Kidney Transplantation — Clinical Case

DCE Long Case

Patient profile

Mr K is a 52-year-old man with end-stage kidney disease from type 2 diabetic kidney disease, now six months post deceased-donor kidney transplant. He presents to the transplant clinic with a subacute rise in creatinine. [1]

Presenting concern: Mr K was reviewed routinely in the transplant clinic at six months. He had been well, with a stable creatinine of 130 micromol/L since month 2. Over the past two weeks he has noticed some mild aching in the region of the graft and reduced energy, but no fever, no dysuria, no change in urine output, and no new medications. His home blood pressure readings have crept up from 128/78 to 142/88. [1]

Past medical history: Type 2 diabetes mellitus for 18 years (HbA1c 7.4 per cent on the transplant list), hypertension, dyslipidaemia, peripheral neuropathy, and background diabetic retinopathy (treated with laser). He reached end-stage kidney disease three years ago and was on haemodialysis via a brachiocephalic fistula for 14 months before transplant. He was referred to the transplant unit when his eGFR fell below 20, was worked up, and received a deceased-donor kidney (donor after brain death) six months ago. Induction was basiliximab; he is maintained on tacrolimus, mycophenolate 500 mg twice daily, and prednisolone 5 mg daily. He is also on ramipril, atorvastatin, aspirin, insulin (glargine plus novorapid), and co-trimoxazole prophylaxis. [1]

Social: Former truck driver, now on a disability pension. Lives with his wife; two adult children. Ex-smoker (stopped at the time of transplant after 30 pack-years). Minimal alcohol. He reports good adherence, collecting and taking his medications reliably. [1]

Examination:

• Afebrile, pulse 78 regular, blood pressure 144/90, respiratory rate 16, SpO2 98 per cent room air. Weight 88 kg (BMI 30).
• Cushingoid facies and central adiposity. A fine tremor of the outstretched hands (tacrolimus). No asterixis. Diabetic background retinopathy on fundoscopy.
• A well-healed transplant scar in the right iliac fossa. The graft is palpable and mildly tender. No bruit. A functioning brachiocephalic AV fistula at the left wrist with a thrill and bruit. No hepatosplenomegaly, no lymphadenopathy.
• Reduced vibration sense and light touch in both feet (diabetic peripheral neuropathy). No peripheral oedema. [1]

Investigations:

• Creatinine 190 micromol/L (baseline 130; eGFR now approximately 35). Potassium 4.8. Bicarbonate 24. HbA1c 8.1 per cent (risen from 7.4 per cent pre-transplant).
• Full blood count normal. Tacrolimus trough 9 ng/mL (target 5 to 10).
• Spot urine protein-to-creatinine ratio 60 mg/mmol (mildly elevated; baseline 30).
• Plasma BK virus PCR 62,000 copies/mL (markedly elevated; baseline undetectable one month ago). CMV PCR negative.
• Donor-specific antibodies negative on the most recent panel.
• Ultrasound with Doppler: graft 11.5 cm, normal echogenicity, good perfusion, no hydronephrosis, patent renal artery and vein.
• Allograft biopsy: tubulointerstitial inflammation with intranuclear viral inclusions in tubular epithelial cells, positive on SV40 immunohistochemistry. No C4d staining in peritubular capillaries. No intimal arteritis. No significant interstitial fibrosis or tubular atrophy. [1]

Candidate's opening statement (SASPOP)

"This is Mr K, a 52-year-old man with end-stage kidney disease from type 2 diabetic kidney disease, now six months post deceased-donor kidney transplant on tacrolimus, mycophenolate and prednisolone, presenting with a subacute rise in creatinine from 130 to 190 micromol/L, found on workup to have BK polyomavirus nephropathy — a plasma BK viral load of 62,000 copies/mL with biopsy-proven viral inclusions positive on SV40 immunohistochemistry, no C4d staining and no intimal arteritis to suggest concurrent antibody-mediated or T-cell mediated rejection. He also has worsening hypertension and a rising HbA1c of 8.1 per cent, consistent with new-onset diabetes after transplant superimposed on his longstanding diabetes. His main problems are the BK nephropathy, the risk of graft loss from progressive viral injury, the competing risk of rejection if I reduce immunosuppression, his cardiovascular risk profile as a diabetic ex-smoker, and his glycaemic control. My immediate priority is to reduce his immunosuppression in a structured way while monitoring the viral load and renal function, having excluded co-existing rejection, and to intensify his cardiovascular and glycaemic management." [1]

Structured problem list (numbered, prioritised)

1. BK polyomavirus nephropathy — biopsy-proven, plasma viral load 62,000 copies/mL; the cause of the graft dysfunction. Managed by structured immunosuppression reduction.
2. Graft dysfunction — creatinine 190 (baseline 130); monitor for progression and recovery.
3. The competing risk of rejection — immunosuppression reduction lowers the BK load but raises the rejection risk; the biopsy has excluded concurrent rejection, but surveillance is ongoing.
4. New-onset/worsening diabetes after transplant — HbA1c risen to 8.1 per cent; tacrolimus and steroids are the drivers; cardiovascular and graft survival implications.
5. Cardiovascular risk — blood pressure 144/90 (above target), diabetic, ex-smoker, dyslipidaemia; cardiovascular disease is the leading cause of death with a functioning graft.
6. The lifelong surveillance agenda — skin cancer, infection, adherence, metabolic complications of immunosuppression. [1]

