and David Contia aDivision of Surgery, Section of Transplantation, Albany Medical Center, Albany, NY, United States; bDepartment of Medicine, Division of Cardiology, Albany Medical College, Albany, NY, United States; cDepartment of Medicine, Albany Medical College, Albany, NY, United States; dDepartment of Surgery, Albany Medical College, Albany, NY, United States; and eDepartment of Transplantation, Einstein Medical Center, Philadelphia, PA, United States ABSTRACT Pericardial effusion and cardiac tamponade following renal transplantation have been recognized as a potentially serious complications associated with the use of sirolimus for immunosuppression. Our study aims to analyze the development of sirolimus-associated pericardial effusion. Patients who underwent renal transplantation at our institution between 2001 and 2014 were reviewed and the correlation between sirolimus exposure and pericardial effusion was determined. Nineteen out of 792 patients who received a renal transplant over this 14-year period (incidence 2.4%) developed symptomatic pericardial effusion (determined by the need for pericardiocentesis or a pericardial window). All patients had a pre-transplantation cardiac workup, including echocardiogram, which did not reveal the presence of pericardial effusion. Our cohort of patients is mostly male (57.9%) and Caucasian (73.7%), which is consistent with the makeup of transplant recipients at our center. The mean age was 52.42 years at the time of transplantation. The development of symptomatic pericardial effusions occurred at a mean of 5.06 (.5e9.8) years after renal transplant while on sirolimus therapy. Sirolimus levels at diagnosis were 5.19e7.47 ng/mL. No significant pericardial effusion (resulting in tamponade physiology) recurred after therapeutic intervention, including cessation of sirolimus with or without pericardial drainage. This study is the largest single- center report of the possible association between pericardial effusion in renal transplant recipients who received sirolimus. Due to the widespread use of sirolimus in organ transplantation, clinicians must remain vigilant for this potential cardiac complication. N important consideration in selecting an immuno- transduction to induce cell cycle arrest in G1- to S-phase [3]. A suppressive regimen is balancing efficacy with side One of the advantages of sirolimus is its decreased long- effects and complications. Sirolimus, isolated in 1972 from term nephrotoxicity compared to calcineurin inhibitors the bacterium Streptomyces hygroscopicus, was approved for resulting in improved long-term glomerular filtration rate use in transplant recipients in 1999 for both kidney and liver [4,5]. Interestingly, sirolimus has both innate antiviral and transplantation. Sirolimus is an inhibitor of antineoplastic properties [6,7]. The antineoplastic effects of cytokine-receptor signal transduction resulting in impaired T-cell proliferation [1,2]. Mechanistically similar to tacroli- mus, sirolimus binds to a family of immunophilins called *Address correspondence to Reynold I. Lopez-Soler, MD, PhD, FK-binding protein 12 (FKBP12), and instead of targeting FACS, Albany Medical College, Department of Surgery, Division calcineurin the sirolimus-FKBP12 complex targets and in- of Transplantation, 43 New Scotland Ave, Albany, NY 12208- hibits the mammalian target of rapamycin (mTOR). mTOR 3479, United States. Tel: (518) 262-5614; Fax: (518) 262-5571. inhibition leads to decreased interleukin 2 signal E-mail: [email protected] ª 2019 Elsevier Inc. All rights reserved. 0041-1345/19 230 Park Avenue, New York, NY 10169 https://doi.org/10.1016/j.transproceed.2019.04.043 Transplantation Proceedings, 51, 1739e1743 (2019) 1739 1740 LOPEZ-SOLER, PATEL, LYUBAROVA ET AL sirolimus were demonstrated in 2 studies that showed Table 1. Immunosupression Protocol ’ decreased incidence of dermal Kaposi s sarcoma in renal Induction þ transplant patients and remission of AKT ( ) lymphoma in Thymoglobulin .5e1.0 mg/kg/d for a total mice when combined with doxorubicin [8,9]. Liacini et al dose of 4e5 mg/kg* also found sirolimus and leflunomide combination therapy Solumedrol Day 0, 375 mg; Day 1, 200 mg; to be effective for post-transplant BK viral infection through Day 2, 160 mg; Day 3, 120 mg; protein kinase pathway inhibition [10]. These characteristics Day 4, 80 mg; Day 5, 40 mg; make sirolimus an attractive alternative for long-term Day 6, 20 mg e † immunosuppression. However, toxicity associated with Tacrolimus 8 10 ng/mL on discharge Mycophenolate Mofetil Days 0e5, 2 g/d; Day 6, 1 g/d sirolimus spans multiple systems: peripheral edema ‡ Sirolimus Day 6, 