Renal transplantation issues - short and long-term complications, including management of BK virus nephropathy, diarrhoea, and neutropenia
Complications by time since transplant
- Complications sort by time since transplant - and the timeline is the diagnostic tool
| Period | Dominant problems |
|---|---|
| <1 month | Surgical (bleeding, leak, lymphocele, vascular thrombosis), delayed graft function, hospital-acquired infection (wound, line, UTI, C. difficile), hyperacute/acute rejection |
| 1-6 months | Opportunistic infection - CMV, BK, PJP, nocardia, listeria, aspergillus, TB reactivation, acute rejection, drug toxicity |
| >6 months | Community-acquired infection, chronic antibody-mediated rejection, CNI nephrotoxicity, malignancy, cardiovascular disease, recurrent disease, PTDM |
- *Cardiovascular disease is the leading cause of long-term death* - pre-existing risk plus hypertension, dyslipidaemia and post-transplant diabetes from the immunosuppression itself
Epidemiology
- Delayed graft function ~20-30% of deceased donor grafts (<5% living donor)
- Acute rejection in the first year now <10-15%
- CMV disease ~10-20% without prophylaxis; highest in D+/R-
- BK viraemia ~10-15%; BK nephropathy ~1-10%
- PTDM ~15-30% in the first year
- Skin SCC risk ~20-65x the general population - highest in Australia of anywhere in the world
Delayed graft function
- Ischaemia-reperfusion injury -> ATN
- Risk: long cold ischaemia time, donation after circulatory death, extended criteria/older donor, donor AKI
- Defined as needing dialysis in the first week; predicts more rejection and shorter graft survival
BK polyomavirus
- Ubiquitous latent virus in uroepithelium; reactivates under immunosuppression
- Sequence: viruria -> viraemia -> nephropathy (weeks apart)
- Causes tubulointerstitial nephritis and ureteric stenosis
- Histologically mimics acute rejection - and the treatments are opposite
CMV
- Highest risk D+/R- (primary infection); then R+ (reactivation); lowest D-/R-
- Causes tissue-invasive disease (colitis, oesophagitis, hepatitis, pneumonitis, retinitis) and immunomodulation -> more rejection and more other infections
- Leucopenia and thrombocytopenia are typical
Post-transplant diarrhoea
- Mycophenolate (dose-related; less with enteric-coated mycophenolate sodium) - the commonest cause
- Infection: **C. difficile, norovirus, CMV colitis**, cryptosporidium, giardia, bacterial
- Tacrolimus, magnesium supplements, sirolimus
- Diarrhoea raises tacrolimus levels (dec P-glycoprotein/CYP3A4 in the gut) -> a further creatinine rise - check the level
Post-transplant neutropenia
- Valganciclovir, mycophenolate, trimethoprim-sulfamethoxazole, ATG, rituximab
- Viral - CMV, parvovirus B19 (also pure red cell aplasia), EBV
- Additive: mycophenolate + valganciclovir + trimethoprim is the classic triple hit
The rising creatinine - work through it in this order
- 1. Pre-renal / drug - volume, diarrhoea, NSAIDs, ACEi, a high CNI level
- 2. Ultrasound - hydronephrosis (ureteric stenosis or stone), collection (lymphocele, urinoma, haematoma), resistive index, arterial and venous flow
- 3. Infection - urine culture, plasma BK PCR, CMV PCR
- 4. DSA - de novo donor-specific antibody
- 5. Biopsy - early, low threshold. The definitive step; nothing above reliably distinguishes rejection from CNI toxicity or BK nephropathy
Surveillance protocol
| Test | Frequency |
|---|---|
| BK plasma PCR | Monthly for 6-9 months, then 3-monthly to 2 years |
| CMV PCR | Weekly-fortnightly after prophylaxis stops in high-risk (D+/R-) |
| Creatinine, UACR | Very frequent early, then 1-3 monthly |
| CNI trough | Every visit early |
| DSA | Baseline, 3, 12 months, then annually or with dysfunction |
| Skin check | At least annually - more often in Australia |
Key histological distinctions
- TCMR - tubulitis, interstitial infiltrate (Banff i/t), arteritis (v)
- ABMR - peritubular capillaritis, glomerulitis, C4d staining, circulating DSA
- BK nephropathy - viral cytopathic inclusions, SV40 large T antigen immunostaining
- CNI toxicity - arteriolar hyalinosis, striped interstitial fibrosis, isometric tubular vacuolisation
Short-term / surgical
- Delayed graft function - dialyse as needed, avoid nephrotoxins, consider reducing CNI or using ATG induction until function returns; biopsy at ~1 week to exclude rejection
