Avoidance of Calcineurin Inhibitors With Use of Proliferation Signal Inhibitors in De Novo Heart Transplantation With Renal Failure

González‐Vílchez, Francisco; Prada, José Antonio Vázquez de; Expósito, Víctor; García-Camarero, Tamara; Fernández‐Friera, Leticia; Llano, Miguel; Ruano, Javier; Martín‐Durán, Rafael

doi:10.1016/j.healun.2008.07.020

Cited by 39 publications

(21 citation statements)

References 22 publications

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“…Twenty-five (83%) had significant preexisting glomerular pathology. Likewise, 15 to 40% of patients who underwent cardiac transplantation had significantly impaired kidney function at the time of transplantation, with only incomplete resolution in many after successful transplantation with or without CNI-based therapy, indicating that other mechanisms may be operative (54). Even so, given the 15 to 20% incidence of CKD attributed to CNI use outside of kidney transplantation (24), it is difficult to extend these observations to support the conclusion that CNI nephrotoxicity is the major cause of late kidney allograft failure.…”

Section: Alternatives To An Incomplete Paradigmmentioning

confidence: 99%

Chronic Calcineurin Inhibitor Nephrotoxicity

Gaston

2009

Clinical Journal of the American Society of Nephrology

113

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Use of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus has revolutionized solid organ transplantation. For more than 30 yr, the transplant community has dealt with nephrotoxicity attributed to these agents. Acute renal vasoconstriction (as described by many investigators, including John Curtis and colleagues) is the unequivocal consequence of their use; chronic CNI nephropathy, although indistinct in terms of histology and pathophysiology, has become accepted as a major cause of late kidney allograft failure. This article examines clinical, laboratory, and histologic findings that evolved into a paradigm that was never fully consistent with observed outcomes and new evidence that may offer an alternative interpretation for adverse events that are attributed to CNI nephrotoxicity in kidney transplant recipients.

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Section: Alternatives To An Incomplete Paradigmmentioning

confidence: 99%

Chronic Calcineurin Inhibitor Nephrotoxicity

Gaston

2009

Clinical Journal of the American Society of Nephrology

113

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“…Additionally, a marked reduction in CNI dose is essential since everolimus with standard-dose CNI actually impairs renal function (13). Thus, immunosuppression based on an mTOR inhibitor and early CNI withdrawal in de novo heart transplant patients has been considered, but caution due to concerns about side effects has meant that experience is limited to a few observational studies of everolimus or sirolimus with CNI avoidance (12,14). The only randomized trial of de novo heart transplant recipients to date, in which sirolimus was administered with CNI withdrawal, was terminated prematurely due to side effects (15).…”

Section: Introductionmentioning

confidence: 99%

Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial

Andreassen

Andersson

Gustafsson

et al. 2014

American Journal of Transplantation

134

118

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“…3 Furthermore, liver-and heart-transplanted patients are likely to have existing renal abnormalities before they are exposed to CNIs, which makes it difficult to interpret interstitial fibrosis occurring some years after their introduction in these patients. 4,5 Lastly, kidneys from rodents experimentally given CNIs for weeks exhibit histologic features that resemble the supposedly CNI-induced IF/TA observed in humans; however, supratherapeutic doses of CNI have often been used that are not necessarily patient-relevant. Whatever the repercussions that CNIs may have on kidneys, the question of whether they correspond to irreversible structural changes or are, on the contrary, reversible once they are withdrawn is of clinical significance: Removing CNIs from the regimen of patients with a well functioning graft is currently in vogue, but it is also risky.…”

mentioning

confidence: 99%

Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients

Hazzan

Hertig²,

Buob³

et al. 2011

Journal of the American Society of Nephrology

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Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and ␤-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P ϭ 0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.

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Avoidance of Calcineurin Inhibitors With Use of Proliferation Signal Inhibitors in De Novo Heart Transplantation With Renal Failure

Cited by 39 publications

References 22 publications

Chronic Calcineurin Inhibitor Nephrotoxicity

Chronic Calcineurin Inhibitor Nephrotoxicity

Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial

Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients

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