8e10 ng/mL (20%-58%), hypertension (49%), deep vein thrombosis, Maintenance pulmonary embolism, hypertriglyceridemia (45%-57%), Tacrolimus Day 90 (discharge), 8e10 ng/mL, anemia (23%-33%), thrombocytopenia (14%-30%), then 2 ng/mL† leukopenia, lymphocele, cytomegalovirus, and Epstein-Barr Mycophenolate Mofetil 1 g/d infection, focal segmental glomerulosclerosis, hepatotoxici- Sirolimus 8e10 ng/mL‡ fi ty, interstitial pneumonitis, pulmonary brosis, pleural *Dose reduced secondary to thrombocytopenia/leukopenia. †12-hour trough. effusion, and lymphedema with ascites [2,11,12]. Recently, ‡ pericardial effusion with or without associated tamponade 24-hour trough. physiology has been described as a potential complication of sirolimus use. However, there is a paucity of data on this were carefully reviewed to extract relevant demographic data, time period from transplant to development of pericardial effusion, condition, despite the associated potential for mortality and treatment received, range of sirolimus levels at the time of diag- morbidity. In this study, we present a single-center case nosis, clinical characteristics (other immunosuppression medica- series, the largest to date, from our institution, focusing on tions, comorbidities, cause of end-stage renal disease), and 19 renal transplant recipients who were all treated with outcomes of intervention. Patients with pericardial effusion and combination immunosuppression including sirolimus (from co-morbid conditions such as lymphoma, graft failure, and previous 792 total patients) who developed symptomatic pericardial coronary artery disease needing cardiac interventions were excluded effusions with and without tamponade physiology. Our from our analysis. center has one of the richest experiences in the use of All patients diagnosed with pericardial effusion were assessed sirolimus as part of a long-term immunosuppression with transthoracic echocardiograms performed by experienced regimen [13]. We analyzed demographic and outcome pa- technicians. Studies were read by experienced cardiologists at our institution. Based on transthoracic echocardiogram, pericardial rameters to determine the incidence of pericardial effusion effusion was graded as small (less than 1 cm in dimension), mod- post-transplant. Because symptomatic pericardial effusions erate (1e2 cm), or large (>2 cm) effusions. can present as life-threatening late complications associated The protocol of this study was approved by our institutional with sirolimus use in renal transplant patients, we aim to review board. highlight our experience. RESULTS MATERIALS AND METHODS Demography of Patients Who Developed Symptomatic We retrospectively reviewed the electronic medical record database Pericardial Effusions While on Sirolimus at our institution, focusing on all renal transplant recipients who A total of 792 renal transplants were performed at Albany received sirolimus between January 2001 and December 2014 as Medical Center between 2001 and 2014, and 19 patients part of their maintenance immunosuppression regimen. In our with a functioning graft at the time of this study (incidence institution, all patients receive a standard post-transplant regimen that includes thymoglobulin (4e5 mg/kg) for induction, and are 2.4%) were found to have a symptomatic pericardial effu- subsequently placed on a combination of tacrolimus, sirolimus, and sion while being maintained on sirolimus as part of their mycophenolate mofetil (MMF) for maintenance immunotherapy immunosuppression regimen. Table 2 illustrates the (see Table 1, reprinted with permission from [13]). Per our proto- demographic characteristics of the study population. The col, sirolimus is introduced on post-transplant day 7 without a median age at time of transplantation was 52.31 years old. loading dose. Serum sirolimus concentrations were maintained at Patients were predominantly male (57.9%) and Caucasian 4e6 ng/mL in the first 3 months and 6e9 ng/mL at 3 months and (73.7%). Most of the patients received deceased donor after, with parallel minimization of tacrolimus dosing (Table 1). renal transplants (89.5%), with primary cause of end-stage fi A total of 31 patients were identi ed through our electronic renal disease being diabetes and/or hypertension. Patients medical record system by searching for a diagnosis of renal trans- underwent an extensive pre-transplant cardiac workup plant and pericardial effusion or cardiac tamponade. Out of those 31 patients, 19 met our inclusion criteria, which were 1. renal including echocardiogram, electrocardiogram, and cardiac transplant patients with a functioning graft at the time of diagnosis