Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects

Klein, Inge H H T; Abrahams, Alferso C; Ede, Thomas; Hené, Ronald J.; Koomans, Hein A.; Ligtenberg, Gerry

doi:10.1097/00007890-200203150-00012

Cited by 136 publications

(79 citation statements)

References 40 publications

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“…Differences in renal function between Larson's and other studies may be explained by the different anti-calcineurinic drugs used in the control group because it seems that CsA induces more profound renal hemodynamic changes than TAC, at least at the current target levels for clinical immunosuppression. 22 By exclusion of those with secondary immunosuppression, group A patients could obtain comparable renal function with group B patients after 5 yr, however, with high exclusion rate that exceeds 50%.…”

Section: Discussionmentioning

confidence: 90%

Long-term Efficacy and Safety of a Calcineurin Inhibitor-free Regimen in Live-Donor Renal Transplant Recipients

Hamdy

Bakr²,

Ghoneim³

2008

Journal of the American Society of Nephrology

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Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P ϭ 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.

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Section: Discussionmentioning

confidence: 90%

Long-term Efficacy and Safety of a Calcineurin Inhibitor-free Regimen in Live-Donor Renal Transplant Recipients

Hamdy

Bakr²,

Ghoneim³

2008

Journal of the American Society of Nephrology

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“…Although some have suggested that TAC is less nephrotoxic than CSA (4,20), these data are controversial and often based on short-term studies and on renal function (21). Most studies comparing TAC and CSA nephrotoxicity are in renal allografts where chronic rejection, hypertension, and recurrent disease may be confounding factors (3).…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus and Cyclosporine Nephrotoxicity in Native Kidneys of Pancreas Transplant Recipients

Fioretto

Najafian

Sutherland³

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Calcineurin inhibitors, while representing advances for solid organ transplantation, have nephrotoxic potential that reduces their net benefit. Tacrolimus has been considered less nephrotoxic than cyclosporine, but direct quantitative comparisons of the changes in renal structure from baseline to follow-up biopsies have not been done. To avoid the pitfalls of renal allograft studies, including rejection and disease recurrence, we compared the development of calcineurin lesions in the native kidneys of 14 tacrolimus-and 12 calcineurin-treated pancreas transplant alone recipients cured of type 1 diabetes.Design, setting, participants, & measurements Research renal biopsies obtained before and at 5 years after transplantation were studied using established morphometric methods. ResultsThe cyclosporine and tacrolimus groups had, respectively, on average, 33% versus 44% decline in GFR (ns), 27% versus 29% increase in cortical interstitial fractional volume (ns), 245% versus 347% increase in the fractional volume of cortical tubules that were atrophic (ns), and 291% versus 392% increase in the percent of globally sclerotic glomeruli (ns). Arteriolar hyalinosis did not change significantly in either group. ConclusionsThese studies indicate that the nephrotoxic potential of tacrolimus and cyclosporine are equivalent and support the development of strategies to reduce these negative effects.

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“…Animal studies have demonstrated that the vasoconstrictive effect of tacrolimus is weaker than of cyclosporine (205)(206)(207), and this was also confirmed in humans (208,209). Moreover, the fibrogenic potential of tacrolimus also appears to be lower (210), although these results could not be confirmed in a more recent study (135).…”

Section: Comparison Between Cyclosporine and Tacrolimusmentioning

confidence: 98%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

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1,000

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects

Cited by 136 publications

References 40 publications

Long-term Efficacy and Safety of a Calcineurin Inhibitor-free Regimen in Live-Donor Renal Transplant Recipients

Long-term Efficacy and Safety of a Calcineurin Inhibitor-free Regimen in Live-Donor Renal Transplant Recipients

Tacrolimus and Cyclosporine Nephrotoxicity in Native Kidneys of Pancreas Transplant Recipients

Calcineurin Inhibitor Nephrotoxicity

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