Providing care for kidney transplant recipients: An overview for generalists

Table 1 Common maintenance immunosuppressants used in kidney transplantation

Drug name	Mechanism of action	Key interactions	Non-immune toxicities	Additional comments
Tacrolimus and tacrolimus XR	Bind to FKBp12 and the complex inhibits the calcineurin phosphatase and T cell proliferation	Inhibitors and inducers of cytochrome P450 system impact drug levels. Common inhibitors include azole antifungals, nondihydropyridine antihypertensives, protease inhibitors, macrolides and grapefruit juice. Common inducers include rifampin, rifabutin, carbamazepine, and phenobarbital	New onset diabetes after transplant, neurotoxicity, hemolytic uremic syndrome, nephrotoxicity, alopecia. Less likely to cause hypertension, hyperlipidemia, gum hyperplasia than cyclosporine	Trough monitoring required, 12-hour troughs for tacrolimus and 24-hour troughs for tacrolimus XR
Cyclosporine and cyclosporine modified	Binds to cyclophilin and the complex inhibits calcineurin phosphatase and T cell proliferation	Inhibitors and inducers of cytochrome P450 system impact drug levels. Common inhibitors include azole antifungals, nondihydropyridine antihypertensives, protease inhibitors, macrolides and grapefruit juice. Common inducers include rifampin, rifabutin, carbamazepine, and phenobarbital	More likely to cause hypertension, hyperlipidemia, gum hyperplasia than tacrolimus but can also cause hemolytic uremic syndrome, nephrotoxicity and neurotoxicity like tacrolimus	12-hour trough monitoring or checking levels 2 hours after administration required
Sirolimus and everolimus	Binds to FKBP12 and the complex inhibits TOR and IL-2 driven T cell proliferation	Increased toxicity of calcineurin inhibitors when used concurrently	Dyslipidemia, delayed wound healing, delayed graft function, proteinuria, pneumonitis, interstitial lung disease, mouth ulcers	Trough monitoring required, 24-hour troughs for sirolimus and 12-hour troughs, for everolimus. Monitoring of lipids and urine protein required
Mycophenolate mofetil and enteric coated mycophenolic sodium	Inhibits inosine monophosphate dehydrogenase and thus synthesis of guanosine monophosphate nucleotides which prevents proliferation of B cells and T cells	Proton pump inhibitors reduce intestinal absorption of mycophenolate mofetil, and cyclosporine reduces enterohepatic recirculation and drug exposure	Gastrointestinal side effects (nausea, heartburn, and especially diarrhea) and cytopenia	Contraindicated in pregnancy, therapeutic monitoring not required though may be used to improve efficacy/assess for adherence
Azathioprine	Inhibits purine nucleotide synthesis, gene replication, and T cell activation by incorporating itself into cellular DNA	Xanthine oxidase inhibitors such as allopurinol and febuxostat increase azathioprine levels	Bone marrow suppression and liver toxicities	Blood count monitoring required
Corticosteroids	Inhibit NFkB which is a transcription factor to express necessary cytokines for T cell activation	N/A	Osteoporosis, impaired wound healing, dyslipidemias, impaired glucose tolerance, and psychological impacts	Early steroid withdrawal based on recipient factors including low immunological risk (e.g. low calculated panel-reactive antibodies) with a non-immune-mediated cause of end stage renal disease (such as, diabetes mellitus, hypertension, polycystic kidney disease)
Belatacept	Binds to CD80/CD86 on antigen presenting cells blocking the interaction with CD28 on T cells and thus inhibiting costimulatory signal 2	Used in lieu of calcineurin inhibitors and used concomitantly with mycophenolate mofetil/mammalian target of rapamycin inhibitors and steroids	Contraindicated in recipients who are Epstein Barr virus seronegative due to prohibitive risk for post-transplant lymphoproliferative disorder	Monthly infusion in steady state for low immunologic risk recipients with benefits to longitudinal creatinine compared with remaining on calcineurin inhibitors

TOR: Target of rapamycin; IL-2: Interleukin 2; NFkB: Nuclear factor kappa B; N/A: Not applicable.