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

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

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)

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

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

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.

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

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

JASN 11:1910, 2000

JASN 11:1910, 2000

JASN 11:1910, 2000

Transplantation : 74 : 1725, 2002

Transplantation : 74 : 1725, 2002

Transplantation : 74 : 1725, 2002

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