sirolimus and Lymphedema

BACKGROUND Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor, which is used in immunosuppressive treatment regimens in organ transplant recipients. Although mTOR inhibitors are well tolerated, their adverse effects have been reported. Sirolimus treatment in transplant recipients has been reported to be associated with lymphedema of the skin and subcutaneous tissues, and with pleural effusion, but edema of internal organs and organomegaly have not been previously reported. A case is presented lymphedema of the transplanted kidney and abdominal wall with ipsilateral pleural effusion following kidney biopsy in a patient treated with sirolimus. CASE REPORT A 32-year-old woman with a history of end-stage renal disease of unknown etiology had undergone right renal transplantation from an unrelated living donor, eight years previously. She was referred to our hospital with dyspnea, localized abdominal pain, and swelling of the transplanted kidney. The symptoms appeared following a kidney biopsy and the replacement of cyclosporin with sirolimus four months previously. On examination, she had localized swelling of the abdominal wall overlying the transplanted kidney, and a right pleural effusion. Hydronephrosis and nephrotic syndrome were excluded as causes of kidney enlargement. Following the withdrawal of sirolimus therapy her symptoms resolved within three months. CONCLUSIONS A case is described of lymphedema of the transplanted kidney and abdominal wall with ipsilateral pleural effusion following kidney biopsy attributed to her change in anti-rejection therapy to sirolimus. This case report should raise awareness of this unusual complication of sirolimus anti-rejection therapy and its possible effects on the lymphatic system.

Topics: Abdominal Wall; Adult; Biopsy; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphedema; Pleural Effusion; Sirolimus

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.

Topics: Adult; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphedema; Male; Middle Aged; Radiography; Sirolimus; Young Adult

Topics: Humans; Lymphedema; Lymphoscintigraphy; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases

Topics: Administration, Topical; Adolescent; Anti-Inflammatory Agents; Biopsy; Crohn Disease; Drug Therapy, Combination; Female; Genitalia; Humans; Immunohistochemistry; Immunosuppressive Agents; Injections, Intralesional; Lymphedema; Pain; Pruritus; Sirolimus; Skin; Treatment Outcome; Triamcinolone; Warts

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor used after organ transplantation and to treat vascular malformations. Among its adverse effects, limb lymphedema has been described.. The aim of this study was to analyze the clinical features, lymphoscintigraphy and lymphedema outcome in patients treated with sirolimus.. Monocentric retrospective study from January 2008 to September 2017 analyzing all consecutive patients having lymphedema occurring with sirolimus.. Fifteen patients (7 men, 8 women), mean age at the first visit, 56 years (range: 38-76), had a kidney transplant (n=12), liver transplant (n=1), or lymphangioleiomyomatosis (n=2) treated with sirolimus at a mean daily dose of 1.8mg were included. Lymphedema involved one (n=4), or both (n=1) lower limbs, upper limb (n=9), lower limbs and upper limb (n=1). Lymphedema affected the whole limb (n=10), or the distal part (n=5). The median time between lymphedema onset and the beginning of sirolimus was 52 weeks (range: 8-232). Lymphoscintigraphy in 7 patients (lower limb: 3, superior: 4) showed no inguinal or axillary nodal fixation (n=6) or decreased uptake (n=1). Sirolimus was discontinued in 7 cases without lymphedema improvement with a median follow-up of 12 months and maintained in 8 cases.. Sirolimus is associated with upper and/or lower limb lymphedema, without predominance of sex, and without disappearance after sirolimus discontinuation. Pathophysiological mechanisms remain unclear. Lymphedema management is based on low-stretch bandages and compression.

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Neoplasms; Lymphangioleiomyomatosis; Lymphedema; Lymphoscintigraphy; Male; Middle Aged; Prognosis; Retrospective Studies; Sirolimus; Transplantation Conditioning

Topics: Antibiotics, Antineoplastic; Humans; Infant; Kasabach-Merritt Syndrome; Lymphedema; Male; Sirolimus; Thigh; Treatment Outcome

Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), used as an immunosuppressant for solid-organ transplant recipients and patients with autoimmune disorders. We report a case of lymphoedema, a rare complication of sirolimus, and discuss the mechanism of drug action, the adverse effects and the challenges of treating a kidney transplant recipient with this complication in a resource-limited environment. Lymphoedema is a rare complication of sirolimus, and the mechanisms are not completely understood; however, early recognition can prevent permanent disfiguration. This case highlights the need for early recognition of adverse drug effects and further research into their pathophysiology and management.

Topics: Adult; Drug Substitution; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lower Extremity; Lymphedema; Lymphography; Male; Prednisone; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Ultrasonography, Doppler, Duplex

Topics: Breast Diseases; Cyclosporine; Drug Substitution; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Middle Aged; Risk Factors; Sirolimus; Ultrasonography, Mammary

Lymphedema induced by mTOR inhibitors is a side-effect rarely reported to date.. Long-lasting bilateral lower-limb lymphedema with left predominance developed in a 71-year-old stable renal transplant recipient after 40 months of sirolimus treatment. Although no change in lymphedema was observed after 21 months despite dosage reduced, it improved markedly after changeover to tacrolimus.. Regardless of the individual drug, mTOR inhibitors can cause lymphedema. This effect may be countered through substitution with tacrolimus.. Physicians should be aware of lymphedema as a side-effect of mTOR inhibitors. It can be improved by substitution with tacrolimus. However, early withdrawal of mTOR inhibitors is recommended before irreversible lymphedema occurs.

