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Volume: 20 Issue: 7 July 2022


Upper Extremity Lymphedema Related to Everolimus in a Renal Transplant Recipient: Efficacy of Complete Decongestive Therapy

We report our experience with a new case of lymphedema of the upper extremity in a renal transplant recipient under treatment with everolimus immunosuppression, and we emphasize the effects of complete decongestive therapy on this chronic condition.

Key words : Immunosuppression, Lymphedema management, Mammalian target of rapamycin inhibitor


Lymphedema is a chronic, progressive debilitating condition characterized by abnormal accumulation of lymph fluid in the tissues due to impairment of lymphatic drainage system and has been reported to be a rare complication of mammalian target of rapamycin (mTOR) inhibitors in past decades.1-11 There are 2 main mTOR inhibitors, sirolimus and everolimus, that are the preferred drugs to prevent rejection after organ transplant in recipients, mainly when a calcineurin-free regimen with less renal toxicity is indicated. The adverse events related to sirolimus and everolimus include delayed wound healing, hyperlipidemia, hypertension, pulmonary toxicity, diabetes, and skin lesions.12 Lymphedema has previously been reported as an adverse side effect in several transplant patients with sirolimus-based immunosuppression,1-10 but there are only 2 cases of everolimus-related lymphedema in lower extremities in the English literature.10,11

We report our experience with a new case of lymphedema of the upper extremity in a renal transplant recipient under treatment with everolimus immunosuppression, and we emphasize the effects of complete decongestive therapy (CDT) on this chronic condition.

Case Report

A 57-year-old woman, who received a living-related kidney transplant 2 years previously for polycystic renal disease, presented with left arm lymphedema that had persisted for 8 months. After the transplant, she received an immunosuppressive regimen of tacrolimus (2 mg/day), mycophenolate mofetil (2 g/day), and corticosteroids. During the first days of treatment with tacrolimus, she developed a pancytopenia reaction and tacrolimus was stopped. After blood transfusion and supportive therapy, she was given oral everolimus at a dose of 1.5 mg/day, and the dose was adjusted to provide through levels of > 5 ng/ml. Nine months after the initiation of everolimus, left arm swelling developed and progressed during the next few months. The dose was decreased after the progression of edema, and her arm swelling was mildly reduced but did not completely resolve. Making the decision to stop treatment with everolimus was challenging. The cost of drugs, the progress of patient with good and stable graft function on everolimus, and the concerns of the possibility that her graft function would be compromised impelled the responsible transplant team to continue to everolimus therapy.

The patient was still on everolimus therapy, with a mean dose of 1.5 mg, when admitted to our clinic with chronic left arm swelling. She did not have any family history of lymphedema and/or malignancy. In the physical examination, vital signs were normal, and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) was 25.7 (weight, 58 kg; height, 150 cm). The range of motion in upper extremity and the neurologic examination were normal. She had edema in left arm, forearm, and hand; Stemmer sign was positive at the left side; and pitting was positive (++) on the hand (Figure 1, left). She had mild hyperemia on the left arm, but heat, scar, incision, fistula, and signs of active inflammation (erysipelas, cellulitis) were absent. Blood cell count and C-reactive protein levels were within reference ranges. Doppler ultrasonography ruled out a venous cause of edema. Lymphoscintigraphy indicated obstruction of lymphatic flow, dermal backflow, and lack of transition to axillary lymph nodes in the left upper extremity. On the basis of these characteristic findings, she was diagnosed with grade 2 left upper extremity lymphedema. Breast and axillary ultrasonography and mammography, as well as chest radiography and tumor markers, were performed to rule out malignant lymphedema, and all tests revealed no abnormalities.

After acceptance to the lymphedema unit, the patient was educated for skin care and exercises. Cone formula was used to obtain limb volumes and difference of percentage volumes of the arms, depending on the circumferential measurements on both extremities.13 Functional status and quality of life were assessed with the Quick Disability of Arm, Shoulder and Hand questionnaire (Quick DASH)14 and Quality of Life measure for Limb Lymphedema-Arm (LYMQOL-ARM)15 questionnaire, respectively, and a photograph of the patient was recorded, as routine workup. Complete decongestive therapy was started, which comprised skin care, manual lymphatic drainage, multilayer short-stretch bandages, and exercises performed for 15 sessions in 3 weeks as outpatient intervention. The differences between right and left upper limb volumes and percentage of volumes, as well as circumferential measurements of the hand, were reduced significantly at the end of phase 1 of CDT (Table 1 and Figure 1, middle). There were also significant improvements in functional status and quality of life scores in all domains (Table 2). The patient was prescribed a suitable pressure garment with a pressure class of CCL2, and she continued self-massage and exercises as phase 2 of CDT. At follow-up visit 4 weeks after CDT, the improvement was stable and patient compliance was good (Figure 1, right).


We report a new case of isolated unilateral upper extremity lymphedema that appeared 9 months after starting everolimus, in a renal transplant recipient. The differential diagnosis of lymphedema was established on clinical examination and imaging modalities. We excluded any secondary causes of lymphedema and attributed it to everolimus after a complete and meticulous workup. Everolimus dose was reduced but was not withdrawn, and the patient was successfully treated with CDT for 3 weeks.

