In this presentation, I explain the role of Calcineurin inhibitors in lupus nephritis.

1. lupus nephritis
Calcineurin inhibitors
Dr. Mohammad Hassan Jokar

2. LN prognosis
 Kidney survival among LN patients has
improved over the last decades.
 5-years kidney survival was 20% before 1980
 Now, only 10%–17% of LN progress ESRD
 Current problems:
o Resistant to treatment
o Intolerance and side effects
o High-dose glucocorticoids
 We should look for drugs with fewer side
effects
CJASN July 2020, 15 (7) 1066-1072; DOI: https://doi.org/10.2215/CJN.13761119

3. History of CNIs use in lupus nephritis
 The introduction of CNIs in the late 1970s revolutionized the
field of organ transplantation
 In 1980 five patients with lupus (2 with nephritis) were given
10mg/kg/day of CsA unacceptable side effects little
used for some years. *
 Cyclosporine was then used in lower doses as an alternative
treatment for LN.
 During the last years, there has been a growing interest role
of new CNIs in the management of LN.
Isenberg D, Snaith M, Morrow W, et al.: Cyclosporin a for the treatment of systemic lupus erythematosus. International journal of immunopharmacology (1981) 3(2):163-169.

4. Mechanism of action
Inhibit calcineurin
preventing T-cell activation
podocyte actin
cytoskeleton stabilization

5. CNIs
● Cyclosporin A
● Tacrolimus:
o 10-100 times more potent
o Fewer side effects
● Voclosporin:
o 4 times more potent than Cyclosporine
o More stable pharmacokinetic profile
o Some side effects are less common

6. Cyclosporin A
 Numerous drugs interaction
 Adverse effects
 Blood level monitoring

7. CNIs in Proliferative LN
 In recent years, various RCTs have demonstrated
that TAK is non-inferior to CYC or MMF as an
induction therapy of LN.
 In Asian patients, TAC demonstrated to be effective
as remission induction therapy as well as in
refractory LN.

8. Tacrolimus-based combination therapy
(Multitarget Therapy)
 A large RCT of 368 with active LN (III/IV/V)
showed that a combination of low-dose MMF
(1 g/day) and TAC (4 mg/day) was superior to
IV CYC.
 However, serious infections were more common in
the MMF/TAC group
*Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015;162:18e26.

9. Tacrolimus-based combination therapy
(Multitarget Therapy)
 TAC/MMF combination has been used with success in
Caucasian and African American patients with
proliferative and MLN who did not respond optimally to
MMF.**
 Multitarget treatment might be considered as an option
for LN with incomplete response to standard treatment,
especially refractory proteinuria.
**Cortes-Hernandez J, Torres-Salido MT, Medrano AS, et al. Long-term outcomese mycophenolate mofetil treatment for lupus nephritis with addition of
tacrolimus for resistant cases. Nephrol Dial Transpl 2010;25:3939e48.

10. Meta-Analyses 2016 tacrolimus in lupus nephritis
● 9 controlled studies (8 from China)
1. TAC versus IV CYC: TAC alone had higher rates
of overall remission and complete remissions
2. TAC versus MMF: no difference for achieving
remission.
3. Multitarget versus IV CYC, more overall
remissions in the multitarget group
Hannah J, Casian A, D’Cruz D: Tacrolimus use in lupus nephritis A systematic review and meta-analysis. Autoimmun Rev 15: 93–101, 2016

11. Induction and Maintenance Immunosuppression Treatment of
Proliferative LN: A Network Meta-analysis of Randomized Trials
● 53 studies (45 induction, 8 maintenance), 4222 patient
● Evaluated the best first-line treatment for LN
● MMF, CNIs or their combination were more effective
for inducing remission compared to IV CYC, While
conferring similar or lower toxicity.
● MMF was the most effective maintenance therapy.
Suetonia C. Induction and Maintenance Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis
of Randomized Trials. Am J Kidney Dis. 2017;70(3):324-336

12. Maintenance therapy
A retrospective, multicenter study
106 patients
All treatments had similar efficacy, despite more severe
baseline clinical features in patients treated with CsA

13. Membranous lupus nephritis
 In an RCT by the NIH group 42 patients with pure MLN were randomised to 3
treatment regimens:
 (1) Prednisone alone (1 mg/kg/day alternate day for 8 weeks and tapered)
 (2) Prednisone + IV CYC
 (3) Prednisone + CsA (5 mg/kg/day)
 At 12 months: complete or partial responses was:
 Highest with CsA (83%)
 CYC (60%)
 Prednisone alone (27%).
 However, relapse of nephrotic syndrome was significantly more frequent after
cessation of CSA therapy than CYC.*
*Austin 3rd HA, Illei GG, Braun MJ, et al. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009;20:901e11.

