Kidney Transplantation — Written Clinical Reasoning

SAQ 1 — Rising creatinine 5 months post-transplant: the integrated diagnostic approach (20 marks, 30 minutes)

Prompt: Outline your structured diagnostic approach to a rising creatinine in a transplant recipient 5 months post-transplant, the role of the biopsy and its classification, and your integrated management plan for each likely diagnosis. Justify each decision with reference to evidence. [1]

Model Answer

Problem list (3 marks): [1]

1. Graft dysfunction 5 months post-transplant — a structured differential spanning acute T-cell mediated rejection, antibody-mediated rejection, BK virus nephropathy, calcineurin inhibitor nephrotoxicity, ureteric obstruction, recurrent disease and chronic allograft injury.
2. The risk of misdiagnosis — BK nephropathy and acute rejection can coexist and mimic each other; treating BK as rejection (more immunosuppression) is catastrophic.
3. The lifelong context — non-adherence, drug interactions and inadequate trough levels are the commonest modifiable drivers of rejection. [1]

Step 1 — The structured history and examination (3 marks): [1]

I would take a focused history: adherence (the commonest hidden cause of rejection), any new medications (especially CYP3A4-interacting drugs), infective symptoms, diarrhoea (which alters tacrolimus absorption), and the timing of the rise. On examination I would look for graft tenderness (a red flag suggesting rejection, pyelonephritis, vascular thrombosis or a perinephric collection), fever, fluid status and blood pressure. A tender graft is never dismissed. [1]

Step 2 — The investigations, run in parallel (4 marks): [1]

• Bloods — tacrolimus trough level (in target here at 9), full blood count, eGFR and electrolytes, BK virus plasma PCR (mandatory beyond one month in a rising creatinine), CMV PCR (if high-risk mismatch or recent prophylaxis cessation), and donor-specific antibodies if AMR is suspected.
• Urine — spot protein-to-creatinine ratio and culture (pyelonephritis is common and treatable).
• Imaging — urgent ultrasound with Doppler to exclude ureteric obstruction (hydronephrosis) and renal vascular thrombosis, and to assess graft perfusion.
• Biopsy — the gold standard. The biopsy is not optional in this setting; the histology determines whether the treatment is steroids (acute T-cell mediated rejection), plasmapheresis and IVIG (antibody-mediated rejection), immunosuppression reduction (BK nephropathy), or regimen modification (CNI toxicity). [1]

Step 3 — The biopsy classification and what each pattern means (4 marks): [1]

The Banff schema classifies the biopsy: [1]

• Acute T-cell mediated rejection — tubulitis, interstitial inflammation, intimal arteritis (graded Banff 1A to 3). Treated with pulse intravenous methylprednisolone 250 to 500 mg daily for 3 days, with optimisation of maintenance immunosuppression and reinforcement of adherence; steroid-resistant rejection is treated with anti-thymocyte globulin.
• Antibody-mediated rejection — microvascular inflammation (glomerulitis, peritubular capillaritis), C4d staining in peritubular capillaries, and donor-specific antibodies. Treated with plasmapheresis, intravenous immunoglobulin (around 2 g/kg in divided doses), rituximab (375 mg/m2), and intensification of maintenance immunosuppression; bortezomib for refractory disease.
• BK nephropathy — tubulointerstitial inflammation with viral inclusions positive on SV40 immunohistochemistry, with high plasma BK viral load. Treated by reduction of immunosuppression (reduce mycophenolate first, then tacrolimus), with close viral load and renal function monitoring. The 2024 consensus guideline does NOT support cidofovir, leflunomide, fluoroquinolones or IVIG [7].
• Calcineurin inhibitor nephrotoxicity — arteriolar hyalinosis and striped interstitial fibrosis (chronic) or normal histology with a high level (acute); managed by dose reduction or conversion to an mTOR inhibitor or belatacept.
• Chronic allograft injury — interstitial fibrosis and tubular atrophy. The term "chronic allograft nephropathy" was eliminated at the Banff 2005 meeting as non-specific [5]; the modern term is IFTA, with the cause identified wherever possible.

Step 4 — The management plan (3 marks): [1]

Pending the biopsy result, I would hold the immunosuppression at the current regimen (the levels are in target), ensure the ultrasound excludes obstruction and thrombosis, and treat any identified infection. Once the biopsy returns: [1]

• If T-cell mediated rejection — pulse methylprednisolone, reinforce adherence, and confirm the tacrolimus level is adequate.
• If antibody-mediated rejection — plasmapheresis, IVIG and rituximab, with intensification of immunosuppression.
• If BK nephropathy — reduce mycophenolate then tacrolimus, monitor the viral load weekly to fortnightly, and counsel the patient on the balance between BK control and rejection risk [7].
• If CNI toxicity or chronic injury — minimise the tacrolimus or convert to sirolimus, and control blood pressure below 130/80.

