This document discusses various topics related to immunosuppressive drugs used in renal transplantation. It begins by reviewing mTOR inhibitors used in combination with calcineurin inhibitors, noting their synergistic effect. It then discusses a study finding lower rates of discontinuation and better graft function with mTORi-CNI compared to MMF/MPA-CNI. Finally, it briefly touches on induction immunosuppression methods, tolerance without immunosuppression, and withdrawal of steroids and calcineurin inhibitors.

1. Immunosuppressive drugs in renal
transplantation ( part 2)
By
Dr. Salwa M. Elwasif, MD
Fellow of Internal Medicine and Nephrology
9/1/2021

2. Last lecture:
• Adherence versus compliance
• Induction versus maintenance
• Groups of maintenance immunosuppressive
drugs
• Side effect ( picture gallery)

3. Last assignment
• What is calcineurin?
• Role of Calcineurin in immunity
• Does CNI need monitoring?
• If side effect occurs, should we stop use or
modify? Who is the stakeholder here?
• What is the future research?

4. General Immunosuppressants animation video -
Bing video
https://www.mometrix.com/academy/immuno
modulators-and-immunosuppressive-agents/

5. Today‫ﹸ‬s agenda
• Use of mTORi in renal transplantation
• Induction of immunosuppression
• Tolerance

6. Use of mTORi in renal transplantation

7. Q1:
mTORi + CNI :
• Synergistic effect
• Competitive antagonist
• Non Competitive antagonist

8. mTORi + CNI
The synergistic action of mTOR inhibitors and
calcineurin inhibitors (CNIs) provide a rationale
for combination therapy, with the potential for
CNI-dose reduction and corresponding clinical
benefits.
Transpl Int (2004) 17: 279–285

9. Everolimus in Kidney
Transplantation

11. Transplant Rev (Orlando). 2019 Oct;33(4):191-199
Everolimus in De Novo Kidney Transplantation

12. Everolimus in De Novo Kidney Transplantation

13. Everolimus in De Novo Kidney Transplantation

14. J Am Soc Nephrol 29: 1979–1991, July 2018
TRANSFORM Study

15. Everolimus in De Novo Kidney Transplantation
Nefrologia. 2017 May - Jun;37(3):253-266.

17. mTORi and CNI
• Transplantation October 2019;103: 2031–2056

18. mTORi and CNI
Transplantation October 2019;103: 2031–2056
24 studies with 7356 participants
Rates of discontinuation
For mTORi varied between 17% and 46% compared
to 0%–26.6% in MMF/MPA groups

19. mTORi and CNI
Transplantation October 2019;103: 2031–2056
RejectionMortality

20. mTORi and CNI
Transplantation October 2019;103: 2031–2056
Graft Loss

21. Graft function (estimated GFR using
MDRD equation)
mTORi and CNI
Transplantation October 2019;103: 2031–2056

22. CMV infection and disease
mTORi and CNI
Transplantation October 2019;103: 2031–2056

23. Transplantation October 2019;103: 2031–2056
There is a decreased risk of CMV infection with the use of
mTORi-CNI compared to MMF/MPA CNI. The biological
mechanism for this effect could be the inhibition of translation of
CMV viral proteins and the stimulation of TH1-specific
interferon-γ–producing T cells and virus-specific CD8 T cells.

24. Take Care

26. Immunosuppression and
Reproductive Health
Transplantation November 2019;103: e325–e333)

27. Immunosuppression and
Reproductive Health
Transplantation November 2019;103: e325–e333)

28. Immunosuppression and
Reproductive Health
Transplantation November 2019;103: e325–e333)

29. Immunosuppression and Reproductive Health
Transplantation November 2019;103: e325–e333)

30. Transplantation Reviews 33 (2019) 55–63
Immunosuppression and GIT
(PPIs) reduces the exposure to MPA due to a decreased
deesterification of MMF

31. Infection and Renal Transplant
The cover image illustrates opportunistic infections
in organ transplant recipients:
Top Left – Brain biopsy Acanthamoeba encephalitis
in a heart transplant recipient,.
Top Right – MRI showing Nocardia lesions of the
brain
Bottom Left – Histoplasma capsulatum from a blood
culture in a renal transplant recipient
Bottom Right – Oral human papillomavirus lesions
in a renal transplant recipient

32. Drug – drug interaction

33. Drug Interactions
Clinical Transplantation. 2019;e13510.

34. Drug Interactions
Clinical Transplantation. 2019;e13510.

35. Drug Interactions
Clinical Transplantation. 2019;e13510.

36. Clinical Transplantation. 2019;e13510.
Drug Interactions

37. Clinical Transplantation. 2019;e13514
Drug Interactions

38. Renal Transplantation: Drugs
Chronic Renal Disease, Second Edition, 2020, Chapter 69

40. Induction of immunosuppression

41. We should know

42. Induction therapy, defined simply as the short-term use of an
immunosuppressive agent at the start of the transplant period
Examples:
• High doses of corticosteroids
• the polyclonal rabbit antithymocyte globulin (rATG;
Thymoglobulin
• The murine anti-CD3 mAb Muromonab-CD3 (OKT3),
• the humanized anti-CD52 mAb alemtuzumab (Campath-1H)
• mAbs directed against the IL-2 receptor (basiliximab,
daclizumab).

43. Living donor in high immunological risk recipients :
– ABO incompatibility
– Transplantation with previous positive crossmatch
– Hypersensitized recipient

46. Dose Side
effectsGraft
survival
Patient
survival

47. Tolerance

48. It is a permanent acceptance of organ allografts aiming for
withdrawal of all immunosuppressive drugs
A stable kidney transplant function with ,150 mol/L creatinine
and ,1 g/day proteinuria in the absence of immunosuppressive
drugs for at least 1 year
Definition:

49. biomarkers for tolerance:
• number of T-reg
• Infiltration of Foxp3 cells in biopsy of kidney graft
• Under expression of TNF-alpha, IL-4, and IL-10
What is next?

50. Time for withdrawal ?

51. Steroid withdrawal
steroid minimization became one of the major goals in
pediatric renal transplantation. Different protocols have been
used by individual centers and multicenter study groups,
including early and late steroid withdrawal or even complete
avoidance.

53. CNI withdrawal

54. THANK YOU