Chronic Lymphedema in Renal Transplant Recipients Under Immunosuppression With Sirolimus

Baliu, Carola; Esforzado, Núria; Campistol, Josep M.; Mascaró, José M.

doi:10.1001/jamadermatol.2014.158

Cited by 12 publications

(9 citation statements)

References 5 publications

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“…Recent studies have shown that CD4 + T cells play a critical role in development of the hallmarks of lymphedema (3)(4)(5)(6)(7)(8)(9). Interestingly, however, there have been reports of immunosuppressed patients with secondary lymphedema despite having low levels of CD4 + T cells (10)(11)(12)(13). In this study, we corroborate this data by demonstrating that mice with relative CD4 + T cell deficiency due to TBI are not protected from developing lymphedema after lymphatic injury.…”

Section: Discussionsupporting

confidence: 81%

“…Although the importance of CD4 + T cells has been corroborated by numerous studies, little is known about the mechanisms that lead to the accumulation of these cells in lymphedematous tissues or whether there is a threshold of cells required to promote lymphedema. Interestingly, there have been a few case reports of renal transplant patients on maintenance immunosuppressive therapy with sirolimus, an mammalian target of rapamycin (mTOR) inhibitor that hinders the proliferation of T cells, who have developed lymphedema (10,11). Similarly, others have described patients with acquired immunodeficiency syndrome (AIDS) due to human immunodeficiency virus (HIV) who have presented with lymphedema secondary to lymphatic obstruction resulting from Kaposi's sarcoma (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Small Numbers of CD4+ T Cells Can Induce Development of Lymphedema

Cuzzone

Kataru

et al. 2019

Plastic &Amp; Reconstructive Surgery

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Background: CD4 + T cells have been implicated in the pathology of lymphedema. Interestingly, however, there have been case reports of lymphedema development in patients with low levels of CD4 + T cells due to immunosuppression. In this study, we sought to delineate the effect of relative CD4 + T cell deficiency on the development of lymphedema in a mouse model. Methods: A mouse model of relative CD4 + T cell deficiency was created through lethal total body irradiation of wild-type (WT) mice that then underwent bone marrow transplantation with progenitors harvested from CD4 knockout (CD4KO) mice (WT/CD4KO). Irradiated CD4KO mice reconstituted with WT mouse-derived progenitors (CD4KO/WT), as well as unirradiated CD4KO and WT mice were used as controls. All mice underwent tail skin and lymphatic excision to induce lymphedema and analysis was performed six weeks later. Results: WT/CD4KO chimeras were not protected from developing lymphedema. Despite a global deficit in CD4 + T cells, these mice had swelling, fibrosis, inflammation, and impaired lymphatic transport function indistinguishable from that in WT and CD4KO/WT mice. In contrast, unirradiated CD4KO mice had no features of lymphedema after lymphatic injury. Conclusions: Relatively few numbers of bone marrow and peripheral CD4 + T cells are sufficient to induce the development of lymphedema. These findings suggest that lymphatic injury results in expansion of CD4 + T cell populations in lymphedematous tissues.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Small Numbers of CD4+ T Cells Can Induce Development of Lymphedema

Cuzzone

Kataru

et al. 2019

Plastic &Amp; Reconstructive Surgery

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“…20 One variable that may be considered in comparing differences between reports is the use of immunosuppressive agents. For example, chronic lymphedema has been reported in renal transplant recipients given sirolimus, 25 whereas observations in many animal models did not utilize immunosuppressants. 20 Another observation that can be inferred…”

Section: Kidney Transplantationmentioning

confidence: 99%

“…In rat renal allografts, sirolimus inhibited lymphangiogenesis, leading to improved graft function and a reduction of chronic kidney allograft injury compared to use of the calcineurin inhibitor cyclosporine . Indeed, chronic lymphedema has been reported in renal transplant patients attributable to sirolimus in the same location where the arteriovenous fistula used for dialysis occurred . Further study of the effects of mTOR inhibitors on lymphangiogenesis and lymphatic function in the context of transplantation is warranted to determine the effects of mTOR inhibition in nonrenal transplants and whether use of mTOR inhibitors in place of calcineurin inhibitors alters effects on LVs and graft outcome.…”

Section: Effect Of Immunosuppressive Drugs On Lymphatic Endothelial Cmentioning

confidence: 99%

Lymphatic vessels in solid organ transplantation and immunobiology

Wong

2020

American Journal of Transplantation

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endothelial hyaluronan receptor 1; MALT, mucosa-associated lymphoid tissue; mTOR, mechanistic target of rapamycin (also known as mammalian target of rapamycin); mTORC1, mechanistic target of rapamycin complex 1; NFAT, nuclear factor of activated T cells; NFκB, nuclear factor kappa B; NRP2, neuropilin 2; PDPN, podoplanin; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PROX1, prospero homeobox transcription factor 1; SLO, secondary lymphoid organ; TGFβ1, transforming growth factor beta 1; TLO, tertiary lymphoid organ; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; VEGF-A, vascular endothelial growth factor A; VEGF-C, vascular endothelial growth factor C; VEGF-D, vascular endothelial growth factor D; VEGFR3, vascular endothelial growth factor receptor 3 (known as Flt4 in the mouse).

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“…Such previously reported cases are summarized in Table 3 . [ 23 – 26 ] The mechanism by which sirolimus interferes with lymphatic drainage is still unclear. However, one hypothesis is that it inhibits lymphangiogenesis by interfering with the activation of intracellular pathways in lymphatic endothelial cells that act as a major initiator of lymphangiogenesis during the postsurgical regeneration period.…”

Section: Discussionmentioning

confidence: 99%

Lymphedema secondary to idiopathic occlusion of the subclavian and innominate veins after renal transplantation

Kim

Moon²,

Goo

et al. 2017

Medicine

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Rationale:Among the causes of swelling in the extremities of renal transplantation patients, secondary lymphedema caused by complete idiopathic obstruction of large veins is rare and may be difficult to diagnose and treat.Patient concerns:A 64-year-old man presented with severe edema and pain that occurred suddenly in the right arm.Diagnoses:The patient was diagnosed as stage-2 secondary lymphedema caused by idiopathic occlusion of the subclavian and innominate veins.Interventions:Lymphoscintigraphy and ascending venography of the right arm confirmed the diagnosis. Intensive complete decongestive therapy for lymphedema was performed.Outcomes:Following 2 weeks of active rehabilitation, the pain level and edema status were significantly improved.Lessons:When idiopathic swelling of the extremities occurs in renal transplant patients, secondary lymphedema caused by venous occlusion may be the cause. When direct intervention for the venous occlusion proves to be difficult, a conservative approach may be helpful.

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Chronic Lymphedema in Renal Transplant Recipients Under Immunosuppression With Sirolimus

Cited by 12 publications

References 5 publications

Small Numbers of CD4+ T Cells Can Induce Development of Lymphedema

Small Numbers of CD4+ T Cells Can Induce Development of Lymphedema

Lymphatic vessels in solid organ transplantation and immunobiology

Lymphedema secondary to idiopathic occlusion of the subclavian and innominate veins after renal transplantation

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