Are calcineurin inhibitors-free regimens ready for prime time?

mini review

http://www.kidney-international.org & 2012 International Society of Nephrology

Are calcineurin inhibitors-free regimens ready for prime time? Flavio Vincenti1 1

University of California, San Francisco, Kidney Transplant Service, San Francisco, California, USA

The goal of research in transplant therapeutics is to achieve safe and effective immunosuppression strategies that allow durable engraftment free of toxicities. The calcineurin inhibitors (CNIs) regimens, because of their inherent toxicities (including nephrotoxicity), have been unable to meet these promises. Over the past decade acute cellular rejection decreased dramatically with a concomitant robust increase in 1-year graft survival; however, long-term graft outcome showed only modest improvement. This is due in part to the toxicities of the immunosuppressive drugs. The quest for a toxicity-free–CNI-free regimen has been both intense and frustrating. A turning point in CNIs-free therapy may have occurred with the recent approval of belatacept, which represents a new paradigm in immunosuppression: biological therapy for chronic immunosuppression devoid of the usual toxicities associated with the CNIs. Belatacept, a fusion receptor protein, blocks costimulation signals necessary for the activation of T cells. Although costimulation blockade has not been shown to induce tolerance, it can provide safe and effective immunosuppression without renal or cardiovascular toxicities. The approval of belatacept in both the United States and Europe for use in renal transplantation will finally push CNI-free regimens into prime time. Novel biologics such as ASKP1240 (a human anti-CD40 monoclonal antibody) and one small molecule, tofacitinib, may advance further the use of CNI-free regimens in organ transplantation. Kidney International (2012) 82, 1054–1060; doi:10.1038/ki.2012.194; published online 23 May 2012 KEYWORDS: immunosuppression; nephrotoxicity; transplantation

Correspondence: Flavio Vincenti, University of California, San Francisco, Kidney Transplant Service, 505 Parnassus Avenue, Room 884M, San Francisco, California 94143-0780, USA. E-mail: [email protected] Received 20 December 2011; revised 27 February 2012; accepted 13 March 2012; published online 23 May 2012 1054

The introduction of cyclosporine in the 1980s transformed the field of transplantation in ways that few would have foreseen.1 The dramatic improvement in outcome of patients treated with cyclosporine established renal transplantation as the treatment of choice for the patients with end-stage renal disease. The addition of tacrolimus and the more potent antiproliferative agents mycophenolate mofetil (MMF) and sirolimus, as well as biological induction, depleting antibodies, and anti-IL2 receptor monoclonals, led to greater efficacy, lower rate of acute complications, and shorter hospital stays.2–5 These novel potent immunosuppression regimens introduced in the 90s reduced acute rejection to levels below 20% and produced substantial gains in 1-year graft survival.3,4 The spectacular success of calcineurin inhibitor (CNI)–based regimens had, however, a dark side that continues to limit better longer-term patient and graft survival. It has been amply documented that the reduction of acute rejection did not appreciably improve patient and graft outcome beyond the first year of transplantation.3,4 In fact in over 50,000 kidney transplant recipients analyzed by the Collaboration Transplant Study, any combination of CNIs and antiproliferatives resulted in exactly the same graft survival at 5 years.6 Table 1 lists five potential reasons for the failure of CNIbased regimens to improve long-term outcome. Even the role of the nephrotoxicity of CNIs as an important cause of graft failure has become a controversial issue. That CNIs are and can be nephrotoxic and that they can induce progressive renal failure is undisputed.7,8 However, their previously documented prominent role in late graft dysfunction has recently been questioned.9,10 The progressive and inexorable nature of CNI nephrotoxicity was documented in an elegant study by Nankivell et al. in renal allografts biopsied yearly over 10-year follow-up. However, a critique of this study is that analysis of donor-specific antibodies (DSAs) and C4d staining were not available at the time the study was conducted, and that the diagnosis of nephrotoxicity is not specific and thus assigning the cause of the histological findings may not have been precise. In fact, three recent histological analyses dispute the conclusions by Nankivell et al. Cosio et al. in a study of protocol kidney biopsies performed at 1 year in low immunological risk recipients reported that the presence of histological abnormalities usually ascribed to CNIs (tubular atrophy and interstitial fibrosis) were not associated with Kidney International (2012) 82, 1054–1060

