Renal transplantation issues - immunosuppression, including drug interactions
Three phases of immunosuppression
- Immunosuppression has three phases, and the drugs differ in each:
- Induction - intense, peri-operative, covers the period of highest rejection risk
- Maintenance - lifelong, usually triple therapy
- Treatment of rejection - episodic
- Standard maintenance triple therapy: tacrolimus + mycophenolate + prednisolone
- The whole art is balancing rejection against infection, malignancy and drug toxicity - and every graft problem is one or the other
Epidemiology
- ~1400 kidney transplants per year in Australia (ANZDATA); ~1/3 from living donors
- Acute rejection now <10-15% in the first year with modern regimens
- 1-yr graft survival >95%; median graft half-life ~12-15 years - chronic loss has improved far less than acute rejection
- Death with a functioning graft (cardiovascular, infection, malignancy) is a leading cause of graft loss
What the drugs block
- Signal 1 - TCR/CD3 recognition of alloantigen -> muromonab, alemtuzumab (CD52)
- Signal 2 - co-stimulation (CD28/B7) -> belatacept (CTLA4-Ig)
- Signal 3 - IL-2 -> receptor -> calcineurin inhibitors (block IL-2 production), basiliximab (blocks IL-2 receptor), mTOR inhibitors (block IL-2 signalling)
- Proliferation - purine synthesis -> mycophenolate (IMPDH), azathioprine
- B cell / antibody - rituximab (CD20), bortezomib (plasma cell), eculizumab (C5), IVIG, plasma exchange
Rejection types
| Type | Timing | Mechanism | Treatment |
|---|---|---|---|
| Hyperacute | Minutes | Preformed DSA | Prevented by crossmatch; graft is lost |
| Acute T-cell mediated (TCMR) | Days-months | T-cell tubulitis, arteritis (Banff i/t/v) | Pulse methylprednisolone; ATG if steroid-resistant or vascular |
| Acute antibody-mediated (ABMR) | Any time | DSA, C4d+, microvascular inflammation | Plasma exchange + IVIG +/- rituximab; poor response |
| Chronic ABMR | Years | Transplant glomerulopathy, chronic DSA | No effective therapy - the main cause of late graft loss |
Rising creatinine in a transplant - the differential
Always exclude the mechanical and pre-renal causes before assuming rejection
- Pre-renal - volume depletion, NSAIDs, ACEi, diarrhoea
- Urological - ureteric obstruction, urine leak, lymphocele (ultrasound first)
- Vascular - transplant renal artery stenosis (refractory HTN, flash pulmonary oedema, dec eGFR on ACEi), renal vein thrombosis
- Rejection - TCMR or ABMR
- CNI nephrotoxicity - acute (vasoconstrictive, reversible) or chronic (striped fibrosis, arteriolar hyalinosis)
- BK polyomavirus nephropathy
- Infection - UTI/pyelonephritis, CMV
- Recurrent or de novo glomerular disease - FSGS, IgAN, MPGN/C3G, membranous, diabetic nephropathy
- Ultrasound + early biopsy is the answer to a rising creatinine - the diagnosis cannot be made clinically
- Send CNI trough level, BK viral load (plasma PCR), CMV PCR, DSA
Monitoring protocol
- Tacrolimus trough: ~8-12 ng/mL early, 5-8 ng/mL maintenance
- BK viraemia screening monthly for 6-9 months, then 3-monthly to 2 years
- DSA surveillance; decoy cells on urine cytology suggest BK
Induction
- Basiliximab (anti-CD25) - standard-risk
- ATG (anti-thymocyte globulin) - high immunological risk (high PRA, DSA, re-transplant, prior rejection), or for delayed graft function to allow CNI avoidance
- Cytokine release syndrome, prolonged lymphopenia, later CMV and PTLD risk
Maintenance - the three classes
1. Calcineurin inhibitor - the backbone
- Tacrolimus (preferred; superior graft survival) or ciclosporin
- CYP3A4 metabolised - the drug interaction question
- inc levels: azoles (fluconazole, voriconazole), macrolides (erythromycin, clarithromycin - not azithromycin), diltiazem, verapamil, grapefruit, protease inhibitors
- dec levels: rifampicin, phenytoin, carbamazepine, St John's wort
- Toxicity: nephrotoxicity (afferent vasoconstriction, chronic fibrosis), HTN, neurotoxicity (tremor, PRES), hyperkalaemia, hypomagnesaemia, type 4 RTA, new-onset diabetes (tacrolimus > ciclosporin)
- Ciclosporin-specific: gum hypertrophy, hirsutism, hyperlipidaemia
