Sirolimus (INN) is a relatively new immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. It is also known as rapamycin. Sirolimus is a macrolide antibiotic (”-mycin”) first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from an island called Rapa Nui, better known as Easter Island. It is marketed under the trade name Rapamune by Wyeth.
Interestingly, sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.
Clin Transplant. 2008 Mar-Apr
Bartolomeis CD, Collini A, Rumberger B, Barni R, Ruggieri G, Bernini M, Carmellini M. UOC Chirurgia dei Trapianti-Azienda Ospedaliera Universitaria Senese, Siena, Italy. email@example.com
Generalized lymphedema is an extremely rare effect of sirolimus therapy in renal transplant recipients. We describe the development of this complication in a 56-yr-old woman, who was given an experimental protocol with cyclosporine, sirolimus, steroids, and basiliximab. Following the protocol, after one month, the patient was randomized to the “sirolimus only” group, while cyclosporine was completely suspended and the oral steroids were continued. Three months later, the patient was admitted for severe lymphedema of the lower limbs, with significant weight increase, massive ascites and dyspnea, but excellent renal function. A chest radiography and an ultrasound study of the heart showed a moderate pleural and pericardial effusion. An abdominal ultrasound scan showed two small lymphoceles next to the transplanted kidney, confirmed with a CT scan. After sirolimus discontinuation the generalized lymphedema started to improve and three months later all the symptoms had disappeared.
Br J Dermatol. 2009 Jun
Desai N, Heenan S, Mortimer PS. Department of Dermatology, St George's Hospital, Tooting, London, UK. firstname.lastname@example.org
KEYWORDS: lymphedema • mammalian target of rapamycin inhibitor • rapamycin • sirolimus • vascular endothelial growth factor C • vascular endothelial growth factor receptor 3
Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is increasingly used as an agent for post-transplant immunosuppression and the treatment of solid organ and haematological malignancies and hamartomas. Its advantages include a lack of nephrotoxicity and a lower incidence of nonmelanoma skin cancers; adverse effects include delayed wound healing, increased lymphocoele formation and rarely lymphoedema. We report a series of eight cases of severe, sustained, unilateral and bilateral lymphoedema in patients receiving sirolimus for post-transplant immunosuppression, classify their lymphoscintigraphy findings and propose a mechanism of aetiology based on the interaction of mTOR with key mediators of lymphangiogenesis.
Transplant Proc. 2007 May
Al-Otaibi T, Ahamed N, Nampoory MR, Al-Kandari N, Nair P, Hallm MA, Said T, Samhan M, Al-Mousawi M. Hamed Al-Essa Organ Transplant Centre, Kuwait.
INTRODUCTION: Lymphedema is an increasingly observed complication of sirolimus (SIR) therapy. In this report, we describe four renal recipients with SIR-induced lymphedema of varying severity.
CASES REPORTS: Patient 1, a 38-year-old man developed lymphedema of the left upper limb after being exposed to SIR for 30 months (mean daily Rapamune dose, 3 mg; trough level, 10-18 ng/mL). Venography and duplex ultrasound were normal. Lymphangiography was showed delayed lymphatic drainage. SIR was replaced with Prograf with significant improvement in the lymphedema over the next 6 months. Patient 2, a 26-year-old woman, developed lymphedema of the left lower limb at 24 months after starting SIR (mean daily dose, 3 mg; trough level, 10-15 ng/mL).
Lymphangiography showed delayed drainage of lymphatics in the left lower limb. The patient was shifted to Prograf and there was some improvement over the next 4 months. Patient 3, a 28-year-old man, developed lymphedema of the left upper limb at 24 months after the start of SIR (mean daily dose, 2 mg, trough level, 6-15 ng/mL). Lymphangiography showed evidence of lymphatic obstruction. SIR was changed to cyclosporine with only mild improvement in lymphedema over the next 6 months. Patient 4, a 46-year-old man, developed lymphedema of the right upper limb at 7 months after starting SIR (mean daily dose, 6 mg; trough level, 10-16 ng/mL). Lymphangiography showed complete blockage of the lymphatic channels. SIR was changed to cyclosporine and there was mild improvement in lymphedema over the next 8 to 10 months.