mini review

F Vincenti: Calcineurin inhibitors-free regimens

progressive renal dysfunction.9 Instead the finding of inflammation in the biopsies adversely affected subsequent renal function. In a study by Snanoudj et al.,11 histological lesions associated with CNI toxicity were present, though less frequently, in kidneys of patients who were never exposed to CNIs. In the multicenter DEKAF (Determination of Late Kidney Failure) trial, transplant recipients who had been assigned a histological diagnosis of CNI nephrotoxicity had better outcome than those without it. The interpretation of these data is not that CNI toxicity is necessarily benign, but that if patients have enough CNI exposure to produce nephrotoxicity, they also may have been optimally immunosuppressed. Furthermore, in the DEKAF trial, chronic antibody–mediated rejection (diagnosed by DSA or C4d or both) and not nephrotoxicity was the predominant cause of late graft dysfunction. The conclusion from the DEKAF trial and the study by Cosio et al. is that alloimmune injury (from under-immunosuppression) rather than nephrotoxicity (from elevated exposure to CNIs) may be the primary cause of late graft failure. This would imply that strategies that were advocated to minimize CNI exposure to decrease nephrotoxicity and to improve renal function in the short term may have the unintended consequence of increasing the risk of chronic rejection and accelerate the loss of renal allografts.12,13 The need for CNI-free regimens has become more urgent yet it has remained elusive.14,15 Withdrawal of CNIs after a period of time after transplantation and conversion to a CNI-free regimen have been attempted with mixed results.16 Even the combination of Tor inhibitors and mycophenolic acid after CNI withdrawal is challenging both in terms of efficacy and toxicity.12,15

Table 1 | Five important reasons for the failure of CNI-based regimens to improve long-term outcome 1. Early cellular rejection, decreased by the CNIs, does not impact longterm graft survival 2. Immunosuppression with CNIs may be inadequate in controlling the emergence of DSA and chronic antibody–mediated rejection, a major cause of late graft failure either because of minimization regimens and/ or non-adherence 3. Late graft failure may occur from mechanisms unrelated to alloimmune injury: nephrotoxicity, accelerated senescence, and glomerular disease 4. Graft loss from BK nephropathy 5. Persistence of graft loss from premature death from infections and cardiovascular disease Abbreviation: BK, polyomavirus; CNIs, calcineurin inhibitors.

CNI-FREE REGIMENS WITH COSTIMULATION BLOCKADE

A more direct approach has been to attempt a CNI-free regimen de novo after transplantation. One of the earliest multicenter trials combined prolonged anti-IL2 receptor antibody therapy with daclizumab, MMF, and steroids.14 This immunosuppression strategy was associated with an unacceptably high rate of acute rejection although the 1-year patient and graft survival was good. The introduction of Tor inhibitors added a new element to this approach, leading to combined use of the antiproliferatives sirolimus and MMF as replacements of the CNIs. Although early results were encouraging, larger randomized trials failed to show satisfactory efficacy and tolerability of this regimen.12,15,17 Thus, new agents that inhibit novel and critical pathways of immune activation are needed for the acceptance of CNI-free regimens in clinical practice. Three agents in clinical trials may help fulfill the promise of non-nephrotoxic, safe, and effective immunosuppression (Table 2). The first agent is belatacept produced by BristolMyers Squibb and approved for use in transplantation in both the United States and Europe in 2011. Belatacept represents a novel paradigm in immunosuppression. It is a biological agent, a fusion receptor protein that is administered intravenously for chronic immunosuppression and developed as a replacement of the CNIs.18,19 The scientific rationale for the therapeutic inhibition of the costimulation pathway with agents such as abatacept (CTLA4Ig) for rheumatoid arthritis and belatacept for transplantation has been a cornerstone basic of research in immunology and is the culmination of experimental investigations for over a quarter of a century20,21 (Figures 1 and 2). Following alloantigen stimulation through the T-cell receptor (signal one), the T cell requires a second signal through the costimulatory pathways for full activation. The binding by the CD28 first to CD86 and then to CD80 results in the activation and proliferation of T cells. Belatacept, a second-generation CTLA4Ig, binds with high affinity to the CD86/CD80 and inhibits delivery of costimulatory signals through the CD28 receptor leading to T-cell anergy. In a phase II trial and two pivotal phase III trials (BENEFIT for recipients of kidneys from standard deceased and living donors and BENEFIT-EXT for recipients of kidneys from extended-criteria donors), two regimens (a more intense and less intense dosing schedule) of belatacept were used in combination with MMF and steroids.22–24 The less intense regimen was approved for use by the Food and Drug