- Urine leak -> stent or re-operate; lymphocele -> drain or fenestrate if obstructing; ureteric stenosis -> stent or reimplant
- Renal artery or vein thrombosis - sudden anuria and graft tenderness; usually loses the graft - a surgical emergency
- Transplant renal artery stenosis - refractory HTN, flash pulmonary oedema, creatinine rise with ACEi -> angioplasty
Rejection
- Acute TCMR -> pulse methylprednisolone, escalate maintenance (azathioprine -> mycophenolate, add or intensify); ATG if steroid-resistant or vascular rejection
- ABMR -> plasma exchange + IVIG +/- rituximab; response is poor
- Chronic ABMR -> no effective therapy; optimise adherence and maintenance, plan for graft failure
BK virus
BK virus
- Reduce immunosuppression stepwise - the primary evidence-based strategy
- Reduce/stop the antimetabolite first, then reduce the CNI
- *Antivirals (cidofovir, leflunomide, IVIG, ciprofloxacin) are unproven; cidofovir is itself nephrotoxic*
- Monitor viral load fortnightly; re-biopsy if creatinine rises after reduction (rejection vs progressive nephropathy)
- A treated BK nephropathy patient stays at lifelong risk of graft loss (~30-50%)
CMV - management
CMV
- Prophylaxis: valganciclovir 3-6 months (longer in D+/R-), or pre-emptive PCR-guided therapy
- Disease: IV ganciclovir or oral valganciclovir, reduce immunosuppression; letermovir or maribavir for resistant/refractory disease
- Resistance (UL97, UL54 mutations) after prolonged low-dose exposure
Diarrhoea - management
Diarrhoea
- *Stool culture, C. difficile toxin, viral PCR; consider colonoscopy for CMV*
- Reduce or switch mycophenolate (divide the dose, or change to enteric-coated mycophenolate sodium)
- Check the tacrolimus level - it rises with diarrhoea
- Rehydrate; avoid loperamide until infection is excluded
Neutropenia - management
Neutropenia
- Stop or reduce the likeliest culprit in order: valganciclovir -> trimethoprim -> mycophenolate
- Check CMV and parvovirus B19 PCR
- G-CSF if severe or febrile
- Do not reflexively stop everything - the graft still needs immunosuppression
Long-term risk reduction
- Cardiovascular: BP <130/80, statin, glycaemic control, smoking cessation, weight
- PTDM: screen with fasting glucose/HbA1c; minimise steroids, consider tacrolimus dose reduction or switch
- Malignancy: annual dermatology review, sun protection; age-appropriate screening; consider switching to an mTOR inhibitor for recurrent skin cancer or Kaposi sarcoma
- Bone: highest loss in the first 6-12 months; vitamin D, calcium, consider antiresorptive
- Vaccination - inactivated only; no live vaccines
- Adherence - address at every visit
Associations
- CMV, BK polyomavirus, EBV (PTLD), HHV-8 (Kaposi), hepatitis B/C, PJP, nocardia, listeria, aspergillus, TB
- Skin cancer (SCC >> BCC), PTLD, renal and anogenital malignancy
- Post-transplant diabetes mellitus - tacrolimus, steroids, hepatitis C, obesity
- Cardiovascular disease - the leading cause of long-term death
- Tertiary hyperparathyroidism, post-transplant bone disease, gout
- Recurrent disease - FSGS (recurs earliest and most often), IgA nephropathy, MPGN/C3G, membranous, diabetic nephropathy, oxalosis
- Erythrocytosis (treated with ACEi/ARB), anaemia, leucopenia
- Non-adherence - a leading cause of late graft loss, especially in adolescents
Outcomes
- 1-yr graft survival >95%; median graft half-life ~12-15 years (deceased donor), longer for living donor
- Death with a functioning graft is a leading cause of graft loss - cardiovascular, infection, malignancy
- Chronic ABMR is the leading immunological cause of late graft loss and has no effective treatment
- Delayed graft function predicts more acute rejection and poorer long-term graft survival
- BK nephropathy: graft loss in ~30-50% historically, lower with early PCR-driven detection and immunosuppression reduction
- Returning to dialysis after graft failure carries higher mortality than an incident dialysis start - plan access and re-listing early
- A failing graft still needs a decision about immunosuppression withdrawal - weigh sensitisation for re-transplant against infection and malignancy risk
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