Step 5 — Communication and follow-up (3 marks): [1]

I would explain the working diagnosis in plain language, the need for the biopsy, and the plan. I would reinforce adherence at every visit because non-adherence is the leading modifiable cause of graft loss. I would arrange close follow-up with weekly to fortnightly renal function and viral load monitoring, involve the transplant coordinator, and coordinate care with the general practitioner. I would address the cardiovascular risk factor agenda (the leading cause of death with a functioning graft) at every contact. [1]

SAQ 2 — The immunosuppression regimen and the post-transplant infection timeline (10 marks, 20 minutes)

Prompt: A 50-year-old man is about to receive a deceased-donor kidney. The donor is CMV seropositive and the recipient is seronegative. Outline your immunosuppression regimen (induction and maintenance), the rationale for each agent, the alternatives, and your infection prophylaxis and surveillance plan for the first year. [1]

Model Answer

Step 1 — Induction (2 marks): [1]

I would use induction therapy to provide potent peri-operative cover. The standard for a recipient of low to moderate immunological risk is basiliximab, a chimeric monoclonal antibody to the interleukin-2 receptor (CD25) on activated T cells, which is non-depleting and has few side effects. For high immunological risk (a sensitised recipient, a re-transplant, or a donor after circulatory death), I would use anti-thymocyte globulin (rabbit polyclonal), a broadly T-cell-depleting antibody, accepting its higher infection and malignancy risk as a dose-related trade-off. [1]

Step 2 — Maintenance triple therapy (3 marks): [1]

I would maintain on the global standard regimen: tacrolimus plus mycophenolate plus prednisolone. The SYMPHONY study randomised recipients to standard-dose ciclosporine, low-dose ciclosporine, low-dose tacrolimus, or low-dose sirolimus (all with mycophenolate and steroid); the low-dose tacrolimus arm gave the best renal function, the lowest acute rejection rate, and the best one-year graft survival [4].

• Tacrolimus — a calcineurin inhibitor that binds FKBP-12, inhibiting calcineurin and reducing interleukin-2 transcription. Monitored by trough (target 5 to 10 early, lower long-term). Key toxicities: nephrotoxicity, tremor, new-onset diabetes, hypertension, alopecia, hyperkalaemia. Major CYP3A4 interactions (macrolides, azoles, diltiazem, grapefruit raise the level; rifampicin, phenytoin, St John wort lower it).
• Mycophenolate — an antimetabolite inhibiting IMPDH, blocking lymphocyte purine synthesis. Key toxicities: diarrhoea, marrow suppression, teratogenicity (must switch to azathioprine 6 weeks before pregnancy).
• Prednisolone — broad immunosuppression, tapered to a low maintenance dose (around 5 mg) by 3 months. [1]

Step 3 — Alternatives (1 mark): [1]

mTOR inhibitors (sirolimus, everolimus) are used to spare calcineurin inhibitors (reduce nephrotoxicity) and to lower skin cancer risk, but they impair wound healing (avoid for at least one month post-operatively), cause dyslipidaemia and proteinuria, and are myelosuppressive. Belatacept (a co-stimulation blocker) is an alternative to CNIs with less nephrotoxicity and a better cardiovascular profile, but a higher early rejection rate and a PTLD risk in EBV-seronegative recipients (contraindicated in EBV-negative patients). [1]

Step 4 — Infection prophylaxis for this D+/R- CMV mismatch (2 marks): [1]

This recipient is at the highest risk for CMV disease. The third international consensus guideline recommends either universal valganciclovir prophylaxis for 3 to 6 months or a pre-emptive strategy with weekly CMV PCR for the first 12 weeks [6]. In addition I would give co-trimoxazole prophylaxis against Pneumocystis jirovecii for 6 to 12 months (and during any rejection treatment), valaciclovir for HSV or VZV seropositive recipients, and nystatin or clotrimazole for oral candidiasis.

Step 5 — Surveillance for the first year (2 marks): [1]

I would monitor the BK virus plasma PCR monthly for the first 9 months, then every 3 months to 2 years, because BK nephropathy is the leading viral cause of graft loss in this period and its management (immunosuppression reduction) is entirely different from rejection [7]. I would monitor tacrolimus trough levels, full blood count and eGFR regularly, blood pressure and glucose (to detect new-onset diabetes after transplant), lipids, and arrange annual dermatological review (squamous cell skin cancer is 65 to 100 times more common after transplant). I would reinforce adherence at every visit, because non-adherence is the leading modifiable cause of graft loss.