Lymphedema in extremities, face, breast, and internal organs has previously been reported as a relatively rare complication of sirolimus,1-9 and there are only 2 reports of everolimus-related lymphedema in the literature.10,11 Ersoy and Koca10 reported lower extremity lymphedema in a renal transplant recipient who was diagnosed at the fifth month of everolimus therapy, which progressed to upper limbs and left breast in 3 months and resolved within several weeks after ceasing sirolimus. Recently, Cellina and colleagues11 reported the second case of everolimus-related lymphedema in a renal transplant recipient. Their patient had bilateral lower extremity lymphedema, which was diagnosed after 10 months of everolimus therapy. The left side lymphedema was reduced over a period of 3 months after everolimus suspension, but the right lower limb lymphedema persisted and advanced despite lymphatic drainage massages and compressive therapies.

The main mechanism of action of sirolimus and everolimus is the inhibition of mTOR, which is a regulatory protein kinase involved in lymphocyte proliferation and developmental processes. The biological and physiological mechanisms by which mTOR inhibitors interfere with lymphatic drainage is unclear, but these are probably related to changes in lymphangiogenesis that prevent lymphatic endothelial cell migration and lymphatic endothelial cell proliferation, leading to lymphatic obstruction.1,5,7,9 The antilymphangiogenic activity is not restricted to a specific mTOR inhibitor; rather, it is a general phenomenon of mTOR inhibition.3-6,12 Interference with lymphatic integrity and disrupted lymphatics due to hemodialysis access and arteriovenous shunts have also been hypothesized,1,3,8,9 but there are cases in the literature of patients without arteriovenous shunts who received transplant before hemodialysis requirement (as was the case with our patient).7,10

The previous case reports were treated with reduction or discontinuation of sirolimus or eve­rolimus with moderate-to-complete improvement of lymphedema, but some of these cases were not improved with any of these treatments. In the majority of sirolimus-related and everolimus-induced cases, the reported lymphedema outcomes were variable, totally regressed after withdrawal,2,5,7,10 or persisted partially after dose suspension or dose reduction.4,6,11 The risk-to-benefit ratio of discontinuation or switch of antirejection therapies must be considered according to each specific patient. In our case, everolimus was continued at the suggestion of the transplant team, and therefore we do not know whether withdrawal of everolimus could lead to complete regression. We performed CDT as symptomatic lymphedema treatment and determined significant improvement, not only in volume of the extremity but also in functional status and quality of life.

There are few reports in the literature related to physiotherapeutic approaches in patients with sirolimus/everolimus-related lymphedema.4,9,11 Vignes and colleagues9 described 5 patients with sirolimus-related lymphedema who were treated with CDT that comprised skin care, manual lymphatic drainage, multilayer bandaging, and exercises, and in all cases, these patients were maintained on treatment with sirolimus. The mean interval from starting sirolimus to onset of lymphedema was 27.5 ± 21 months, and the mean excess volume was 44%. However, Vignes and colleagues did not mention the results of CDT with regard to volume or any other outcome variables. Motse and Mashabane4 indicated slight improvement with physiotherapy and com­pression bandaging in a male kidney transplant recipient with lower extremity sirolimus-related lymphedema. Our case report is the first to indicate the effectiveness of CDT in a renal transplant recipient with upper limb lymphedema related to everolimus therapy. Our patient had a relatively short duration of lymphedema (9 months) since the initiation of everolimus, and the volume difference was 47.9% compared with unaffected extremity. After initiation of CDT, improvements in not only volume occurred but also in functional status and quality of life. The patient is currently receiving everolimus and mycophenolate mofetil for immunosuppression, and her graft function remains stable at the time of this writing. For future CDT therapy, she is directed to wear a pressure garment continuously during the day and to perform self-massage and exercises regularly, to sustain the improvements in arm volume, functional status, and quality of life.


We described the third case of everolimus-related lymphedema in the literature and the first case of an everolimus-treated patient who presented with upper extremity lymphedema. We also emphasized the effects of physiotherapeutic approaches with regard to volume reduction, functional status, and quality of life in our patient during the continuation of the drug. The discontinuation of the drug may be unnecessary in patients with lymphedema com­plications of everolimus because they can be effectively treated with CDT to mitigate adverse side effects of the drug. We suggest early recognition of lymphedema (as an adverse side effect of everolimus therapy) and prompt initiation of decongestive therapies to prevent disfigurement, disability, and impaired quality of life in patients who must continue mTOR inhibitors as an antirejection therapy after kidney transplant.


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Volume : 20
Issue : 7
Pages : 698 - 701
DOI : 10.6002/ect.2020.0165

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From the 1University of Kastamonu Faculty of Medicine, Department of Physical Medicine and Rehabilitation; the 2Ankara City Hospital Department of Physical Medicine and Rehabilitation, Bilkent, Ankara, Turkey; the 3Gulhane Education and Research Hospital Department of Physical Medicine and Rehabilitation, Ankara, Turkey; and the 4Hendek State Hospital, Department of Physical Medicine and Rehabilitation, Sakarya, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no further declarations of potential interest. This case report was orally presented in 7th International Lymphoedema Framework Conference, 21-24 June 2017, Siracusa, Italy.
Corresponding author: Pinar Borman, Ankara City Hospital Department of Physical Medicine and Rehabilitation, Bilkent, 06800 Ankara, Turkey
Phone: +90 5324649897