Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: Calcineurin-inhibitors conversion or minimization?

González‐Vílchez, Francisco; Prada, José Antonio Vázquez de; Paniagua, María; Gómez‐Bueno, Manuel; Arizón, J.M.; Almenar, Luís; Roig, Eulàlia; Delgado, Juan; Lambert, José Luis; Pérez‐Villa, Félix; Sanz-Julve, Marisa; Crespo-Leiro, María G.; Segovia, Javier; López‐Granados, Amador; Dolz, Luis Martínez; Mirabet, Sònia; Escribano, P. Martín; Díaz‐Molina, Beatriz; Farrero, Marta; Blasco, Teresa

doi:10.1016/j.ijcard.2013.11.036

Cited by 39 publications

(21 citation statements)

References 45 publications

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“…In this regard González-Vílchez et al [16] compared, in a retrospective multi-centre cohort of 394 maintenance cardiac recipients with renal failure (GFR < 60 mL/min per 1.73 m 2 ), 235 patients in whom CNI was replaced with an mTOR-i (sirolimus or EVL) with 159 patients in whom mTOR-i was used to minimise CNIs. They concluded that in terms of renal benefits, irrespective of the strategy (minimisation vs withdrawal) the results support an earlier use of mTOR-i.…”

Section: Discussionmentioning

confidence: 99%

“…They concluded that in terms of renal benefits, irrespective of the strategy (minimisation vs withdrawal) the results support an earlier use of mTOR-i. The selection of either a conversion or a CNI minimisation protocol should be based on the clinical characteristics of the patients, particularly their rejection risk [16] . Controversy remains regarding the indicated type of CNI withdrawal -abrupt (overnight) or gradualfollowing the introduction of EVL.…”

Section: Discussionmentioning

confidence: 99%

“…In de novo HT patients, EVL in combination with CNIs has demonstrated immunosuppressive efficacy in reducing the frequency of acute rejection and chronic allograft vasculopathy (CAV) [9][10][11] . In patients in the maintenance phase, some studies have suggested that the introduction of EVL makes it possible to reduce or even discontinue CNI therapy -generally in association with preservation or improvement of kidney function while maintaining immunosuppressive efficacy [12][13][14][15][16] . In addition, as a result of their antiproliferative properties, mTOR inhibitors offer additional benefits such as a demonstrated antitumor effect [17,18] , the capacity to prevent or slow CAV progression [19] and they are associated with a lower incidence of cytomegalovirus (CMV) infection [20] .…”

Section: Introductionmentioning

confidence: 99%

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Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Manito

Delgado

Crespo‐Leiro

et al. 2015

WJT

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AIM:To determine the clinical reasons for conversion to everolimus (EVL) and long-term outcomes in heart transplant (HT) recipients. METHODS:A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients. RESULTS:Two hundred and twenty-two patients were included (mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity (30%), chronic allograft vasculopathy (20%) and neoplasms (17%). The doses and mean levels of EVL at baseline (conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors (CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d (P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL (P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL (P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min (P < 0.001). There were 37 episodes of acute rejection in 24 patients (11%). The most frequent adverse events were oedemas (12%), infections (9%) and gastrointestinal problems (6%). EVL was suspended in 44 patients (20%). Since the database was closed at the end of the study, no further followup data is available. CONCLUSION:Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Manito

Delgado

Crespo‐Leiro

et al. 2015

WJT

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“…Initial randomized trials by Eisen et al [54], and Keogh et al [55], indicated that EVL and SRL actually potentiate the nephrotoxic side effects of CNIs unless the doses of the CNIs are reduced. Several studies have, subsequently, studied HT patients in whom an m-TOR inhibitor has been introduced together with a CNI-reduction [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] or a CNI-withdrawal . Altogether, it appears as if both of the two strategies have beneficial effects on renal function, although questions remain regarding the safety and efficacy compared with ordinary CNI-therapy.…”

Section: Cni-minimizationmentioning

confidence: 99%

Immunosuppressive therapies after heart transplantation — The balance between under- and over-immunosuppression

Söderlund

Rådegran

2015

Transplantation Reviews

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“…[11][12][13][14][15][16] According to these conflicting data, shortsighted administration of EVL would not be recommended because there may be a considerable number of non-responders to EVL-incorporated regimens from the viewpoint of renal function. Hence, it is very important to select responders to EVL for the preservation of renal function during immunosuppressive therapy.…”

mentioning

confidence: 99%

Plasma Neutrophil Gelatinase-Associated Lipocalin and Worsening Renal Function During Everolimus Therapy After Heart Transplantation

et al. 2015

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SummaryRecently, the mammalian target of rapamycin inhibitor everolimus (EVL) has been introduced as a novel immunosuppressant for heart transplant (HTx) recipients, and is expected to preserve renal function compared to conventional calcineurin inhibitors (CNIs). However, a considerable number of recipients treated with EVL were not free from worsening renal function regardless of CNI reduction. Data were collected retrospectively from 27 HTx recipients who had received EVL (trough concentration, 3.1-9.2 ng/mL) along with reduced CNIs (%decreases in trough concentration, 27.3 ± 13.0%) because of switching from mycophenolate mophetil due to digestive symptoms or neutropenia, progressive coronary artery vasculopathy, or persistent renal dysfunction, and had been followed over 1 year between August 2008 and January 2013. Estimated glomerular filtration rate (eGFR) decreased in 5 recipients (18.5%) during the study period. Univariate logistic regression analysis demonstrated that a higher plasma neutrophil gelatinase-associated lipocalin (P-NGAL) level was the only significant predictor for a decrease in eGFR over a 1-year EVL treatment period among all baseline parameters (P = 0.008). eGFR and proteinuria worsened almost exclusively in patients with baseline P-NGAL ≥ 85 ng/mL, which was the cutoff value calculated by an ROC analysis (area under the curve, 0.955; sensitivity, 1.000; specificity, 0.955). In conclusion, higher P-NGAL may be a novel predictor for the worsening of renal function after EVL treatment that is resistant to CNI reduction in HTx recipients. (Int Heart J 2015; 56: 73-79)

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Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: Calcineurin-inhibitors conversion or minimization?

Cited by 39 publications

References 45 publications

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

Immunosuppressive therapies after heart transplantation — The balance between under- and over-immunosuppression

Plasma Neutrophil Gelatinase-Associated Lipocalin and Worsening Renal Function During Everolimus Therapy After Heart Transplantation

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