Transplant Immunosuppression
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Direct answer
Calcineurin inhibition sits at the centre of every modern kidney transplant regimen: tacrolimus plus mycophenolate plus a tapering glucocorticoid, with induction chosen by immunological risk — basiliximab, an interleukin-2 receptor antibody, for low risk, and lymphocyte-depleting antithymocyte globulin for the sensitised or retransplant recipient. Tacrolimus trades cyclosporine's hirsutism and gingival hyperplasia for new-onset diabetes, tremor, alopecia and hyperkalaemia, and its window is narrow — under-dosing invites rejection while accumulations burn the graft with striped interstitial fibrosis. Nothing tests prescribing judgement harder than the CYP3A4 interactions: azole antifungals and diltiazem drive levels toxic, while rifampicin and phenytoin drive them to rejection.
What you must remember
- Tacrolimus troughs: commonly 8–12 ng/mL in the early months, easing to 5–8 ng/mL at maintenance; twelve-hour troughs before the morning dose.
- Tacrolimus toxicities: nephrotoxicity, neurotoxicity (tremor, headache), hyperkalaemia, hypomagnesaemia, alopecia and post-transplant diabetes; cyclosporine instead produces hirsutism, gum hypertrophy, hypertension and hyperuricaemia.
- Chronic calcineurin toxicity on biopsy: arteriolar hyalinosis and striped fibrosis — the lesion that mimics chronic rejection and forces dose reduction, not escalation.
- Mycophenolate: diarrhoea, cytopenias and teratogenicity — mandatory contraception; the leading cause of dose reduction, and never combined in pregnancy, where azathioprine takes over.
- mTOR inhibitors (sirolimus, everolimus): delayed wound healing, lymphocele, mouth ulcers, proteinuria, hyperlipidaemia and pneumonitis; avoid loading them at implantation — early use increases vascular and wound complications.
- Induction: basiliximab for standard risk; antithymocyte globulin for high immunological risk, prior rejection or delayed graft function, accepting infection and cytopenia risks.
- Interactions that raise levels: azoles, macrolides, diltiazem, verapamil, grapefruit juice — all CYP3A4 inhibitors.
- Interactions that lower levels: rifampicin, isoniazid to a lesser degree, phenytoin, carbamazepine, St John's wort — the classic transplant-tuberculosis collision in Indian practice.
Building a regimen for a sensitised recipient
A 31-year-old woman, second transplant, panel-reactive antibody 70 per cent, receives induction with antithymocyte globulin rather than basiliximab because her rejection risk outruns her infection risk. Maintenance opens with tacrolimus targeting 8–10 ng/mL, mycophenolate 720 mg twice daily and a rapid prednisolone taper to 10 mg by week four. At week three she is admitted with fever and a cough; sputum grows nothing but the treating team starts fluconazole empirically for candidiasis. Three days later her tacrolimus trough reads 22 ng/mL and her creatinine has climbed — the azole has shut down her CYP3A4, and the correct moves are to hold or halve the dose, recheck at 48 hours, and document the interaction permanently in her chart. Contrast the companion case: a recipient on stable troughs of 6 ng/mL starts rifampicin for latent tuberculosis and lands in hospital with biopsy-proven acute cellular rejection eight weeks later, because induction on hepatic enzymes stripped his tacrolimus. Both cases teach the same rule the viva examiner wants voiced: with calcineurin inhibitors, every new prescription is a tacrolimus level waiting to be checked. A distinctly Indian wrinkle worth quoting: many units deliberately add low-dose diltiazem to reduce the tacrolimus dose requirement and drug cost — pharmacology used as an economy, and a favourite discussion point in transplant vivas.
Where students slip
Candidates memorise the toxicity lists but miss the timing rules. Sirolimus started on the operating table is a recognised error pattern — wound dehiscence and lymphocele follow — whereas introducing it later, or in a patient already on a calcineurin inhibitor with preserved function, is routine. The second slip is reading every rising creatinine as rejection: tacrolimus nephrotoxicity produces the same number, and the discriminator is a trough level plus a biopsy showing arteriolar hyalinosis and striped fibrosis rather than tubulitis. The third is forgetting that abrupt withdrawal of any component — steroids included — is a rejection experiment, which is why non-adherence, not drug toxicity, remains the leading correlate of late graft loss.
Frequently asked questions
Which calcineurin inhibitor is first-line in current regimens?
Tacrolimus, for superior rejection prevention; cyclosporine is reserved for specific indications such as intolerable tacrolimus toxicity or diabetes risk.
When should sirolimus not be started?
Immediately post-transplant — early initiation increases wound, vascular and urological complications; introduce it only after healing is complete.
Which drugs most dangerously interact with tacrolimus?
CYP3A4 inhibitors — azoles, macrolides, diltiazem — raise levels toward toxicity, while rifampicin and anticonvulsants lower them toward rejection.
What induction agent suits a highly sensitised recipient?
Lymphocyte-depleting antithymocyte globulin; basiliximab suffices for low immunological risk.
Which immunosuppressant demands contraception in women of childbearing age?
Mycophenolate, which is teratogenic; pregnancy is managed on azathioprine, a calcineurin inhibitor and steroids.