Topics: Aged; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Sirolimus; Tacrolimus; Transplant Recipients

Primary intestinal lymphangiectasia (PIL) is a rare protein-losing enteropathy characterized by a congenital malformation of the lymphatic vessels of the small intestine causing insufficient drainage and leakage of lymph fluid. Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas in multiple organ systems. While the lymphatic system has been implicated in TSC through lymphangioleiomyomatosis (LAM) and lymphedema, this paper reports the first case of PIL in TSC, a female patient with a TSC2 mutation. She developed persistent and significant abdominal distension with chronic diarrhea during her first year of life. Due to lack of treatment options and the involvement of the mTOR pathway in TSC, a trial of an mTOR inhibitor, rapamycin, was initiated. This treatment was highly effective, with improvement in clinical symptoms of PIL as well as abnormal laboratory values including VEGF-C, which was elevated to over seven times the normal upper limit before treatment. This case suggests that PIL is a rare manifestation of TSC, warranting the use of mTOR inhibitors in future studies.

Topics: Adult; Female; Humans; Lymphangiectasis, Intestinal; Lymphedema; Mutation; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Young Adult

Topics: Adult; Chronic Disease; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Male; Postoperative Complications; Sirolimus

To analyze upper-limb lymphedema characteristics of renal transplant recipients taking sirolimus, an mTOR inhibitor.. Cross-sectional study of sirolimus-treated upper-limb lymphedema patients (01/2009-12/2013).. Three men and two women, whose mean age at transplantation was 60 (range: 49-76) years, were included. Sirolimus (1-2.5 mg/day) had been taken for 27.5 ± 21 (range: 7-58) months before left (n=4) or right (n=1), whole limb (n=4), or hand and forearm (n=1) upper-limb lymphedema onset, always ipsilateral to the functional arteriovenous fistula. Ultrasonography or fistulography excluded venous thrombosis in all patients. At the time lymphedema appeared, all five arteriovenous fistulas were functional. Mean upper-limb lymphedema volume, calculated with the truncated-cone formula, was 774 ± 162 [range: 594-1035] mL, (i.e. 44%± 11% [range: 36%-64%] excess volume compared to the contralateral limb. One patient also had ipsilateral breast lymphedema. The three lymphoscintigraphies obtained showed total absence of ipsilateral axillary-region tracer uptake. Sirolimus was maintained in all cases. Upper-limb lymphedema treatment included low-stretch bandages (n=4) and elastic sleeve (20-36 mm Hg) (n=5) without fistula complications. Two patients had their fistulas closed without any impact on lymphedema volume.. Sirolimus may be implicated in large-volume upper-limb lymphedema in kidney-transplant recipients, ipsilateral to the arteriovenous fistula, and requires compression-based therapy.

Topics: Adult; Aged; Arm; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Lymphoscintigraphy; Male; Middle Aged; Sirolimus

Proliferation signal inhibitors are increasingly used as immunosuppressive drugs in solid organ transplantation. Among their side effects peripheral lymphedema is rarely described in literature.. All heart transplant patients treated with everolimus (de novo or maintenance) at our center (135 patients: age 50.72±11.1 y, 115 male) were retrospectively analyzed. We considered the incidence of adverse events, particularly the appearance of peripheral edema (13 patients, 9.6%), and the correlation with preoperative characteristics, concomitant medications, other possible causes of edema, as well as all the measures developed for its therapeutic treatment.. Edema appearance, especially in lower limbs, was considered to be one of the most frequent side effects in heart transplant patients treated with everolimus. In some cases its regression was possible with an adjustment of drug dosages associated with diuretics and lymphatic drainage, but more often a suspension of the drug itself was required for complete regression of the symptoms.

Topics: Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Lymphedema; Male; Middle Aged; Retrospective Studies; Sirolimus

