Modern immunosuppression has improved early graft survival but has had little impact on late graft loss, which is largely driven by chronic rejection. This tab covers the mechanisms of the immunosuppressive agents, infection prophylaxis and drug interactions, and the malignancy risk of chronic immunosuppression.
Mechanisms of Immunosuppressants
| Agent | Mechanism of action |
|---|---|
| Glucocorticoids | Reduce transcription of cytokine genes |
| Azathioprine, mycophenolate mofetil | Inhibit purine synthesis |
| Sirolimus, everolimus | Inhibit cell-cycle progression (mTOR inhibitors) |
| Tacrolimus, cyclosporine | Inhibit calcineurin → reduce IL-2 production |
| Basiliximab | Blocks the IL-2 receptor |
| Antithymocyte globulin | Depletes T lymphocytes |
| Rituximab | Depletes B lymphocytes |
| Alemtuzumab | Depletes T and B lymphocytes |
| Belatacept | Costimulation blockade |
| Bortezomib | Proteasome inhibitor |
| Eculizumab | Complement inhibitor |
Corticosteroids most impair wound healing, and prednisone, cyclosporine, and sirolimus all cause hyperlipidemia.
Infection Prophylaxis and Drug Interactions
- Prophylaxis — TMP-SMX for 3 months against Pneumocystis pneumonia, and ganciclovir, acyclovir, valacyclovir, or CMV immune globulin against cytomegalovirus.
- CYP450 metabolism — cyclosporine and tacrolimus are metabolised by cytochrome P450, so doses must be adjusted with interacting drugs (e.g. fluconazole, ketoconazole). Diltiazem and ketoconazole are sometimes used deliberately to reduce calcineurin-inhibitor dosing and cost while maintaining levels.
- P450 inducers (lower calcineurin-inhibitor levels): barbiturates, phenobarbital, phenytoin, carbamazepine, rifampin, griseofulvin, sulfonylureas, St. John's wort, and chronic alcohol.
- P450 inhibitors (raise levels): valproate, isoniazid, cimetidine, ketoconazole, fluconazole, sulfonamides, chloramphenicol, erythromycin (macrolides except azithromycin), amiodarone, omeprazole, quinidine, grapefruit juice, and acute alcohol.
Malignancy Risk
Chronic immunosuppression raises cancer risk, and skin cancer is the most common malignancy after solid-organ transplant. Several virus-associated cancers are increased — Kaposi sarcoma (HHV-8), non-Hodgkin lymphoma (EBV), vulvar cancer (HPV), and hepatocellular carcinoma (hepatitis C) — as are kidney, penile, and bladder cancers. (For contrast: HIV raises kidney, penile, and testis cancer risk, and metabolic syndrome raises kidney, bladder, and prostate risk.) Notably, prostate cancer incidence is decreased in transplant recipients, and lymphoma may respond to reducing immunosuppression.