transplant nephrology
Triple immunosuppression (CNI + antimetabolite ± steroid) is the backbone. Allograft dysfunction is framed by time since transplant. BK has no antiviral — treatment is immunosuppression reduction. Death with a functioning graft (cardiovascular) is a leading cause of graft loss.
induction
Given at time of transplant to prevent early rejection.
| Agent | Use |
|---|---|
| Basiliximab (anti-CD25) | Standard / low immunological risk |
| Rabbit ATG (thymoglobulin) | High immunological risk, or steroid-avoidance protocols |
maintenance immunosuppression
Standard = triple therapy: calcineurin inhibitor + antimetabolite ± corticosteroid.
| Drug | Mechanism | Monitoring | Signature toxicities |
|---|---|---|---|
| Tacrolimus (CNI) | Calcineurin → ↓ IL-2 | 12-hr trough: 7–12 ng/mL early (first year), then ~5–8 ng/mL long-term | Nephrotoxicity, tremor, hyperK⁺, hypoMg²⁺, new-onset diabetes, HTN |
| Cyclosporine (CNI) | Calcineurin | Trough | Nephrotoxicity, gum hyperplasia, hirsutism (cosmetic side effects); rarely first-line now |
| Mycophenolate | IMPDH → ↓ purine synthesis | CBC (levels not routine) | Leucopenia, diarrhoea/GI, teratogenic |
| Azathioprine | Purine analogue | CBC; check TPMT | Myelosuppression; preferred in pregnancy (switch from MMF pre-conception) |
| Prednisone | Broad anti-inflammatory | Glucose, BP, bone | Hyperglycaemia, weight gain, osteoporosis |
| Sirolimus / everolimus (mTOR) | mTOR inhibition | Trough | Everything leaky and slow to heal: proteinuria, mouth ulcers, poor wound healing, pneumonitis, dyslipidaemia; role in skin-cancer conversion |
| Belatacept | CD80/86 costimulation block | IV monthly | ↑ early rejection; contraindicated in EBV-seronegative recipients (PTLD risk); better long-term GFR vs cyclosporine |
rising creatinine — differential by timeframe
A ≥25% rise above the patient’s own baseline is clinically significant. Frame every allograft dysfunction question by time since transplant:
| Timeframe | Leading causes |
|---|---|
| Immediate (days–weeks) | Delayed graft function / ATN, vascular/surgical, ureteric obstruction, hyperacute rejection |
| First year | Acute rejection (T-cell or antibody-mediated), CNI toxicity, BK nephropathy, CMV, volume depletion |
| Late (>1 year) | Chronic antibody-mediated rejection / transplant glomerulopathy, CNI toxicity, recurrent or de novo GN, renal artery stenosis, non-adherence |
workup of an acute creatinine bump
- Exclude prerenal / nephrotoxins (NSAIDs, contrast, ACEi/ARB changes)
- CNI trough — high → toxicity; low/variable → underdosing or non-adherence
- Urinalysis (new proteinuria/haematuria → glomerular process) + urine culture
- Transplant ultrasound with Dopplers — obstruction, arterial flow
- BK and CMV PCR
- Allograft biopsy — definitive for rejection vs CNI toxicity vs BK nephropathy
BK nephropathy can look identical to rejection on biopsy — and their treatments are opposite (reduce vs intensify immunosuppression). Biopsy with SV40 staining differentiates.
Trimethoprim (in TMP-SMX prophylaxis) causes a benign creatinine rise via blocked tubular secretion — no true GFR change.
acute rejection — treatment
| Type | Treatment |
|---|---|
| T-cell mediated (TCMR) | Pulse IV methylprednisolone (± ATG for higher-grade / steroid-resistant) |
| Antibody-mediated (AMR) | Plasmapheresis + IVIG (± rituximab) |
infections — the big three
| Infection | Key points | Management |
|---|---|---|
| CMV | Most common opportunistic infection; D+/R− = highest risk | Prophylaxis (valganciclovir) or preemptive PCR; treat with val/ganciclovir; resistance (UL97/UL54) → foscarnet/cidofovir; letermovir (approved for prophylaxis in high-risk D+/R−), maribavir (approved for refractory/resistant CMV) |
| BK virus | Viruria → viraemia → nephropathy → graft loss; mimics rejection on biopsy | Reduce immunosuppression — no reliable antiviral; screen plasma BK DNAemia monthly through month 9, then every 3 months until 2 years; reduce IS at >1000 copies/mL sustained ≥3 weeks |
| PTLD | EBV-associated B-cell lymphoproliferative disorder; often extranodal | Reduce immunosuppression |
TMP-SMX covers PJP + UTI prophylaxis. Only inactivated vaccines post-transplant — no live vaccines.
drug interactions — CYP3A4 / P-glycoprotein
CNIs and mTOR inhibitors are CYP3A4/3A5 and P-gp substrates.
- Inhibitors RAISE levels (→ toxicity): azole antifungals, clarithromycin/erythromycin (use azithromycin instead), diltiazem, verapamil, protease inhibitors, grapefruit
- Inducers LOWER levels (→ rejection): rifampin, phenytoin, carbamazepine, St John’s wort
Clarithromycin/erythromycin → tacrolimus toxicity within days. Azithromycin is the safe macrolide in transplant recipients.
long-term recipient health
Death with a functioning graft (mostly cardiovascular) is a leading cause of graft loss — manage the recipient, not just the kidney.
- Cardiovascular — BP target generally <130/80; statin, diabetes management, smoking cessation; SGLT2i and GLP-1 agonists emerging
- Malignancy — ≥2× cancer risk; skin cancer is the classic association → sun protection + dermatology screening + age-appropriate cancer screening
- Metabolic/bone — glucose, lipids, K⁺/Mg²⁺/phosphate, bone density
classic exam scenarios
| Presentation | Diagnosis |
|---|---|
| Tremor + headache + high tacrolimus trough | CNI toxicity |
| Rising Cr + rising BK viraemia at ~3–6 months | BK nephropathy → reduce immunosuppression |
| Started clarithromycin → Cr rising | CYP3A4 inhibition → tacrolimus toxicity |
| Started rifampin → rejection | CYP3A4 induction → subtherapeutic CNI |
| Fever + leucopenia + D+/R− at ~1–4 months off prophylaxis | CMV disease |
| Low/variable troughs + late graft dysfunction (young recipient) | Non-adherence |
| Gum hypertrophy + hirsutism | Cyclosporine |