The exact mechanism of SIR-induced lymphedema is unknown. The absence of other demonstrable etiologies and spontaneous improvement after discontinuation of SIR suggest that this drug was the responsible factor in these four patients. It occurred 7 to 30 months after transplantation. This is the fourth such report in the literature to the best of our knowledge.
Transplantation. 77(7):1094-1096, April 15, 2004. Aboujaoude, Walid 2; Milgrom, Martin L. 3; Govani, Mahendra V. 2 4
Lymphoceles are common in renal transplant recipients who receive sirolimus (SRL). However, a recent MEDLINE search revealed no reports of lymphedema related to SRL. We describe three cases of lymphedema that resolved or improved on discontinuation of SRL. No other likely causes of lymphedema were discovered. Recognizing the association may lead to early discontinuation of SRL, which may prevent permanent disfigurement. It may also prevent unnecessary investigations. The mechanisms of this phenomenon are not clear. We hypothesize that increased lymph flow along with disrupted lymphatics in the affected extremities may explain this complication of SRL. Further studies are necessary to confirm our findings.
(C) 2004 Lippincott Williams & Wilkins, Inc.
Transplant Proc. 2005 Mar
Romagnoli J, Citterio F, Nanni G, Tondolo V, Castagneto M. Department of Surgery, Organ Transplantation, Policlinico Gemelli, Rome, Italy.
We report two kidney transplant recipients who developed severe limb lymphedema under sirolimus (SRL) immunosuppression. The patients received SRL 10 and 2 mg/d to achieve target levels of 10 to 20 ng/mL with tapering doses of prednisone. Renal function and drug levels were monitored monthly. Patient 1 developed lymphedema of the left upper limb 3 years posttransplantation, after having been exposed to high SRL doses in the preceding 2 years (mean SRL dose-9.5 mg/d, mean trough level-26.3 ng/mL, mean serum creatinine-1.63 mg/dL). In patient 2 lymphedema of both upper and lower right limbs occurred 18 months posttransplantation (mean SRL dose-3.2 mg/d, mean trough level-8.8 ng/ mL, mean serum creatinine-2.9 mg/dL). Hypercholesterolemia and hypertriglyceridemia were also observed in both patients before SRL reduction/conversion. No signs of hematopoietic toxicity were observed. In both patients magnetic resonance (MR) angiography of the limb was negative for vascular obstruction, and lymphoscintigraphy revealed lymphatic obstruction. In patient 1 lymphedema improved significantly following SRL reduction and lymphatic drainage massage therapy. Patient 2 was converted to cyclosporine (CsA) improving markedly after conversion. Hypercholesterolemia and hypertriglyceridemia also improved significantly in both patients after reduction/conversion. We conclude that SRL may facilitate the occurrence of lymphatic obstruction by mechanisms that are presently unexplained. Lymphedema of the limbs in renal transplant recipients under SRL treatment, especially if on the same side as the hemodialysis access, should warn the transplant physician to rapidly reduce or withdraw SRL before the occurrence of complete obstruction.
Journal of Drugs in Dermatology, March, 2006 by Lindsey Warino, James Libecco Abstract
Cancer is a major cause of death in immunosuppressed transplant patients. Therefore, sirolimus is frequently used in these patients for its immunosuppressive and antineoplastic properties. However, a variety of cutaneous side effects have resulted from sirolimus therapy. Consequently, dermatologists must be aware of such adverse events and understand the risks and benefits of discontinuing therapy.
Sirolimus (Rapamycin) is an immunosuppressive agent often used in combination with cyclosporine and corticosteroids in renal transplant patients. In contrast to the calcineurin inhibitors, sirolimus, a macrocyclic lactone isolated from Streptomyces Hygroscopicus, has no effect on calcineurin activity. (1-15) Rather, it acts to suppress cytokine-driven T cell proliferation and inhibits the progression from G1 to the S phase of the cell cycle. Not only is sirolimus used for its immunosuppressive properties, but it is also commonly used in order to avoid the nephrotoxicity and increased risk of cutaneous malignancies found in transplant recipients treated with cyclosporine. (3,16,17) Because cancer has become a major cause of death in immunosuppressed transplant patients, sirolimus is used more frequently due to its antineoplastic effects. Sirolimus exhibits antiangiogenic properties and inhibits tumor growth factor by reducing production of vascular endothelial growth factor (VEGF) and by blocking VEGF-induced endothelial cell signaling. (16,17)
Although it appears to be an efficacious agent, many side effects have been the result of sirolimus therapy including arthralgia, headache, thrombocytopenia, interstitial pneumonitis, and hypercholesterolemia. (5-8) Perhaps most impressive, several different cutaneous adverse events have been reported following sirolimus therapy in renal transplant recipients. It is important for dermatologists to be aware of such events in order to recognize sirolimus as the causative agent and properly treat affected patients.