Table 2 | Novel agents to replace CNIs Agent

Mechanism of action

Formulation

Status

Belatacept

Costimulation blockade

Approved for use in renal transplantation in 2011

Tofacitinib

Inhibits JAK3 signaling pathway

Fusion-receptor protein for i.v. administration Small molecule in pill form

ASKP1240

Fully human anti-CD40 mAb

Biological for i.v. administration

Phase IIb completed; phase III in RA completed with possible approval in 2012 for RA Phase I in renal transplantation-completed

Abbreviations: CNIs, calcineurin inhibitors; i.v., intravenous; mAb, monoclonal antibody; RA, rheumatoid arthritis.

Kidney International (2012) 82, 1054–1060

1055

mini review

F Vincenti: Calcineurin inhibitors-free regimens

Administration because it was as effective as cyclosporine and provided a better safety profile than the more intense regimen (Figure 3). The 3-year outcome of patients treated with the lower intensity regimen of belatacept vs. cyclosporine in the phase III trials are shown in Table 3. Signal 2 Costimulation is the critical second signal

Activated T cell

APC

• Proliferation • Cytokine production

Costimulation

Signal 1 Antigen triggers T-cell receptor No costimulation

T cell • No cell division • No cytokine production • Anergy • Apoptosis

No costimulation

Signal 1 Antigen triggers T-cell receptor

MHC

TCR

Figure 1 | T-cell activation requires two signals. APC, antigenpresenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor.

The mechanism of action

The molecule

Belatacept

CD80 (B7-1) CD80

APC

CD86

CD28 CD86 (B7-2)

Belatacept MHC

T cell

TCR

Figure 2 | Belatacept binds with high affinity to CD86 and Cd80 and prevents T-cell activation. APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor.

Although there were more cases of histologically severe acute cellular rejections in belatacept-treated patients as compared with cyclosporine, very few patients on belatacept developed DSAs (3% vs. 8% for belatacept vs. cyclosporine). In the intent-to-treat analysis, the calculated glomerular filtration rate (GFR) was better and continued to improve over 3 years in the belatacept-treated patients. In fact, in the BENEFIT trial, the belatacept-treated patients had a positive GFR slope compared with 2 ml/min/year GFR loss in the cyclosporine-treated patients. The increase in GFR after transplantation in the belatacept-treated patients, especially in the BENEFIT trial, is reminiscent of the hyperfiltration observed in the solitary kidney of the living donor. The compensatory hyperfiltration maximizes the function of the solitary kidney and, as has been demonstrated in kidney donors, is not associated with glomerular injury.25,26 Furthermore, a risk-predictive model based on the outcome at 3 years projects a 2-year increase in graft half-life with belatacept as compared with cyclosporine in both the BENEFIT and BENEFIT-EXT trials (Figure 4). There are three reasons for the disparity between higher rejection and better outcome in the belatacept-treated patients. Recent detailed histological data show that early acute cellular rejection unlike antibody-mediated rejection (rare in the belatacept trial) does not impact graft survival adversely.27 The second reason, as noted above, is the low levels of DSAs. Rejection episodes that are not associated with the development of DSAs are associated with good outcome.28 DSAs are emerging as important biomarkers for subsequent graft loss.29 This novel effect of belatacept on DSAs has also been previously observed in experimental models of transplantation.30 In islet and kidney transplantation in non-human primates, anti-donor antibodies were suppressed with the use of belatacept. Although costimulatory blockade has no direct effect on B cells, an important mechanism of action of belatacept is the suppression of T helper effects on B cell. The third reason is the lack of

Clinical end points (months) Transplantation

Primary

Day 1

12

3 Months

Secondary

24

36

10 mg/kg Belatacept (LI)*

5 mg/kg Every 4 weeks i.v.

