Early Withdrawal of Calcineurin Inhibitors and Rescue Immunosuppression with Sirolimus-Based Therapy in Renal Transplant Recipients with Moderate to Severe Renal Dysfunction

Wali, Ravinder K.; Mohanlal, Viresh; Ramos, Esther; Blahut, Steven A.; Drachenberg, Cinthia; Papadimitriou, J; Dinits, M.; Joshi, Anand; Philosophe, Benjamin; Foster, Clarence E.; Cangro, Charles B.; Nogueira, Joseph M.; Cooper, Matthew; Bartlett, Stephen T.; Weir, Matthew R.

doi:10.1111/j.1600-6143.2007.01825.x

Cited by 43 publications

(27 citation statements)

References 56 publications

(104 reference statements)

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“…The addition of sirolimus to the list of approved drugs to prevent kidney graft rejection has further facilitated trials in CNI withdrawal (116 -118) or avoidance (114,119 -122), and such strategies have been met with mixed results. The use of sirolimus in and of itself could provide some benefit as a result of its recognized antiproliferative effects on fibroblast proliferation as demonstrated recently by the stabilization of TA/IF grade and a reduction in ␣-smooth muscle actin expression after treatment in patients with moderate graft dysfunction (123) as well as the reduction in arteriolar hyalinosis and tubular degeneration in another study (124). Further studies should be considered and reviewed with the recognition that approaches for long-term maintenance of stable graft function may differ from those for the already failing transplanted kidney.…”

Section: Altering Immunosuppression: What Can Help?mentioning

confidence: 96%

Late Kidney Allograft Loss

Jevnikar

Mannon

2008

Clinical Journal of the American Society of Nephrology

103

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Despite dramatic improvements in immunosuppression, late graft loss after kidney transplantation remains a common and difficult problem. Histologic evaluation may reveal changes related to BK polyomavirus infection, hypertension, or calcineurin inhibitor toxicity, which can help to guide therapy. The designation chronic allograft nephropathy should thus be reserved for biopsies with tubular atrophy and interstitial fibrosis without an apparent cause. Although the cause clearly includes both antigen-dependent and antigen-independent events, the approach remains largely to exclude immune mechanisms. Although this review discusses the potential contribution of antibody to chronic injury, it focuses on the basic elements of kidney injury, the role of parenchymal cells in promoting injury, and the proliferative and inflammatory responses that accompanying injury. Strategies to manage these recipients include close attention to accompanying hypertension, diabetes, and hyperlipidemia, as well as consideration for altering immunosuppression; however, therapies that limit epithelial-to-mesenchymal transition or directly block fibrosis pathways may reduce chronic allograft fibrosis and may prove to be useful. Understanding the basic pathogenesis sufficiently to allow early intervention may finally benefit patients who are at high risk for tubular atrophy and interstitial fibrosis and promote their long-term graft function.

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Section: Altering Immunosuppression: What Can Help?mentioning

confidence: 96%

Late Kidney Allograft Loss

Jevnikar

Mannon

2008

Clinical Journal of the American Society of Nephrology

103

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“…Although CNIs are associated with renal injury, whether acute or chronic, many trials to minimize or even avoid CNIs, particularly cyclosporine, have been conducted (51,(67)(68)(69)(70)(71)(72)(73)(74).…”

Section: Cyclosporine Versus Tacrolimusmentioning

confidence: 99%

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

Azzi

Sayegh

Mallat

2013

The Journal of Immunology

285

210

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Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.

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“…2 Sirolimus was introduced to liver transplant to minimize the use of calcineurin inhibitors recently, especially for reducing calcineurin inhibitor-induced renal dysfunction. Sirolimus can limit or even avoid the adverse effects of calcineurin inhibitors and simultaneously guarantee adequate immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Sirolimus Conversion in Liver Transplant Recipients With Calcineurin Inhibitor-Induced Complications: Efficacy and Safety

Ju¹,

Guo²,

Liang³

et al. 2012

Exp Clin Transplant

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Objectives: To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications. Materials and Methods: After receiving liver transplants, 25 patients with calcineurin inhibitorinduced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored. Results: The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 ± 21.8 µmol/L vs 163.2 ± 45.3 µmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 ± 23.4 µmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial. Conclusions: Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes.

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Early Withdrawal of Calcineurin Inhibitors and Rescue Immunosuppression with Sirolimus-Based Therapy in Renal Transplant Recipients with Moderate to Severe Renal Dysfunction

Cited by 43 publications

References 56 publications

Late Kidney Allograft Loss

Late Kidney Allograft Loss

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

Sirolimus Conversion in Liver Transplant Recipients With Calcineurin Inhibitor-Induced Complications: Efficacy and Safety

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