In order to find the true incidence, clinical characteristics, and severity of dermatologic adverse events in patients on sirolimus-based therapy, Mahe et al conducted a study in 95 renal transplant recipients. (1) Every patient received sirolimus either immediately after transplantation or after transfer from calcineurin inhibitor to sirolimus. Eighty of 95 patients were examined separately by 2 dermatologists following a specific protocol in which a history and physical was done before transplantation and sirolimus introduction as well as after initiation of sirolimus. Following sirolimus administration, 99% of patients presented with at least one new cutaneous adverse event with the mean being 7 events per patient. Several other reports revealing similar outcomes have also been reported in the transplant literature. (9-15)
Infections and acne-like eruptions were common cutaneous effects of the drug. More specifically, 34% of patients developed viral infections, 4% developed bacterial, and 16% of patients developed fungal infections. With predominance in men, inflammatory eruptions resembling acne appeared in 46% of patients. (1,6-8) The lesions were often combined with scalp folliculitis and 10 patients developed hidradenitis suppurativa. (1) Other skin eruptions resembling seborrheic dermatitis involving almost every body part have also been reported. (8)
Edema and swelling have also been reported in transplant recipients treated with sirolimus. (1,8) Mahe et al reports that 12 patients developed angioedema with facial and oral cavity involvement. Other reports describe edema either limited to the left upper extremity or generalized. In such instances, patients are limited in their daily activities due to pain and decreased range of motion, and swelling often takes weeks to months to resolve after the discontinuation of sirolimus. (8) The mechanism of edema is unknown; however, Kaplan et al suggests that it may be related to the capillary leak syndrome caused by the apoptotic effect of sirolimus. (9) In addition, a separate clinical trial reported that 5 of 11 patients treated with sirolimus after renal transplantation developed uni- or bilateral eyelid edema 1 to 5 months after the initiation of therapy. In all patients, the edema resolved within months of discontinuation of sirolimus. (10)
Furthermore, Aboujaoude et al reported 3 cases of lymphedema following sirolimus therapy in renal transplant recipients, which resolved or improved significantly after its withdrawal. There was no family history of lymphedema or history of cutaneous malignancies in any of the patients studied. It is speculated that the disruption of lymph flow was caused by a combination of the multiple vascular pretransplantation procedures and increased vascular permeability and prostacyclin induced vasodilatation associated with sirolimus. (11)
Leukocytoclastic vasculitis of the hands and lower extremities has also been described as an adverse affect of sirolimus administration. Two cases have been reported in which painful, necrotic ulcers appeared after the initiation of sirolimus and resolved upon withdrawal. Both patients were diagnosed with sirolimus-induced vasculitis based on the temporal relationship between drug therapy and biopsy-proven vascular inflammation. Furthermore, upon rechallenge of sirolimus, the vasculitis reappeared in both cases. (12,13)
Another side effect that has been repeatedly described with sirolimus therapy is mucosal membrane disease. Mahe et al reported that 60% of patients in the trial developed aphthous ulcerations and recurrent epistaxis. Chronic fissuring of lips and gingivitis were also common. (1,3,6) This side effect has been documented in many cases regardless of the sirolimus constitution pill formulation verses suspension. Relief measures including antifungal, antiviral, and topical anesthetics alone or in combination have been ineffective in treating aphthous ulcers unless sirolimus is withdrawn. (8) Gelder et al hypothesized that the antiproliferative effect of sirolimus combined with the effect of sirolimus on growth factors, which has been linked to the greater prevalence of wound infections and delayed wound healing, may be responsible for the occurrence of mucosal ulcerations. Therefore, it is implied that sirolimus may not be the source of ulcerations, but it may be the cause of defective repair. (14)
Mahe et al reported nail abnormalities in 74% of patients studied. Pathologies included nail fragility, slow growth, longitudinal ridging or fissures, distal onycholysis, erythema, and splinter hemorrhages of the nail plate. Mild hair loss of the scalp and hypertrichosis of the face was also reported. (1) However, patients receiving hemodialysis and renal transplants often have nail findings including onychomycosis, splinter hemorrhages, leukonychia, longitudinal ridging, and half-and-half nails. (15)
In the study performed by Mahe et al, few non-melanoma skin cancers were reported. Other miscellaneous skin changes including xerosis, fragility, hyperpigmentation of the face, acrocyanosis, Raynaud's phenomenon, Henoch-Schonlein purpura in one patient, psoriasis and alopecia areata in one patient, and alopecia areata in a single patient developed over the course of the trial. Whether or not these events were related to the administration of sirolimus could not be determined.
