COMMENTARY
Editor's Note: The introduction of calcineurin inhibitors (CNI) unquestionably revolutionized kidney transplantation outcomes, helping to generate exceptionally low acute rejection rates and excellent graft survival. However, success in achieving long-term graft survival remains a significant problem. CNI nephrotoxicity remains an issue. Dr. Michael Casey from the University of Florida, Gainesville, discusses various strategies to either reduce or avoid the use of CNIs and evaluates other drugs, such as belatacept and tofacitinib that have shown promise (see his full article in Current Opinion in Nephrology and Hypertension (August 31 online publication).
Calcineurin Inhibitors in Kidney Transplantation: Friend or Foe?
Michael Jin Casey, MD, Clinical Assistant Professor of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida, U.S.A.
Since the introduction of calcineurin inhibitors (CNIs), kidney transplant recipients have achieved excellent short-term outcomes but meaningful gains in long-term outcomes have remained elusive (1). CNI nephrotoxicity is the major obstacle impeding progress in graft survival (2). This review assesses CNI efficacy and strategies used to limit CNI nephrotoxicity.
Over the past decade, three CNI-sparing strategies have emerged: CNI withdrawal, CNI avoidance, and CNI minimization (3). CNI withdrawal eliminates CNIs from recipients who have already been transplanted. CNI avoidance is the omission of CNIs from a de novo regimen. CNI minimization uses reduced-dose CNI to limit toxicity.
CNI Withdrawal with sirolimus replacement was evaluated by three multicenter trials: CONCEPT (4), Spare-the-Nephron (5), and CONVERT (6). Despite better renal function in the CNI withdrawal group in CONCEPT, the larger Spare-the-Nephron and CONVERT trials saw no improvement in renal function at 24 months. In fact, CONVERT found that late CNI withdrawal was actually harmful to patients with proteinuria or impaired renal function and halted the CNI withdrawal study arm in patients with GFR<40 mL/min. These equivocal results plus sirolimus’ significant side effect profile has limited its use in clinical practice (7).
The CAESAR trial (8) evaluated CNI-minimization and CNI-withdrawal strategies by randomizing patients to reduced-dose cyclosporine, reduced-dose cyclosporine with early withdrawal, and standard-dose cyclosporine. Renal function was similar in all 3 groups. However, the biopsy-proven acute rejection (BPAR) rate was higher in the cyclosporine withdrawal group but not in the low-dose cyclosporine group.
The landmark ELITE-Symphony study (9) compared CNI-avoidance and CNI-minimization strategies by randomizing recipients to 1 of 4 groups: low-dose sirolimus, low-dose tacrolimus, low-dose cyclosporine, or standard-dose cyclosporine. Renal function and BPAR rate were better with low-dose tacrolimus than all other treatment groups. Also, graft survival was better with low-dose tacrolimus compared to standard-dose cyclosporine and low-dose sirolimus. Surprisingly, CNI-avoidance with low-dose sirolimus failed to show improvement in renal function, and the BPAR rate and graft survival were significantly worse than low-dose tacrolimus. Given the problems associated with CNI avoidance and uncertain efficacy of CNI withdrawal, CNI minimization is the leading clinical strategy for managing CNI side effects.
Looking ahead, some novel agents—belatacept and tofacitinib (CP-690-550)—show promise in achieving sustained CNI-free regimens and prolonging graft survival. Belatacept is a T-cell costimulation blocker and was recently approved by the FDA for adult EBV-positive kidney transplant patients. In the BENEFIT trial, the 3-year mean calculated GFR was 21mL/min better with belatacept than the cyclosporine arm (10) However, belatacept saw more cases of PTLD, especially in EBV-negative patients (11) Tofacitinib is a Janus kinase inhibitor that recently completed its phase IIB trial (12) Compared to cyclosporine, tofacitinib had better renal function and more importantly, less chronic allograft nephropathy on protocol biopsies.
In conclusion, CNI-based immunosuppression regimens remain the proven standard in kidney transplantation, therefore making CNIs a necessary evil. Presently, CNI-minimization appears to be the most effective CNI-sparing strategy. However, recent advances in drug development show real promise in developing sustained CNI-sparing regimens.
References
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7. Meier-Kriesche HU, Lodhi S. 30-Year Retrospective on Organ Transplant Immunosuppression in the Era of Calcineurin Inhibitors. http://www.medscape.org/viewarticle/726494. Viewed 1 April 2011.
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9. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562-2575.
10. Vincenti F, Larsen CP, Alberu J, et al. Three-Year Outcomes from BENEFIT: A Phase III Study of Belatacept vs Cyclosporine in Kidney Transplant Recipients. 2011 American Transplant Congress. Philadelphia, USA. Abstract #227. Am J Transplant. 2011;11(Suppl 2):99.
11. Larsen CP, Grinyó J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010 Dec 27;90(12):1528-35.
12. Vincenti F, Silva HT, Busque S, et al. Efficacy and Safety of CP-690,550-MPA Combination Regimens in De Novo Kidney Transplant Patients: 12-Month Final Results of a Phase 2b Study. 2011 American Transplant Congress. Philadelphia, USA. Abstract #4. Am J Transplant. 2011;11(Suppl 2):30.
