1. History of Kidney Transplantation
First successful kidney transplant
Total body irradiation for immunosuppression
Steroids
1960’s
Azathioprine
1970’s
Polyclonal anitbodies – anti-lymphocyte globulin (now Atgam, Thymoglobulin)
1980’s
Cyclosporine (Sandimmune ), “triple drug therapy”
Monoclonal antibody, OKT3 (Orthoclone ) in 1985

2. Immunosuppressant Discoveries 1990-2000
Tacrolimus (Prograf)
Mycophenolate Mofetil (Cellcept )
Basiliximab (Simulect )
Cyclosporine Microemulsion (Neoral )
Daclizumab (Zenapax )
Rabbit Antithymocyte globulin (Thymoglobulin )
Sirolimus (Rapamune )

3. Modes of Action of Currently Available Immunosuppressants
Calcineurin inhibitors
Cyclosporine
Tacrolimus
Purine synthesis inhibitors
Azathioprine
Mycophenolate mofetil
Nonspecific
prednisone
Target of Rapamycin inhibitor
Sirolimus(Rapamune )
Polyclonal antibodies (bind several CD’s)
Thymoglobulin 
Atgam 
Monoclonal Antibodies
Blocks Il-2 receptor
Daclizumab(Zenapax )
Basiliximab(Simulect )
OKT3 (anti-CD3)

4. Anti-CD3
IL-2 receptor Ab
Cyclophylin
FKBP
TOR
Lancet 353 :1083, 1999

5. Oxford clinical nephrology, 3rd edition Immunosuppressive regimen
Rejection rates (1 year) in (%)
Main features
CNI + MMF + steroids
15–20
Most popular regimen; withdrawal of CNI, steroids or MMF can be undertaken after 3–6 months in low-risk patients
Tacrolimus + AZA + steroids
20–25
Reasonable efficacy; AZA less costly than MMF
CsA + sirolimus + steroids
CsA or sirolimus must be stopped after 3 months because of nephrotoxicity; excellent 1 year renal function under sirolimus + steroids
Tacrolimus + sirolimus + steroids
10–15
Validation ongoing, but already popular. Apparently not nephrotoxic like the CsA-sirolimus combination
Anti-IL-2R mAb + CNI + MMF + steroids 10
Very low rejection rates; appropriate for patients with immunological risk factors. Allows for the use of low-dose/withdrawal of CNI and/or steroids
ATG/OKT3 + CNI + MMF + steroids
5–10
Very potent combination; appropriate for high-risk patients
Oxford
clinical
nephrology,
3rd edition

6. Choosing between the two - side effects
Increased polyoma infection (viruria and viremia) with tacrolimus and MMF compared to Csa and MMF (Am J Transplant 5: 582, 2005)
Anecdotal reports of cardiomyopathy with tacrolimus.

7. Calcineurin Inhibitor Adverse Effects
Cyclosporine
nephrotoxicity
hypertension
hyperlipidemia
hyperglycemia
neurotoxicity
GI side effects
K, Na, Mg
gingival hyperplasia
hirsutism
Tacrolimus
nephrotoxicity
hypertension
hyperlipidemia
hyperglycemia
neurotoxicity
GI side effects
K, Na, Mg

8. Calcineurin inhibitors withdrawal and avoidance
Increasing evidence indicates that the toxic effects of CNIs contribute to kidney graft loss by cardiovascular death and chronic allograft nephropathy.  two major causes of late graft loss.
avoiding long-term vascular and renal toxicity.
Attempts to discontinue CsA have been actively pursued, first by switching to AZA, and later to MMF and sirolimus.
Oxford clinical nephrology, 3rd edition

10. JASN 11:1910, 2000

11. JASN 11:1910, 2000

12. JASN 11:1910, 2000

13. Transplantation : 74 : 1725, 2002

14. Transplantation : 74 : 1725, 2002

15. Transplantation : 74 : 1725, 2002

16. CNI withdrawal and avoidance: summary
CNI withdrawal/avoidance is a highly valuable goal in renal transplantation.
long-term follow-up figures are available only for AZA-based regimen  equivalent, but not superior, graft survival. : It is likely that what is gained with respect to graft failure from CNI nephrotoxicity is lost from increased rates of chronic rejection in AZA-treated patients.
AR rates after CNI withdrawal appear to be lower in patients switched to MMF or sirolimus, but obviously the possible benefits of this strategy will only be fully appreciated in a decade.
The same is true for CNI avoidance regimens where antibody induction is given together with sirolimus + MMF.
In the meantime, it seems premature to propose systematic CsA withdrawal/avoidance to all patients. Rather, this strategy is likely to be of particular benefit in low-risk recipients who receive poorly functioning kidneys, or who develop severe CNI toxicities.
Oxford clinical nephrology, 3rd edition