Day 1 5 14 28 Cyclosporine* (start 4 –10 mg/kg daily, adjusted based on target trough levels)

150 – 300 ng/ml

Day 1

56

84

150–250 ng/ml 28

* All patients received basiliximab induction, mycophenolate mofetil, and corticosteroid taper. LI=less intensive regimens

Figure 3 | The low intensity belatacept treatment regimen in the phase III studies (BENEFIT and BENEFIT-EXT). i.v., intravenous. 1056

Kidney International (2012) 82, 1054–1060

mini review

F Vincenti: Calcineurin inhibitors-free regimens

Table 3 | 3-Year outcome of the BENEFIT and BENEFIT-EXT trials BENEFIT trial

BENEFIT-EXT trial

Belatacept (n=226)

CsA (n=215)

Belatacept (n=174)

CsA (n=179)

92 22 66±27 +1.2 1a

89 14 44±24 2.0 o1b

82 24 42±25 0.6 2

80 23 31±22 1.2 0

Patient surviving with functioning kidneys (%) BPAR (%) cGFR (MDRD) ml/min per 1.73 m3 (s.d.) cGFR slope over 3 years mg/min/year Post transplant lymphoproliferative disease (%)

Abbreviations: BPAR, all biopsy-proven rejection; cGFR, calculated glomerular filtration rate; CsA, cyclosporine; MDRD, Modification of Diet in Renal Disease formula. a Three patients. b One patient.

Percentage of patients with a functioning graft

100 80

BENEFIT

60

Predicated survival 4676

Half-life (days): 3990

40 Belatacept (LI) CsA

20 0 0

2

4

6

8

10

12

14

Years after transplant

Proportion of patients with a functioning graft

100 80 BENEFIT-EXT

60 Half-life (days): 2902

40

3558

Belatacept (LI) CsA

20 0 3

4

5

6

7 8 9 10 Years after transplant

11

12

13

14

Figure 4 | The projected mean graft half-life based on the clinical profile at 3 years for the BENEFIT and BENEFIT-EXT trials (for the approved low intensity regimen). CsA, cyclosporine; LI, less intensive regimens.

nephrotoxicity of belatacept leading to the preservation of renal function. In addition, in the absence of CNI, the reduction in hypertension and hyperlipidemia with belatacept may ultimately have a beneficial impact on cardiovascular morbidities, a major cause of death with function. Although all subgroups of patients in the trials benefited from belatacept therapy, Epstein–Barr virus negative patients had an unacceptable high risk for post transplant lymphoproliferative disease (PTLD) and are not eligible for de novo therapy with belatacept. Are all transplant recipients potentially good candidates for belatacept? While Caucasian patients and non-Caucasian patients (such as African Americans) as well as recipients of kidneys from deceased donors and living donors responded well to belatacept, some categories of patients may not be suitable for immunosuppression with costimulation blockade. As mentioned, Epstein–Barr virus negative patients are at high risk of PTLD and should not be considered for belatacept therapy. Caution should also be Kidney International (2012) 82, 1054–1060

used in highly sensitized patients who were not included in the phase III trials. Memory T cells do not require costimulation for full activation and so patients with an expanded memory repertoire from alloreactive precursor T cells may be resistant to belatacept. Finally, recipients of non-renal organ transplants may be the greatest beneficiary of non-nephrotoxic immunosuppression regimen. Although no trials of belatacept have been performed in intra-thoracic organ transplantation, a phase II study in liver transplantation was terminated because of an increase in graft loss and death in 2/3 belatacept treatment arms. At present clinicians are cautioned not to use belatacept in liver transplantation.31 One important issue in the renal function assessment of belatacept is whether it has any direct effect on the kidney. Is the observed difference in the GFR between belatacept and cyclosporine a relative effect of each drug or due to the absolute lack of nephrotoxicity and/or vasoconstriction of belatacept? In an experimental study, 40 cynomolgus monkeys were infused for 6 months with weekly doses of belatacept, ranging from 10 to 50 mg/kg reaching a 20-fold increase in exposure of belatacept compared with the patients in the phase III trials.32 At 6 months, the renal function remained normal and stable, and kidney histology showed no abnormalities. These observations provide convincing evidence that belatacept lacks functional and histological nephrotoxicity that clearly differentiates it from the CNIs. Belatacept may also provide the opportunity to eliminate both CNIs and steroids. CNI-based immunosuppression regimens with rapid steroid withdrawal have been associated with a high rejection rate but excellent short-term outcomes.33,34 However, in a blinded randomized trial reported by Woodle et al.34 after a 5-year follow-up, more patients withdrawn from steroids developed chronic allograft nephropathy. Thus, the absence of steroids from CNI-based regimens either leads to more chronic alloimmune injury, or the fibrogenic effects of CNIs are exaggerated by the lack of steroids. A steroid sparing CNI-free regimen has not been available to patients. In a pilot study, patients treated with belatacept were withdrawn from steroids at day 5 and were maintained on either MMF or sirolimus.35 The control arm regimen consisted of tacrolimus, MMF, and a similar rapid steroid withdrawal. All patients had a short induction with thymoglobulin. At 1 year, rejection rates were low in all 1057

