Calcineurin Inhibitor Nephrotoxicity

Abstract

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...

Simultaneous Liver–Kidney Allocation Policy: A Proposal to Optimize Appropriate Utilization of Scarce Resources

“…The definition of CKD chosen was formulated by incorporating the current published literature with the observed characteristic of SLK patients discussed above. In addition, although the published literature is conflicting, it supports the clinical impression that in a patient with low GFR, the addition of calcineurin inhibitor to the medical regimen causes an 10 mL/min reduction in eGFR (13)(14)(15). Consequently, CKD was defined as eGFR of <60 mL/min for >90 days prior to listing and an eGFR of <35 mL/min at the time of listing.…”

Current Status of Immunosuppression in Liver Transplantation

“…The chronic form of CNI nephrotoxicity is characterized by develop ment of irreversible structural damage-obliterative arteriolo pathy, glomerular collapse and scarring, tubular vacuo lization, tubular atrophy and interstitial fibrosis, which are probably the long-term consequences of renal hypoxia secondary to renal vasoconstriction. [50][51][52] With concomitant use with CNIs, mTOR inhibitors such as Sirolimus may worsen nephropathy possibly because of inhibition of renal tubular cell proliferation (part of tubular repair) and increase in TGF-b expression in experimental CsA nephrotoxicity. A characteristic cast nephropathy lesion has also been reported with use of mTOR inhibitors.…”

Fludarabine metabolite level on day zero does not affect outcomes of hematopoietic cell transplantation in patients with normal renal function

“…Covariates considered were (1) for acute and chronic GVHD, donor type (HLA-matched sibling vs other), gender combination (male/male vs other) and patient age (above vs below 45 years); (2) for CMV reactivation above our institutional threshold for preemptive antiviral therapy (25 000 IU/mL plasma), CMV IgG serostatus pretransplant ( Letter to the Editor role. For example, the earlier start of cyclosporine by Long-Boyle might have led to a decreased glomerular filtration rate 5 and thus higher F-ara-A levels on day 0, possibly explaining why anti-GVHD effect was detected in Long-Boyle's but not our study. ); (3) cord blood was the predominant graft type in Long-Boyle's study; the cord blood stem cells may have been more sensitive to the myelotoxic effects of F-ara-A compared with the adult donor blood stem cells used in our study.…”