Calcineurin inhibitor nephrotoxicity - once and for all?
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Presentation at the Dutch Papendal Nephrology course - how to avoid CNI nephrotoxicity after kidney transplantation
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Calcineurin inhibitor nephrotoxicity - once and for all?
- 1. Calcineurin inhibitor after Kidney transplantation – once and for all? Maarten Naesens, MD PhD University Hospitals Leuven, Belgium
- 2. There are two calcineurin inhibitors currently in clinical use: cyclosporine and tacrolimus cyclosporine tacrolimus
- 3. Calcineurin inhibitors are powerful immunosuppressive agents Calcineurin inhibitors cause renal toxicity We should avoid calcineurin inhibitors in kidney transplants
- 4. The success of organ transplantation relates to the successful development of immunosuppressive agents
- 5. Cyclosporine was the drug that made kidney transplantation the first-choice treatment
- 6. Canadian study NEJM 1983 Azathioprine + steroids Cyclosporine + steroids 1-year graft survival 80.4% (24% failure due to rejection) 64.0% (74% failure due to rejection*) * 80% <50 days post-transplant
- 7. Calcineurin inhibitors were the first, and last drug to show benefit in terms of kidney transplant survival Naesens & Thaunat. Nat Rev Nephrol 2016
- 8. Calcineurin inhibitors were the first, and last drug to show benefit in terms of kidney transplant survival Naesens & Thaunat. Nat Rev Nephrol 2016
- 9. Calcineurin inhibitors were the first, and last drug to show benefit in terms of kidney transplant survival Naesens & Thaunat. Nat Rev Nephrol 2016
- 10. Calcineurin inhibitor nephrotoxicity was considered a main reason for loss of kidney function after transplantation cyclosporine tacrolimus Acute CNI nephrotoxicity Chronic CNI nephrotoxicity
- 11. Calcineurin inhibitor nephrotoxicity was considered a main reason for loss of kidney function after transplantation cyclosporine tacrolimus Acute CNI nephrotoxicity Chronic CNI nephrotoxicity
- 12. Calcineurin inhibitor nephrotoxicity was considered a main reason for loss of kidney function after transplantation cyclosporine tacrolimus Acute CNI nephrotoxicity Chronic CNI nephrotoxicity
- 13. The clinical risk factors for development of CNI nephrotoxicity have been partially elucidated Naesens et al cJASN 2009
- 14. Calcineurin avoidance, minimization and conversion was a main goal in clinical research in the years after ’00 Time after transplantation Drug levels Other drug CNI Other drug CNI avoidance CNI minimization CNI conversion CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI
- 15. Calcineurin avoidance, minimization and conversion was a main goal in clinical research in the years after ’00 Time after transplantation Drug levels Other drug CNI Other drug CNI avoidance CNI minimization CNI conversion CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI
- 16. Calcineurin avoidance: the Symphony study demonstrated superior outcome with CNIs than without Ekberg et al NEJM 2007
- 17. Calcineurin avoidance: the Symphony study demonstrated superior outcome with CNIs than without (C0 4-8) (C0 3-7) (C0 50-100) (C0 100-200) Ekberg et al NEJM 2007 & AJT 2009 (C0 4-8) (C0 3-7) (C0 50-100) (C0 100-200)
- 18. Calcineurin avoidance: the Symphony study demonstrated superior outcome with CNIs than without Sharif et al JASN 2011
- 19. Belatacept is a new drug on the market, with very different profile than previous immunosuppressants Naesens & Thaunat. Nat Rev Nephrol 2016
- 20. Belatacept is a new drug on the market, with very different profile than previous immunosuppressants Naesens & Thaunat. Nat Rev Nephrol 2016
- 21. Belatacept is a new drug on the market, with very different profile than previous immunosuppressants 7 years FUNaesens & Thaunat. Nat Rev Nephrol 2016
- 22. The rejections in the BENEFIT study were T-cell mediated with low risk of DSA formation Vincenti F et al. N Eng J Med 2016 BELA MI BELA LI CsA 0% 5% 10% 15% 20% 14% 9% 6% Acute rejection occurence BELA MI BELA LI CsA 0% 5% 10% 15% 20% 1.4% 3.1% 11.6% De novo DSA occurence *** *
- 23. The rejections in the BENEFIT study were T-cell mediated with low risk of DSA formation Vincenti F et al. N Eng J Med 2016 No difference in ABMR! BELA MI BELA LI CsA 0% 5% 10% 15% 20% 14% 9% 6% Acute rejection occurence BELA MI BELA LI CsA 0% 5% 10% 15% 20% 1.4% 3.1% 11.6% De novo DSA occurence *** * ***
- 24. The BENEFIT study confirms the beneficial effect of belatacept in terms of eGFR Vincenti et al NEJM 2016
- 25. Belatacept is the first IS agent to show improved overall graft survival since CsA Patient survival Graft survival P = 0.06 P = NS Vincenti et al NEJM 2016
- 26. Conclusion: CNI avoidance was not successful, only belatacept shows some promise Time after transplantation Drug levels Other drug CNI Other drug CNI avoidance CNI minimization CNI conversion CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI
- 27. CNI conversion = stop CNI and replace with other IS Time after transplantation Drug levels Other drug CNI Other drug CNI avoidance CNI minimization CNI conversion CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI
- 28. Conversion from CNI to mTORi leads to better renal function Sawinski et al Am J Transplant 2016 And similar acute rejection And similar graft survival
- 29. Budde et al Lancet 2011; AJT 2014 Conversion from CNI to mTORi leads to better renal function
- 30. Conversion from CNI to mTORi leads to more rejection? Sawinski et al Am J Transplant 2016
- 31. Grinyo et al Am J Kidney Dis 2017 Conversion from CNI to belatacept leads to better eGFR And similar acute rejection And similar graft survival
- 32. Conclusion: CNI conversion improves graft function but does not improve graft or patient survival Time after transplantation Drug levels Other drug CNI Other drug CNI avoidance CNI minimization CNI conversion CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI
