Immunosuppressants aim to prevent this from happening:
But too much immunosuppression can cause this:
That’s why people can’t just be on ONE immunosuppressant after transplant: the doses required would be too toxic, so the effect is spread out over 2-3 medications.
Considering that the historical option was total body irradiation, we’ve come a long way. Azathioprine was the first chemical immunosuppressant, but cyclosporine, which came onto the scene in the 1970s, revolutionized kidney transplant survival rates.
***One of my chiefs last year made an amazing figure on maintenance transplant immunosuppression. It is worth this whole post and I highly encourage you to take a look!***
For us peons, what are the commonly used immunosuppressants?
|Mechanism of Action||Starting doses||Monitoring required||Side effects|
|Tacrolimus (Prograf)||Calcineurin inhibitor (CNI)||0.075-0.2 mg/kg/day||Cr, drug trough||Neurotoxicity, nephrotoxicity, diabetes, alopecia *many drug interactions|
|Cyclosporine (Neoral)||Calcineurin inhibitor (CNI)||2-6 mg/kg/day||Cr, drug level||Neurotoxicity, nephrotoxicity, diabetes, hypertrichosis, gingival hypertrophy|
|Mycophenolate mofetil ## (CellCept, MMF)||Purine analogue, prevents T cell proliferation||500-1000 mg daily||CBC, drug trough||GI/diarrhea, myelosuppression, lymphoid neoplasm *many drug interactions, needs dose adjusted for renal failure|
|Azathioprine (Imuran)||Purine analogue, prevents T cell proliferation||1-3 mg/kg/day (maintenance)||CBC, LFTs, Cr, check TPMT||Nausea/vomiting, myalgias, leukopenia, transaminitis|
|Sirolimus (Rapamycin)||mTOR inhibitor||Weight based; 1-5 mg/day (maintenance)||Drug level||Pneumonitis, arthralgias, edema, hypertension, bone marrow suppression, hyperlipidemia|
|Everolimus (Afinitor)||mTOR inhibitor||0.75-1 mg twice daily||Drug level||arthralgias, edema, hypertension, bone marrow suppression, hyperlipidemia|
|Prednisone||The dozens of things steroids do||Varies widely, minimum 7.5 mg every other day or 5 mg daily||n/a||Osteopenia, diabetes, headache, Cushing’s, weight, cataracts, psychosis (and many others)|
## Mycophenolate can be either mycophenolate mofetil vs. sodium. The difference is that the sodium formulation (Myfortic) is an enteric capsule that may prevent some GI effects like diarrhea(?) but the jury is still out.
What are the major side effects of immunosuppression?
What is the underlying biology? ***This is a gross oversimplification.
Normally, T cells go scouting and if they encounter an antigen-presenting cell with foreign material on it, a chain reaction of events is started: calcineurin is activated, leading to a surge of IL-2 and its receptor, IL-2R, which upregulates the mTOR pathway, which leads to DNA nucleotide synthesis so that the T cell can multiply and generate an immune response.
Notice that the bolded words are the targets of the 6 immunosuppresants in the chart above.
Transplant pharmacology is REALLY COMPLICATED and you can do an entire fellowship training program for this. This is an excellent, but 100-page document from a Canadian transplant website. Here are two organ-specific guides/reviews regarding immunosuppression:
- Kidney – National Kidney Foundation
- Liver– Moini et al 2015
- This introductory powerpoint to transplant immunosuppression has some great tips on tailoring drug therapy at the end!