Table 1: Pharmacodynamic inter-relationship of steroids and contemporary maintenance immunosuppressive agents in renal transplantation

Steroids + Drugs Mechanisms of action Pros Cons
Tacrolimus (TAC) *Binds FKBP12 and inhibits calcineurin dephosphorylation of NFAT, a transcription factor (TF) for IL-2 synthesis. *TAC/MMF/steroids most effective maintenance ISA
*GC supports Tregs/ graft tolerance
*GC inhibits TF: AP-1 and NFKB
*Activate renal P-glycop/ cyt P450: reduce nephrotoxicity
*TAC diminishes IL-2 support for AICC and graft tolerance
*TAC/MMF/GC may promote BK virus infection
*GC + TAC promote NODAT/ Hypertension/ hyperlipemia
Cyclosporine (CsA) *Binds cyclophillin and inhibits calcineurin dephosphorylation of NFAT, a TF for IL-2 synthesis. *Similar to TAC but may be less effective *Similar to TAC but more hyperlipemia and less NODAT *Increases serum MMF + toxicity
Mycophenolate Mofetil (MMF) *Inhibits IMDH + progression of cell cycle *Allows lower doses of CNI/ GC
*GC enhances UDPGT + decrease toxicity
*GC attenuates BM depression
*Bone marrow depression
*CsA increases serum MMF + toxicity
Sirolimus (SRL) *Binds FKBP12 + mTOR to arrest growth cycle
*Anti-proliferative agent
*Reduces non-melanoma skin cancer
*Survival of Tregs/ graft tolerance?
*GC/RAP delay wound healing, cause NODAT + hyperlipemia
*RAP delays graft function/ nephrotoxicity/ proteinuria
*TAC/ RAP promote PTLD in EBV (-) / TMA
Belatacept CTLA4Ig: blocks co-stimulatory CD28 receptor *Better short-term graft function vs. CsA
*GC+Belatacept: Less CV morbidity vs. GC/CsA?
*Promotes PTLD in EBV (-)
*Does not inhibit memory T cell
*More frequent early AR vs. CsA

AICD: Activation-Induced Cell Death, AP-1: Activated Protein-1, AR: Acute Rejection, BM: Bone Marrow, CD28-r: CD28 Receptor on T-lymphocyte, CNI: Calcineurin Inhibitors, CTLA-4Ig: Cytotoxic T Lymphocyte Antigen-4: cyt P450: Cytochrome P450, FKBP-12: FK506-Binding Protein 12, dePP: Dephosphorylation, IMDH: Inosine Monophosphate Dehydrogenase; ISA: Immunosuppressive Agents, EBV (-): Epstein Barr Virus Seronegative, MMF: Mycophenolate Mofetil, Mtor: Mammalian Target of Rapamycin, NFAT: Nuclear Factor of Activated T cells, NF?B: Nuclear Factor Kappa B, NODAT: New Onset Diabetes Mellitus After Transplant, P-glycop: P-Glycoprotein Efflux System, PTLD: Post Transplant Lymphoproliferative Disorder, TAC: Tacrolimus, TF: Transcription Factor, TMA: Thrombotic Microangiopathy, UDGT: Uridine Diphosphate Glucuronosyl-transferase