- Tacrolimus-specific: alopecia, diabetes, more neurotoxicity
2. Antiproliferative
- Mycophenolate (more potent than azathioprine) - IMPDH inhibitor
- GI toxicity (bloating, diarrhoea; less with enteric-coated mycophenolate sodium), marrow suppression
- Marrow suppression is additive with sirolimus, everolimus and valganciclovir
- Mycophenolate levels are lower when co-administered with ciclosporin (interrupted enterohepatic recirculation) - so ciclosporin regimens need a higher MMF dose
- Azathioprine - *never with allopurinol or febuxostat (xanthine oxidase inhibition -> life-threatening myelosuppression); check TPMT/NUDT15*
3. Corticosteroid - prednisolone; early withdrawal possible in low-risk patients
Others
- mTOR inhibitors (sirolimus, everolimus) - CNI-sparing; anti-neoplastic (useful with skin cancer or Kaposi sarcoma)
- Poor wound healing, lymphocele, proteinuria, mouth ulcers, pneumonitis, hyperlipidaemia - avoid early post-op
- Belatacept - CNI-free; only in EBV-seropositive recipients (PTLD risk)
Managing specific graft problems
Managing specific graft problems
- Acute TCMR -> pulse methylprednisolone, then escalate maintenance (azathioprine -> mycophenolate, add or intensify agents); ATG if steroid-resistant
- ABMR -> plasma exchange + IVIG +/- rituximab
- BK virus nephropathy -> **reduce immunosuppression - stepwise reduction of the antimetabolite then the CNI**
- This is the primary evidence-based strategy; cidofovir, leflunomide and IVIG are unproven and cidofovir is itself nephrotoxic
- The trade-off is rejection - re-biopsy if creatinine rises after reduction
- CNI nephrotoxicity -> reduce dose, or convert to an mTOR inhibitor or belatacept
- Recurrent disease -> disease-specific
Infection prophylaxis
- Trimethoprim-sulfamethoxazole - PJP (and nocardia, toxoplasma, UTI) for 6-12 months
- Valganciclovir for CMV - 3-6 months, especially D+/R-
- Nystatin/fluconazole; hepatitis B and pneumococcal vaccination pre-transplant; *no live vaccines post-transplant*
Pregnancy
Pregnancy
- Wait >=1 year post-transplant with stable function, eGFR >45, proteinuria <1 g/day, no recent rejection
- Safe to continue: tacrolimus, ciclosporin, azathioprine, prednisolone
- Ciclosporin crosses the placenta but is not associated with fetal abnormality; tacrolimus is now also regarded as compatible
- Contraindicated: mycophenolate (first-trimester loss, ear/facial malformations) and mTOR inhibitors
- *Switch mycophenolate to azathioprine at least 6 weeks before conception*
- CNI levels fall in pregnancy - monitor and increase dose
Complications
- Malignancy - skin (SCC >> BCC, ~20-fold), PTLD (EBV-driven, highest in D+/R- and after ATG), Kaposi sarcoma (HHV-8), renal and anogenital cancer
- Annual dermatology review, sun protection, consider mTOR conversion
- Infection - CMV, BK, PJP, nocardia, aspergillus, TB reactivation, listeria
- Cardiovascular disease - the leading cause of death with a functioning graft
- Post-transplant diabetes mellitus (~15-30%) - tacrolimus and steroids
- Tertiary hyperparathyroidism - persistent hypercalcaemia and hypophosphataemia post-transplant
- Bone disease: rapid loss in the first 6-12 months; avascular necrosis
- Gout - CNI-induced; the azathioprine-allopurinol interaction makes this hard to treat
- Erythrocytosis, anaemia, leucopenia
Natural history
- Acute rejection is now uncommon and usually reversible; chronic antibody-mediated rejection and death with a functioning graft dominate late loss
- Non-adherence is a leading cause of late graft loss - especially in adolescents and young adults
- De novo DSA predicts chronic ABMR and graft loss; often preceded by subtherapeutic CNI levels
- Median graft survival ~12-15 yrs (deceased donor), longer for living donor
What to monitor lifelong
- Creatinine, UACR, CNI trough, FBE, glucose/HbA1c, lipids, Ca/PO4/PTH
- Annual skin check, age-appropriate cancer screening
- BP, cardiovascular risk, vaccination status, bone density
- Adherence at every visit
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