mini review

At present only one small molecule, tofacitinib, currently in clinical development, offers the potential of CNI-free regimens (Figure 5). Tofacitinib is a predominant Janus 3/2 kinase inhibitor.38 Janus kinases are cytoplasmic tyrosine protein kinases that participate in the signaling from a broad range of surface receptors; JAK3 is most relevant in transplant immunology because it is linked to the g-chain, which is part of receptors for the signaling pathway for cytokines essential for the proliferation and activation of T and B cells. This is not a redundant pathway, as natural mutations of the g-chain or JAK3 lead to combined severe immunode1058

Tofacitinib β

JAK P

STAT

P

γ

JAK P

P

STAT

α

STAT

CNI-FREE REGIMENS WITH SMALL MOLECULES

Tofacitinib Cytokine

STAT

groups (3%, 4%, and 12% in the tacrolimus MMF arm, belatacept sirolimus arm, and belatacept MMF arm, respectively) but the belatacept arms had better GFR. This regimen, if confirmed in a larger cohort of patients, would be an attractive option for patients desiring elimination of both CNIs and steroids. Transplant professionals optimize immunosuppression strategies through the use of drugs off label and/or not in the registered regimen. A recent example is the combination of tacrolimus and MMF that was embraced as the standard of care for a decade before its actual recognition by the Food and Drug Administration in 2009.36 Thus, it is possible that an optimum regimen with belatacept will emerge through similar clinical experimentation. In the interim, the clinical progress of a second biological targeting the CD40 receptor will be of great interest. The binding of CD40 to its ligands is important in the activation of several immune cells, including B cells, T cells, and macrophages. Inhibition of this pathway was initially attempted with monoclonal antibodies to CD40L (CD154) and resulted in prolonged graft survival in several animal models without the requirement for CNIs.37 A clinical trial with a humanized antibody to CD40L (5HuC8) was halted because of thromboembolic events.38 It became apparent that CD40L is upregulated on platelets and also has a role in stabilizing the clot, which is disrupted by anti-CD40L monoclonal antibodies. As the CD40 receptor is not expressed on platelets, renewed interest in inhibiting this pathway is being tested with several novel monoclonals targeting CD40. The most promising for transplantation is ASKP1240, a fully human IgG4 monoclonal antibodies to CD40. In a phase I double-blind single-dose-escalating study in normal volunteers, ASKP1240 has been shown to be safe in doses up to 10 mg/kg.39 ASKP1240 is currently in clinical trials in renal transplantation. Although anti-CD40 on its own could prove to be a potent immunosuppressant, its greatest potential could be achieved when it is combined with belatacept resulting in dual blockade of the CD40-CD40 L and CD28 pathways. In the seminal study in mice heart and skin transplants, indefinite graft survival could be achieved with this combination.40 Similar results were obtained in non-human primate models of transplantation.41 Thus, this dual protein therapy, if safe, could lead to potentially CNIfree tolerogenic regimens.

