Oedema, solid organ transplantation and mammalian target of rapamycin inhibitor/proliferation signal inhibitors (mTOR-I/PSIs)

Abstract

Mammalian target of rapamycin inhibitor (mTOR-I)/proliferation signal inhibitors (PSI) including sirolimus and everolimus represent a new class of drugs increasingly used in solid-organ transplantation as alternatives to calcineurin inhibitors for patients with renal dysfunction, transplant coronary arterial vasculopathy or malignancy. The most frequently occurring mTOR-I/PSI-related adverse events are similar to those associated with other immunosuppressive therapies, but some side effects are more characteristic of proliferation signal inhibitors (e.g. lymphocele, arthralgia, oedema and hyperlipidaemia). The present paper review incidence, clinical presentation and mechanism of oedema within the clinical experience of mTOR-I/PSI in solid organ transplantation.

Lymphedema of the Transplanted Kidney and Abdominal Wall with Ipsilateral Pleural Effusion Following Kidney Biopsy in a Patient Treated with Sirolimus: A Case Report and Review of the Literature

“…Treatment of transplant patients with the mammalian target of rapamycin (mTOR) inhibitors, sirolimus or everolimus, have been reported to be associated with increased incidence of lymphocele following kidney transplantation surgery [ 5 ]. This finding is suggestive of the potential of mTOR inhibitors to prevent the healing of lymphatic channels damaged during surgery.…”

“…This finding is suggestive of the potential of mTOR inhibitors to prevent the healing of lymphatic channels damaged during surgery. Furthermore, mTOR inhibitors can create localized or generalized lymphedema in different parts of the body at any time after transplantation [ 5 – 20 ]. The exact pathophysiology of lymphedema attributed to mTOR inhibitors is not understood, but mTOR inhibition has been shown to blocks cytokine-mediated T-cell proliferation, and this is the basis for their clinical use in preventing organ transplant rejection.…”

“…Also, recent studies have shown that sirolimus may increase capillary permeability, and the resultant overproduction of lymphatic fluid enhances interstitial pressure leading to compression of lymphatic vessels [ 6 ]. Localized lymphedema, secondary to sirolimus or everolimus treatment, has been reported to involve the extremities, but other locations such as eyelid, face, breast, and flanks can be affected [ 5 – 20 ]. Swelling of tissues associated with sirolimus treatment has been reported either as an isolated, localized lymphedema, or with edema of the extremities.…”

“…Inhibitors of the mammalian target of rapamycin (mTOR) are increasingly used as immunosuppressive agents in organ transplant recipients, especially when a calcineurin–free regimen with less renal toxicity is desired. However, mTOR inhibitors, including sirolimus, are reported to be associated with a variety of adverse effects that include impaired wound healing [ 1 ], interstitial pneumonitis [ 2 ], anemia, hyperlipidemia [ 3 ], vascular thrombosis [ 4 ], ascites, lymphocele, peripheral edema, and pleural effusion [ 5 ].…”

Sirolimus-induced lymphoedema

“…[5] Patients with lymphatic obstruction can present with lymphoceles (12 -13%), eyelid oedema, angio-oedema, pleural/pericardial effusions and lymphoedema. [6] Bilateral limb oedema is commonly associated with mTOR inhibitors, more commonly in patients on sirolimus than in those on evarolimus, [7] but the recent literature has indicated an increase in lymphoedema related to the drug, which is often permanently disfiguring. [8][9][10] According to previous case reports, it occurs between 7 months and 2 years on treatment and does not have a gender predisposition.…”