14. Membranous lupus nephritis
 In another study 150 LN (28 pure MLN) treated with TAC or
MMF.
 A subgroup analysis: superiority of TAC to MMF in reducing
proteinuria after 6 months, although the difference did not
achieve statistical sig. **
 Because of the increased risk of thromboembolism in pure
MLN, the European consensus recommends the use of the
CNIs as alternative options to MMF.
*Austin 3rd HA, Illei GG, Braun MJ, et al. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009;20:901e11.
**Mok CC, Ying KY, Yim CW, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis
2016;75:30e6.

15. Lupus Podocytopathy
 First line treatment: corticosteroid± Immunosuppressive
 In patients with LN with severe podocyte effacement,
CNIs can have better remission rates and better long-
term renal outcomes.
 In patients with greater foot process width, complete
remission rates were significantly higher and the long-
term renal outcome was better in the group with CNIs
compared with other regimens.
Oliva-Damaso N, Payan J, Oliva-Damaso E, Pereda T, Bomback AS. Lupus Podocytopathy: An Overview. Adv Chronic Kidney Dis. 2019 Sep;26(5):369-375. doi: 10.1053/j.ackd.2019.08.011. PMID: 31733721.

16. Voclosporin
 AURA-LV study: phase 2, multicenter, randomized,
control trial, 265 subjects, 79 centers, 20 countries
 MMF + one of:
 VCS 23.7 mg BID
 VCS 39.5 mg BID
 Placebo
 Complete remission: in 49.4% in low-dose, 39.8% in
high-dose, and 23.9% of in placebo group.
Rovin B, HAURA-LV Study Group: A randomized, controlled doubleblind study comparing the efficacy and safety of dose ranging
voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int 95: 219–231, 2019

17. ● 357 patients, 27 countries, 52-week, were randomized 1:1 to
VCS (23.7 mg BID) or placebo + MMF (1 g BID) and rapidly
tapered oral steroids.
● Renal response at 52 weeks was: 40.8% for the VCS arm
and 22.5% for the control arm (p< 0.001)
● The overall incidence of SAEs were (VCS 20.8% and control
21.3%).
● Overall mortality was low (1 death in the voclosporin arm
and 5 in the control arm)
● Conclusion: The AURORA study met its primary endpoint
and VCS was efficacious in Hispanic/Latino ethnicity
patients

18. Obinutuzumab (Gazyva)
Voclosporin

19. Concerns about CNIs
 Race
 Duration
 Nephrotoxicity
 Thrombotic effects
 Serious infections
 Relatively narrow therapeutic window
 Renal flares after discontinuation

20. • 29 patients were included Ethnicity was
predominantly Caucasian (82%), Black African
(11%), Hispanic (3.5%) and Caribbean (3.5%).
• Conclusions: TAC can be considered a valid
therapeutic option in patients with SLE,
especially for renal involvement.

21. Duration
 Long term data from two of these trials with
a mean follow up of 7.7 * years (CSA vs CYC)
and 5 years (TAC vs MMF) respectively
showed no difference in renal function and
incidence of ESRF
*Chen W, Liu Q, Chen W, et al. Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. Lupus 2012;21:944e52.

22. Safety
 Available data give mixed results
 More patients in the multitarget group dropped
out because of adverse events (5.5% versus 1.7%).
 A higher rate of serious adverse events in the
multitarget group (7.2% versus 2.8 %)
 There was usually no difference in kidney function
at the end of the trial
Hannah J, Casian A, D’Cruz D: Tacrolimus use in lupus nephritis A systematic review and meta-analysis. Autoimmun Rev 15: 93–101, 2016

23. • Class III or IV (±V) LN: Combination of MMF + a CNI (especially
TAC) is an alternative, particularly in patients with nephrotic-range
proteinuria.
• Pure class V: Alternative options include IV CY, or CNIs (especially
TAC) ± MMF/MPA, particularly in patients with nephrotic-range
proteinuria.
• Non-responding/refractory disease

26. Recommendations
CNIs is an alternative option for:
● Younger patients
● Refractory LN
● CYC and MMF Intolerant
● Pregnant patients
● In breast feeding
● Heavy proteinuria