Although the mechanism may be unclear, it is apparent that sirolimus is capable of producing a variety of skin disorders. Acne-like eruptions, edemas, xerosis, aphthous ulceration, epistaxis, and nail involvement are the most frequently reported and nearly all of these resolved only with the discontinuation of sirolimus. Therefore, in order for a dermatologist to effectively and efficiently treat a patient with such a reaction, he must be acquainted with the many cutaneous effects of sirolimus as well as the risks and benefits of discontinuing therapy. Further, as the use of sirolimus increases due to transplant-related malignancy, dermatologists may be faced with the dilemma of battling sirolimus related cutaneous side effects or the return to prior therapies, such as cyclosporine and their associated toxicities.
Address for Correspondence
James Libecco MD
Cleveland Clinic Foundation
Department of Dermatology
5900 Euclid Avenue–A61
Cleveland, Ohio 44195
Lindsey Warino BS, (a) James Libecco MD (b)
a. Northeastern Ohio Universities College of Medicine, Rootstown, OH
b. Department of Dermatology, Cleveland Clinic Foundation, Cleveland, OH
Sahin GM, Sahin S, Kantarci G, Ergin H. Source Department of Nephrology, Goztepe Research and Teaching Hospital, Istanbul, Turkey. email@example.com Abstract Sirolimus (SRL) is a new, potent immunosuppressive agent. More recently, proteinuria has been reported as a consequence of sirolimus therapy, although the mechanism has remained unclear. We retrospectively examined the records of 25 renal transplant patients, who developed or displayed increased proteinuria after SRL conversion. The patient cohort (14 men, 11 women) was treated with SRL as conversion therapy, due to chronic allograft nephropathy (CAN) (n = 15) neoplasia (n = 8); Kaposi's sarcoma, Four skin cancers, One intestinal tumors, One renal cell carsinom) or BK virus nephropathy (n = 2). SRL was started at a mean of 78 +/- 42 (15 to 163) months after transplantation. Mean follow-up on SRL therapy was 20 +/- 12 (6 to 43) months. Proteinuria increased from 0.445 (0 to 1.5) g/d before conversion to 3.2 g/dL (0.2 to 12) after conversion (P = 0.001). Before conversion 8 (32%) patients had no proteinuria, whereas afterwards all patients had proteinuria. In 28% of patients proteinuria remained unchanged, whereas it increased in 68% of patients. In 40% it increased by more than 100%. Twenty-eight percent of patients showed increased proteinuria to the nephrotic range. Biopsies performed in five patients revealed new pathological changes: One membranoproliferative glomerulopathy and interstitial nephritis. These patients showed persistently good graft function. Serum creatinine values did not change significantly: 1.98 +/- 0.8 mg/dL before SRL therapy and 2.53 +/- 1.9 mg/dL at last follow-up (P = .14). Five grafts were lost and the patients returned to dialysis. Five patients displayed CAN and Kaposi's sarcoma. Mean urinary protein of patients who returned to dialysis was 1.26 (0.5 to 3.5) g/d before and 4.7 (3 to 12) g/d after conversion (P = .01). Mean serum creatinine level before conversion was 2.21 mg/dL and thereafter, 4.93 mg/dL (P = .02). Heavy proteinuria was common after the use of SRL as rescue therapy for renal transplantation. Therefore, conversion should be considered for patients who have not developed advanced CAN and proteinuria. The possibility of de novo glomerular pathology under SRL treatment requires further investigation by renal biopsy.