FTY720 combined with tacrolimus in de novo renal transplantation: 1-year, multicenter, open-label randomized study

Hoitsma, Andries J.; Woodle, E. Steve; Abramowicz, Daniel; Proot, Pieter; Vanrenterghem, Yves

doi:10.1093/ndt/gfr503

Cited by 39 publications

(30 citation statements)

References 9 publications

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“…Originally, fingolimod was evaluated as a treatment for renal transplant rejection, wherein patients received higher doses of fingolimod (2.5 and 5 mg), in combination with cyclosporine, tacrolimus, and/or steroids [3,4,5,6]. In this context, macular edema (ME) has been identified as a specific adverse event of fingolimod in renal transplant patients [3,4,5,6].…”

Section: Introductionmentioning

confidence: 99%

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Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

Pul

Osmanovic

Schmalstieg

et al. 2016

IJMS

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Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME.

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Section: Introductionmentioning

confidence: 99%

“…In this context, macular edema (ME) has been identified as a specific adverse event of fingolimod in renal transplant patients [3,4,5,6]. In the phase II core study of fingolimod in multiple sclerosis (MS) and its extensions, two high doses of fingolimod (1.25 and 5.0 mg) were administered and none of the patients developed ME [7,8,9,10].…”

Section: Introductionmentioning

confidence: 99%

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

Pul

Osmanovic

Schmalstieg

et al. 2016

IJMS

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“…FTY720 {fingolimod; 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride} is a sphingosine-1-phosphate (S1P) analog originally developed as a novel immunosuppressant and has currently been tested in phase III studies for the treatment of renal transplantation. 7 The mechanism of immunosuppressive action of FTY720 has not been fully elucidated, although a characteristic depletion of circulating lymphocytes in the peripheral blood and a reduction of lymphocyte infiltration into injured tissues by accelerating lymphocyte homing into peripheral lymph nodes has been observed in some experimental models. 8 More interestingly, previous studies have shown that FTY720 attenuates renal injury in many experimental models, such as antithy1-induced chronic glomerulosclerosis, 9 renal ischemia reperfusion injury, 10 subtotal nephrectomy, 11 experimental hypertensive nephropathy 12 and antiglomerular basement membrane glomerulonephritis.…”

Section: Introductionmentioning

confidence: 99%

FTY720 attenuates tubulointerstitial inflammation and fibrosis in subtotally nephrectomized rats

Chen

Zhang

et al. 2013

Renal Failure

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Tubulointerstitial fibrosis is a common pathway that leads to kidney failure, and persistent tubulointerstitial inflammation is a key event in the development of tubulointerstitial fibrosis. The new immunosuppressive drug FTY720 modifies lymphocyte migration into injured tissues by sequestering lymphocytes within secondary lymphoid organs. However, its therapeutic effect on tubulointerstitial inflammation and fibrosis had not been well understood. This study was designed to explore the effect of FTY720 on tubulointerstitial inflammation and fibrosis in subtotally nephrectomized (SNX) rats. In total, 24 male Sprague-Dawley rats were used. Seven days after 5/6 nephrectomy, rats were randomized to FTY720 (1 mg/kg/d) and placebotreated groups. Sham-operated rats served as controls. FTY720 significantly attenuated the rise in proteinuria, serum creatinine, urea nitrogen and N-acetyl-b-D-glucosaminidase activity in SNX rats, and reduced the count of peripheral white blood cells and lymphocytes in SNX rats. Morphological analysis revealed that there was severe tubulointerstitial inflammation and fibrosis in SNX group and much more tubulointerstitial infiltrating inflammatory cells with high expression of CD3, CD4, CD8, CD20, CD68, CD163 and CCR-7 in SNX group, as compared with the controls, but the lesions were attenuated significantly by treatment with FTY720. Furthermore, the expressions of proinflammatory molecules (IL-6, TNF-a and MCP-1), profibrotic molecule (TGF-b1) and production of extracellular matrix proteins such as fibronectin and types I and III collagens were upregulated in SNX rats. FTY720 administration significantly reduced these abnormalities. In summary, FTY720 exerts therapeutic effects on tubulointerstitial fibrosis in SNX rats by inhibiting the tubulointerstitial inflammatory response.

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“…16 Coexisting disease like diabetes, diabetic retinopathy, retinal vascular disease, past ocular surgery, and uveitis increase the risk of ME. 16,17 In patients who develop fingolimod-associated ME, cessation of the drug results in the resolution of symptoms.…”

Section: 17mentioning

confidence: 99%

Fingolimod and macular edema

et al. 2014

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SummaryFingolimod causes macular edema (ME) by acting via the S1P3 receptor agonism, thereby reducing the tight junction between the endothelial cells of the retinal capillaries. This results in the breakdown of the inner blood retinal barrier, causing ME. Ophthalmologic evaluation including optical coherence tomography is recommended at baseline and then at 3 months, 6 months, and annually thereafter in all patients on fingolimod. The risk of ME increases in patients who are diabetic, have had uveitis, or who undergo intraocular procedures such as cataract surgery, and hence these patients need close monitoring. Cessation of the drug results in resolution of the ME. However, ME can also be treated using anti-inflammatory medication (steroids) in patients who opt to remain on fingolimod.F ingolimod is the first oral disease-modifying therapy approved for the treatment of multiple sclerosis (MS). The efficacy of fingolimod has been demonstrated in 2 large, phase III, double-blind, randomized trials.1,2 Practical aspects related to the use of fingolimod and its systemic side effects have been described. 3Fingolimod was used initially as an immunomodulator to augment the immunosuppressive effect of other drugs in renal transplant rejection. The dosage for renal transplant ranged between 2.5 and 5 mg, 5 and 10 times that approved for treatment of MS. Fingolimod failed to show a benefit for the prevention of renal allograft rejection over the conventional treatment in large phase III studies and hence further development in renal transplantation was stopped. In these studies, fingolimod was associated with the development of macular edema (ME).4 As

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FTY720 combined with tacrolimus in de novo renal transplantation: 1-year, multicenter, open-label randomized study

Abstract: FTY720 combined with tacrolimus and steroids did not show a significant therapeutic advantage over MMF for the prevention of acute rejection in de novo renal transplant recipients.

Cited by 39 publications

References 9 publications

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

FTY720 attenuates tubulointerstitial inflammation and fibrosis in subtotally nephrectomized rats

Fingolimod and macular edema

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