A 45-year-old woman presented with marked edema of both lower extremities over 6 weeks for a nephrological work-up; she had gained 8 kg of body weight. Voiding was asymptomatic and she had a stable diuresis. The patient took oestrogens for contraception over 10 years. Blood pressure was normotensive. Serum-creatinine was 0.8 mg/dl; a slight microalbuminuria was noted. Left and right ventricular systolic function were normal. DIAGNOSTIC FINDINGS, TREATMENT AND CLINICAL COURSE: Computed tomography of the abdomen revealed a hemodynamically relevant obstruction of the venous blood flow or the lymphatic vessels as cause for the edema of both legs. Masses of lymphangioleiomyomas located around the v. cava inferior were documented. Biopsy of the masses proved a massive proliferation of smooth muscle cells and epitheloid cells with an immunohistochemically typical staining. Furthermore, CT revealed multiple pulmonary cysts in both lungs, results which are pathognomic for lymphangioleiomyomatosis (LAM). In our patient, the structural impairment of the lungs was not substantiated clinically, i. e. she had only slight dyspnoe during exertion. By mild diuretic treatment with HCT and fluid control, a moderate regression of the edema was achieved. At present, the mTOR inhibitor rapamycin as antiproliferative treatment is considered to reduce the retroperitoneal LAM-related masses on an individual basis.. LAM is a rare genetically determined progressive disease occurring frequently in women in childbearing age. LAM is characterized by a proliferation of smooth muscle cells, lymphangioma, renal angiomyolipoma, pulmonary cysts and progressive destruction of lung parenchyma. Refractory edema can result from an obstruction of the venous blood and lymphatic flow by lymphangioma masses located paracaval, which was the impressive and first clinical feature of LAM in our case report.

Topics: Antibiotics, Antineoplastic; Biopsy; Diuretics; Drinking; Female; Humans; Hydrochlorothiazide; Lung Neoplasms; Lymphangioleiomyomatosis; Lymphedema; Magnetic Resonance Imaging; Middle Aged; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed; Vena Cava, Inferior

The mammalian target of rapamycin inhibitors is commonly preferred for solid organs for transplantation. Although these drugs have various adverse effects, sirolimus-related lymphedema has been rarely reported. We report a case of lymphedema related to everolimus after a kidney transplant. A 60-year-old woman successfully received a deceased-donor kidney. Everolimus was added to the treatment in postoperative month 3 owing to other immunosuppressive drugs' adverse effects. Edema occurred first on her feet in the first year after the transplant. During 3 months' follow-up, with no immunosuppressive adjustment, the edema progressed. Diagnosis of lymphedema was established. Several weeks after discontinuing everolimus, the patient's lymphedema began to resolve itself and completely disappeared in 3 months. The mammalian target of rapamycin inhibitors rarely causes lymphedema by inhibiting different subtypes of vascular endothelial growth factors, which results in impaired lymphangiogenesis. While there are few reports about sirolimus-related lymphedema, this case represents the first everolimus-related case of lymphedema. Further studies are warranted to explain the underlying mechanisms.

Topics: Everolimus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphedema; Lymphoscintigraphy; Middle Aged; Sirolimus; Time Factors; Transplantation; Treatment Outcome; Withholding Treatment

A common situation presented in any clinical facility is a woman with swelling and redness of the breast. Diagnosis upon suspicion is often mastitis or inflammatory breast cancer, which are popular and well-known diseases of the breast. However, there is one main differential diagnosis which has to be taken into consideration: lymphedema of the breast. Twenty patients with internal diseases presented in our Breast Care Unit over a 4-year period with breast-affecting lymphedema. The patients suffered from cardiac failure, nephrotic syndrome, liver failure, lymphadenopathy, and central vein occlusion. Additionally, we identified 5 patients with a history of organ transplantation and under immunosupressive medication with sirolimus or everolimus. These mTor inhibitors are known to have unwanted side effects such as unilateral or bilateral upper/lower extremity peripheral edema or facial/eyelid edema, but as we know, isolated lymphedema of the breast represents a previously unreported complication.

Topics: Adult; Aged; Aged, 80 and over; Breast; Diagnosis, Differential; Everolimus; Female; Heart Failure; Humans; Immunosuppressive Agents; Liver Failure; Lymphatic Diseases; Lymphedema; Middle Aged; Nephrotic Syndrome; Sirolimus; Tissue Transplantation; TOR Serine-Threonine Kinases; Vascular Diseases

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by diffuse thin-walled cysts throughout the lungs on computed tomography and diffuse proliferation of abnormal smooth muscle-like cells (LAM cells) on lung biopsy. LAM affects women almost exclusively, predominantly in their reproductive age. The most typical presenting symptoms include dyspnea, spontaneous pneumothorax, cough and chylothorax. Abdominal findings represent less common initial manifestations of the disease and may pose diagnostic difficulties. The treatment of LAM has not been fully established. Recent studies report effectiveness of sirolimus in LAM patients. We report the case of a 45-year-old woman with sporadic LAM, successfully treated with sirolimus, in whom the first manifestation of the disease was chyloperitoneum and after three and nine years, respectively, lymphedema of the left lower extremity and right sided chylothorax occurred.

Topics: Chylothorax; Chylous Ascites; Female; Humans; Immunosuppressive Agents; Leg; Lymphangioleiomyomatosis; Lymphedema; Middle Aged; Prognosis; Sirolimus; Tomography, X-Ray Computed

Topics: Female; Humans; Immunosuppressive Agents; Lymphedema; Middle Aged; Severity of Illness Index; Sirolimus; Upper Extremity

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.. 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.

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Male; Sirolimus

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.

Topics: Adult; Arm; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leg; Lymphedema; Magnetic Resonance Imaging; Male; Middle Aged; Sirolimus; Wound Healing

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.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Middle Aged; Sirolimus