Conversion From Calcineurin Inhibitors to Sirolimus in Kidney Transplant Patients Reduces the Urinary Transforming Growth Factor-β1 Concentration

The mammalian target of rapamycin inhibitors (mTOR-I), sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

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“…However, some in vitro experiments have also reported a prooxidant induced by mTOR-I whose effects may decrease NO availability [106–111]. …”

Section: Cardiovascular Diseasementioning

confidence: 99%

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

Zaza

Tomei

Ria

et al. 2013

Clinical and Developmental Immunology

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“…Calcineurin inhibitors (CNI) as cyclosporin A (CsA) have been suggested to play a role in the pathogenesis of this endothelial dysfunction [8–10]. Indeed, their long‐term administration may be associated with the decrease in endothelium‐derived NO availability, intrarenal vasoconstriction and stimulation of fibrogenic cytokines [11–19] that are involved in CNI‐induced hypertension and chronic allograft dysfunction [20]. More recently, new CNI agents and dose minimization strategies have been proposed with a better tolerance and efficacy on renal function, but their effects on endothelial function remain a matter of debate [7,21–26].…”

Section: Introductionmentioning

confidence: 99%

“…Another approach consisted in the development of immunosuppressant regimens that spare or avoid CNI, such as those based on the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (SRL) [20,27]. Its administration in animals and humans is accompanied by beneficial vascular effects dominated by the decrease in arterial neo‐intimal proliferation and allograft vasculopathy, although some in vitro experiments have also reported an oxidant effect that may compromise the endothelial NO availability [17,18,27–32]. In transplant patients, SRL is less frequently associated with the onset of hypertension, and its nephrotoxicity has also been demonstrated to be lesser than that of CNI when used at standard or lower doses [33–35].…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of sirolimus and cyclosporin on conduit arteries endothelial function in kidney recipients

Joannidès

Étienne

Iacob

et al. 2010

Transplant International

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Summary This study attempted to establish whether a calcineurin inhibitor (CNI)‐free immunosuppressant regimen based on sirolimus (SRL) is associated with a preservation of conduit arteries endothelial function in kidney recipients or not. Twenty‐nine kidney recipients were randomized to receive since transplantation SRL (n = 15) or cyclosporin A (CsA, n = 14) associated with mycophenolate mofetil (MMF) and steroids (6 months) in a parallel prospective study. Systolic, diastolic blood pressures, glomerular filtration rate (GFR) and radial artery flow‐mediated dilatation (FMD) induced by postischaemic hyperaemia were assessed in a blind manner at one (M1) and 7 months (M7) after transplantation. Endothelium‐independent dilatation was assessed by glyceryl trinitrate spray. There was no difference between the groups for all vascular parameters at M1. At M7, systolic blood pressure was lower (SRL: 119 ± 3 vs. CsA: 138 ± 4 mmHg, P < 0.05) and FMD was higher in SRL compared with CsA (SRL: 13.1 ± 0.9 vs. CsA: 9.9 ± 0.9%, P < 0.05) without any difference for hyperaemia, endothelium‐independent dilatation and GFR (SRL: 66.7 ± 1.05 vs. CsA: 67.5 ± 1.22 ml/min). Our results demonstrate that a CNI‐free regimen based on SRL and MMF prevents conduit artery endothelial dysfunction compared with CsA and MMF in kidney recipients suggesting a beneficial arterial wall effect that may also contribute to the decrease in systolic blood pressure.

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“…Improvement of proteinuria after SRL withdrawal has suggested direct association of proteinuria with the drug. This condition has been mostly observed after withdrawal of CNI and conversion to SRL, although de novo treatment by SRL has not been found so far associated (58, 63). The mechanism has been explained through a hemodynamic effect as reduction of renal blood flow with the use of CNIs at the level of afferent arteriole and increased renal blood flow and associated proteinuria after withdrawal of the CNIs (58).…”

mentioning

confidence: 99%

Sirolimus in pediatric renal transplantation

Kasap

2011

Pediatric Transplantation

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SRL, an mTOR inhibitor that inhibits cell cycle progression, represents an important alternative to CNIs, which are still the cornerstones of pediatric solid organ tx. Because there are still limited data on SRL use among pediatric solid organ recipients, further studies are needed to verify the efficacy and safety of SRL. It has unique pharmacokinetic characteristics concerning dosing intervals and reduction of the dose in combination with other immunosuppressants. SRL also has antineoplastic, antiviral, and antiatherogenic advantages over other immunosuppressive agents. The adverse effects of SRL including thrombocytopenia, hyperlipidemia, proteinuria, impaired wound healing, mouth ulcers, edema, male hypogonadism, TMA, and interstitial pneumonitis must be considered carefully in pediatric population. This article reviews the most recent data on SRL application in the field of pediatric renal tx.

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Conversion From Calcineurin Inhibitors to Sirolimus in Kidney Transplant Patients Reduces the Urinary Transforming Growth Factor-β1 Concentration

Cited by 12 publications

References 13 publications

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

Comparative effects of sirolimus and cyclosporin on conduit arteries endothelial function in kidney recipients

Sirolimus in pediatric renal transplantation

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