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
**
*
***
***
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)
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.