Calcineurin Inhibitor Nephrotoxicity: Longitudinal Assessment by Protocol Histology

Nankivell, Brian J.; Borrows, Richard; Fung, Caroline; O’Connell, Philip J.; Chapman, Jeremy R.; Allen, Richard D.

doi:10.1097/01.tp.0000128636.70499.6e

Cited by 444 publications

(344 citation statements)

References 27 publications

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“…Kidney transplant patients receiving immunosuppressive therapy with mTOR inhibitors can benefit from less nephrotoxicity by reducing their exposure to CNIs 3, 4, 5, 6, 7, 8. There is a paucity of published data on the use of EVR in combination with Tac in de novo renal transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus

Shihab

Qazi

Mulgaonkar

et al. 2017

American Journal of Transplantation

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A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open‐label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low‐dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time‐normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy‐proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3–8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. Trial registration: NCT01025817.

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Section: Discussionmentioning

confidence: 99%

Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus

Shihab

Qazi

Mulgaonkar

et al. 2017

American Journal of Transplantation

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“…Results have demonstrated that immunosuppressive efficacy is maintained, but although an improvement in graft function has been observed (13) a significant difference may not be sustained (17). Evidence from a series of randomized studies indicates that longer-term renal benefit may be achieved if an mTOR inhibitor is introduced and CNI therapy is withdrawn during the first 6 months after kidney transplantation (18)(19)(20)(21), before extensive, irreversible CNI-related nephrotoxicity develops (2).…”

Section: Introductionmentioning

confidence: 98%

“…Immunosuppressive regimens that minimize exposure to calcineurin inhibitors (CNIs) following kidney transplantation have been widely investigated in order to reduce the burden of CNI-related complications (1), particularly nephrotoxicity (2). These efforts have focused on three possible strategies: total avoidance of CNI therapy, low-exposure CNI regimens, or CNI withdrawal (3,4).…”

Section: Introductionmentioning

confidence: 99%

Five-Year Outcomes in Kidney Transplant Patients Converted From Cyclosporine to Everolimus: The Randomized ZEUS Study

Budde

Lehner

Sommerer

et al. 2015

American Journal of Transplantation

113

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“…The chronic use of CNIs can induce many different types of glomerular injury. Most commonly, global glomerulosclerosis results from severe CNI-associated arteriolar hyalinosis and arteriolopathy and secondary glomerular ischemia (115,155,156), as was also seen in diabetes mellitus (157). Furthermore, tubular damage (see above) leads to the development of atubular glomeruli, which are perfused glomeruli that are disconnected from their proximal tubule.…”

Section: Chronic Cni Nephrotoxicitymentioning

confidence: 99%

“…Acute CNI nephrotoxicity has been associated with relatively higher systemic exposure to cyclosporine (156) and tacrolimus (85,91). A recent study could not confirm this association, although there was a clear trend for tacrolimus, without reaching statistical significance (257).…”

Section: Systemic Levels Of Cyclosporine and Tacrolimusmentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,217

1,014

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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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Calcineurin Inhibitor Nephrotoxicity: Longitudinal Assessment by Protocol Histology

Cited by 444 publications

References 27 publications

Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus

Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus

Five-Year Outcomes in Kidney Transplant Patients Converted From Cyclosporine to Everolimus: The Randomized ZEUS Study

Calcineurin Inhibitor Nephrotoxicity

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