- 33. Conclusion: CNI withdrawal (not replacing by another IS) is not safe Time after transplantation Drug levels Other drug CNI CNI avoidance CNI minimization CNI withdrawal CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI Increased risk of BPAR (x3)
- 34. CNI minimization: add another immunosuppressant to lower level CNI Time after transplantation Drug levels Other drug CNI Other drug CNI avoidance CNI minimization CNI conversion CNI (Tac, CsA) Other drug (MPA, mTORi, belatacept etc.) Day 0 Other drug CNI
- 35. Low CNI + MPA = better renal function Sawinski et al Am J Transplant 2016
- 36. Low CNI + MPA = lower risk of graft failure Sawinski et al Am J Transplant 2016
- 37. CNI + mTORi = a nephrotoxic combination Kahan et al Lancet 2000 40 45 50 55 60 65 70 75 2 mg SIR 5 mg SIR AZA GFR (mL/min) 6 months 12 months ** * *** ***
- 38. Meta-analyses suggests benefit of CNI minimization for kidney transplantation Sharif et al JASN 2011
- 39. Sharif et al JASN 2011 Sir+T Eve+C Sir+T Eve+C Eve+T Meta-analyses suggests benefit of CNI minimization for kidney transplantation Sharif et al JASN 2011
- 40. TRANSFORM: low-dose CNI + low-dose EVR in the largest trial ever in kidney transplantation Abstract LOS001; Pascual et al.
- 41. TRANSFORM: low-dose CNI + low-dose EVR in the largest trial ever in kidney transplantation: equal primary endpoint Abstract LOS001; Pascual et al. Composite of eGFR <50 mL/min/1.73 m2 or tBPAR†
- 42. TRANSFORM: low-dose CNI + low-dose EVR in the largest trial ever in kidney transplantation: equal graft function Abstract LOS010; Oppenheimer et al. Mean difference in eGFR at M12: −1.39 (−3.29, 0.51), P = 0.15
- 43. TRANSFORM: low-dose CNI + low-dose EVR in the largest trial ever in kidney transplantation: lower infection risk Abstract LOS002; Cruzado et al.
- 44. Calcineurin avoidance, minimization and conversion was a main goal in clinical research in the years after ’00 Time after transplantation Drug levels Other drug CNI CNI withdrawal CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 CNI avoidance - mTORi - belatacept ✓
- 45. Calcineurin avoidance, minimization and conversion was a main goal in clinical research in the years after ’00 Time after transplantation Drug levels Other drug CNI Other drug CNI minimization CNI conversion - mTORi - belatacept CNI (Tac, CsA) Other drug (mTORi, belatacept etc.) Day 0 Other drug CNI ✓ ? CNI avoidance - mTORi - belatacept ✓
- 46. mTORi use in kidney transplantation is declining Hart et al Am J Transplant 2015 mTORi use (US – SRTR data)
- 47. CNI use in kidney transplantation is virtually universal Hart et al Am J Transplant 2015 CNI use (US – SRTR data)
Editor's Notes
- This title was given to me by the organizers of this congress. I did not choose it myself, and I have to say that the title seems to give me somewhat limited freedom of speech and free thinking. In this presentation, I will discuss with you what I really think about this statement.
- I admire those of you that are here without being involved in this clinical problem. To sit here, in beautiful Nice, with a presentation that does not affect you. Either the rest of the program this morning is uninteresting, or it must be raining outside. Of course, Hopital Necker uses this. I suppose they do everything that is possible, including this. But the fact that so few of you actually use biopsies for decision-making on kidney allocation, is very different than current practice in the US.
- Sawinski et al AJT 2016: We evaluated 92 comparisons from 88 randomized controlled trials and found moderate- to high-strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard-dose regimens; moderate-strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate- to high-strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine-based strategies and low-risk populations. Additional research is needed with tacrolimus-based regimens and higher risk populations.
- The non-inferiority trial design actually saved the whole study, and the future of belatacept. Without this non-inferiority, the study would have failed and we would have had approval for this still promising but little used drug. Superiority for GFR, as illustrated in the beginning of my presentation.
- Shows that this is still a drug with great potential in the field of transplantation.
- A very important lesson that we learn from the BENEFIT study is however that TCMR is not a good endpoint, certainly not in this low-risk population
- Background: In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. Study Design: 36-month follow-up of the intention-to-treat population. Setting & Participants: CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75 mL/min/1.73 m2). Interventions: At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n 5 84) or continue CNI-based therapy (n 5 89). Outcomes: Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. Measurements: Treatment exposure2adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. Results: Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure2adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 personyears). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07 mL/min/1.73 m2 per year; P for time-bytreatment interaction effect 5 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P 5 0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P 5 0.9). Limitations: Exploratory post hoc analysis with a small sample size. Conclusions: Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.
- NB. Withdrawal, not replacing by another drug (and continue with only MMF), was tried but highly significant risk of BPAR. eGFR somewhat better, and impact on survival fully unclear.
- NB. Withdrawal, not replacing by another drug (and continue with only one IS), was tried but highly significant risk of BPAR: X 3 with only MMF X 1.7 with only mTORi (according to Sawinski et al). eGFR somewhat better, and impact on survival fully unclear.