F Vincenti: Calcineurin inhibitors-free regimens

P

mRNA

Figure 5 | The mechanism of action of tofacitinib. JAK, Janus kinase; STAT, signal transducer and activator of transcription.

ficiency. The challenge for this therapy is to induce immunosuppression without tipping the balance to immunodeficiency. The importance of this pathway also suggests that CNIs would not be required for the desired immunosuppression effect. A recently reported phase 2b dose finding study utilized tofacitinib in a more intense and a less intense regimen (a combination of 15 mg b.i.d. and 10 mg b.i.d.) vs. cyclosporine.42 All patients had induction with basiliximab and had the same concomitant therapy consisting of mycophenolic acid and steroids. At 12 months, patient and graft were comparable in all the treatment groups, as were in rejection episodes (all below 20%). There were very few moderate or severe rejections (Banff II-III) with tofacitinib and no episodes of antibody-mediated rejection. At 12 weeks, measured GFR was significantly higher in patients who were on tofacitinib and who also had significantly less histological abnormalities (interstitial fibrosis and tubular atrophy) than the cyclosporine-treated patients. However, the use of tofacitinib, especially with the higher intensity regimen, was associated with more infections and PTLD. Exposure response relationships using a 2-h post dose serum concentration of tofacitinib in the first 6 months after transplantation showed that exposure below the median of 100 ng/ml maintained efficacy but decreased complications of overimmunosuppression. In fact, no case of PTLD occurred below this median concentration. Thus, the lower intensity regimen of tofacitinib is effective and safe but therapeutic drug monitoring may be required to ensure optimal outcomes. An even lower dose of tofacitinib (5 mg b.i.d.) has successfully completed phase III trials for rheumatoid arthritis and may become available for that use. The promise of a non-nephrotoxic potent CNI, which is an alternative agent available in a pill form, may tempt its usage off label by transplant physicians. Without the availability of therapeutic drug monitoring (not required for the lower dose in rheumatoid patients), however, the use of tofacitinib in transplantation could be challenging. Kidney International (2012) 82, 1054–1060

mini review

F Vincenti: Calcineurin inhibitors-free regimens

LONG-TERM VS. SHORT-TERM

At present belatacept is approved for use as a CNI alternative and but is it ready for prime time? Clearly there are challenges for the wider acceptance of this novel agent in de novo therapy. Transplant physicians have in the past placed the emphasis on reducing acute rejection, even though this strategy with the current regimens has failed to improve long-term outcome substantially. Embracing therapy with belatacept may require wider acceptance of a novel therapeutic paradigm for achieving better renal function, lower DSAs, and improved cardiovascular profile with a rejection rate that may be slightly higher than obtained with the use of CNIs. Although it is desirable to prevent early cellular acute rejections, they do not appear to affect longterm outcome adversely and thus the rate of acute rejection should not be the only measure of successful therapy.27 A better balance between preservation of renal function, renal histology, and reduction of acute rejection needs to be incorporated in the immunosuppressive strategies of transplant professionals. The increasing concern about nonadherence as an important cause of chronic rejection may also enhance the attractiveness of the intravenous delivery of belatacept that assures compliance. Of course, these benefits of belatacept need to be balanced by the increased costs of the drug (approximately $24,000 per year in the United States) and its intravenous administration. Although CNIs will continue to have an important role in immunosuppression regimens in the near future, belatacept is now (and other novel drugs in a few years) ready for prime time as first-line therapy for selected patients and may offer a useful therapeutic alternative with the promise of achieving improved outcome.

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

DISCLOSURE

FV has received research grants from Bristol-Myers Squibb, Roche/ Genentech, Pfizer, Astellas, Novartis, and Amgen. REFERENCES 1. Kaplan B, Meier-Kriesche HU. Renal transplantation: a half century of success and the long road ahead. J Am Soc Nephrol 2004; 15: 3270–3271. 2. McCullough KP, Keith DS, Meyer KH et al. Kidney and pancreas transplantation in the United States, 1998–2007: access for patients with diabetes and end-stage renal disease. Am J Transplant 2009; 9(Part 2): 894–906. 3. Meier-Kriesche HU, Schold JD, Srinivas TR et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4: 378–383. 4. Lamb KE, Lodhi S, Meier-Krieshe H-U. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011; 11: 450–462. 5. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351: 2715–2729 (review; no abstract available; Erratum in: N Engl J Med 2005; 352: 1056). 6. Opelz G, Do¨hler B. Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation 2009; 87: 795–802. 7. Nankivell BJ, Borrows RJ, Fung CL et al. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation 2004; 78: 557–565. 8. Ojo AO, Held PJ, Port FK et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003; 349: 931–940. 9. Gaston RS, Cecka JM, Kasiske BL et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation 2010; 90: 68–74. Kidney International (2012) 82, 1054–1060

25. 26.

27.

28.

29.

30.

31.

32. 33.

34.

Park WD, Griffin MD, Cornell LD et al. Fibrosis with inflammation at one year predicts transplant functional decline. J Am Soc Nephrol 2010; 21: 1987–1997. Snanoudj R, Royal V, Elie C et al. Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under lowdose cyclosporine therapy. Am J Transplant 2011; 11: 2635–2646. Ekberg H, Bernasconi C, Tedesco-Silva H et al. Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant 2009; 9: 1876–1885. Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003; 14: 1940–1948. Vincenti F, Ramos E, Brattstrom C et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001; 71: 1282–1287. Flechner SM, Glyda M, Cockfield S et al. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant 2011; 11: 1633–1644. Schena FP, Pascoe MD, Alberu J et al. Sirolimus CONVERT Trial Study Group. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87: 233–242. Flechner SM, Goldfarb D, Modin C et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002; 74: 1070. Vincenti F, Charpentier B, Vanrenterghem Y et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535–546. Durrbach A, Pestana JM, Pearson T et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant 2010; 10: 547–557. Larsen CP, Pearson TC, Adams AB et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005; 5: 443–453. Vincenti F, Luggen M. T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. Annu Rev Med 2007; 58: 347–358. Vincenti F, Larsen C, Durrbach A et al. Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation. N Eng J Med 2005; 353: 770–781. Vincenti F, Larsen CP, Alberu J et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant 2012; 12: 210–217. Pestana JO, Grinyo JM, Vanrenterghem Y et al. Three-year outcomes from BENEFIT_EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant 2012; 12: 630–639. Goldfarb DA, Matin SF, Braun WE et al. Renal outcome 25 years after donor nephrectomy. J Urology 2001; 166: 2043–2047. Vincenti F, Amend WJ, Kaysen G et al. Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects. Transplantation 1983; 36: 626–629. Sellare´s J, de Freitas DG, Mengel M et al. Inflammation lesions in kidney transplant biopsies: association with survival is due to the underlying diseases. Am J Transplant 2011; 11: 489–499. Everly MJ, Everly JJ, Arend LJ et al. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am J Transplant 2009; 9: 1063–1071. Terasaki P, Ozawa M. Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial. Transplantation 2005; 80: 1194–1197. Larsen CP, Knechtle SJ, Adams A et al. A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression. Am J Transplant 2006; 6: 876–883. Klintmalm GB, Feng S, Lake JR et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II study. Am J Transplant 2011; 11(Suppl 2): 137 (abstract no. 355). Hagerty H. Belatacept 6-month intravenous toxicity study in monkeys. Transplant Int 2011; 24: 257. Vincenti F, Schena FP, Parakevas S et al. FREEDOM Study Group. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant 2008; 8: 307–316. Woodle ES, First MR, Pirsch J et al. A prospective, randomized, doubleblind, placebo-controlled multicenter trial comparing early (7 day)

1059

mini review

35.

36. 37.

38.

corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248: 564–577. Ferguson R, Grinyo´ J, Vincenti F et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant 2011; 11: 56–76. Vincenti F, Klintmalm G, Halloran PF. Open letter to the FDA: new drug trials must be relevant. Am J Transplant 2008; 8: 733–734. Kirk AD, Burkly LC, Batty DS et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999; 5: 686. Vincenti F, Kirk A. What’s next in the pipeline. Am J Transplant 2009; 8: 1972–1981.

1060

F Vincenti: Calcineurin inhibitors-free regimens

39.

40.

41.

42.

Goldwater R, Keirns J, Blahunka P et al. A phase I single ascending dose study of ASKP1240 (Anti-CD40 MAB) in healthy subjects. Am J Transplant 2011; 11(Suppl 2): 127 (abstract no. 321). Larsen CP, Elwood ET, Alexander DZ et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381: 434. Kirk AD, Harlan DM, Armstrong NN et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94: 8789. 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. Am J Transplant 2012 (in press).

Kidney International (2012) 82, 1054–1060