Integrated management plan

Pillar 1 — Structured reduction of immunosuppression: The 2024 Second International Consensus Guidelines state that the mainstay of BK nephropathy management is reduction of immunosuppression, with no evidence to support cidofovir, leflunomide, fluoroquinolones or IVIG [7]. I would reduce the mycophenolate first by 25 to 50 per cent (to 250 to 500 mg twice daily), then, if the viral load does not fall over two to four weeks, reduce the tacrolimus towards the lower end of target (around 5 ng/mL). I would monitor the plasma BK viral load and the creatinine every one to two weeks, expecting the viral load to fall over four to eight weeks. I would not add cidofovir (nephrotoxic) or leflunomide (no proven benefit).

Pillar 2 — Ongoing surveillance for rejection during immunosuppression reduction: BK nephropathy and acute rejection can coexist and mimic each other, and treating BK as rejection — escalating immunosuppression — would be catastrophic. The biopsy has confirmed BK nephropathy with no C4d, no intimal arteritis and no donor-specific antibodies, so there is no concurrent antibody-mediated or significant T-cell mediated rejection at present [5]. If the creatinine were to rise despite adequate immunosuppression reduction, I would re-biopsy to look for evolving rejection, recognising that BK nephropathy, T-cell mediated rejection and antibody-mediated rejection can coexist.

Pillar 3 — Glycaemic and cardiovascular risk factor modification: His HbA1c has risen to 8.1 per cent. Tacrolimus and steroids contribute to insulin resistance and beta-cell dysfunction. I would intensify his insulin regimen (consider adding or adjusting the basal insulin), reinforce dietary advice with a diabetes educator, and aim for an HbA1c below 7.5 per cent (balancing the harm of hypoglycaemia). For his blood pressure of 144/90, I would uptitrate the ramipril (monitoring potassium and creatinine, which ACE inhibitors can affect), aim for below 130/80, and ensure he is on a statin (he is, on atorvastatin) and aspirin. I would reinforce that cardiovascular disease is the leading cause of death with a functioning graft, and that this agenda is central to his long-term survival [1].

Pillar 4 — The lifelong surveillance agenda: I would continue BK screening monthly to 9 months then quarterly to 2 years, maintain co-trimoxazole prophylaxis for Pneumocystis for the first 12 months, arrange annual dermatological review (squamous cell skin cancer is 65 to 100 times more common after transplant), continue age-appropriate cancer screening, maintain inactivated vaccinations (avoid live vaccines), monitor tacrolimus troughs and the full blood count for mycophenolate marrow toxicity, and reinforce adherence at every visit. [1]

Pillar 5 — Communication and shared decision-making: I would explain to Mr K that his rising creatinine is caused by a virus called BK that has taken hold because his immunosuppression, which he needs to protect the kidney, has also dampened the cells that keep the virus in check. The treatment is a careful, structured reduction of that immunosuppression, with close monitoring of both the virus and the kidney. I would explain the trade-off in plain language — less drug means less virus but a small extra risk of rejection — and that we will watch both closely and re-biopsy if the kidney does not improve. I would involve the transplant coordinator and his general practitioner, and ensure he has a clear sick-day plan and contact details for the transplant unit. [1]

Probing questions the examiner would ask

Q: What is BK virus and why does it reactivate after transplant? [1]

A: "BK polyomavirus is a ubiquitous double-stranded DNA virus that infects most of the population in childhood and establishes lifelong latency in the renal tubular epithelium and urothelium. It reactivates under calcineurin-inhibitor-based immunosuppression, when T-cell surveillance is suppressed, typically between month 1 and 6 post-transplant. Reactivation progresses from viruria to viraemia to nephropathy, which is why surveillance of the plasma viral load allows early intervention before graft injury. The 2024 consensus guideline recommends screening plasma BK viral load monthly for the first 9 months, then every 3 months to 2 years [7]."

Q: Why is the biopsy essential before you reduce the immunosuppression? [1]

A: "Because BK nephropathy and acute rejection can coexist and mimic each other, and their treatments pull in opposite directions — BK requires less immunosuppression, rejection requires more. Treating BK as rejection would dramatically worsen the viral infection. The biopsy confirms the diagnosis (viral inclusions on SV40 immunohistochemistry) and excludes concurrent rejection (no C4d, no intimal arteritis, no donor-specific antibodies), so I can confidently reduce the immunosuppression without undertreating rejection [5]."

Q: How would you manage this patient's blood pressure, and what is your target? [1]

A: "My target is below 130/80, because cardiovascular disease is the leading cause of death with a functioning graft and blood pressure control also protects the graft. I would uptitrate his ramipril (an ACE inhibitor is a good first-line choice in a transplant recipient, with the additional benefit of reducing proteinuria), monitor the potassium and creatinine closely (ACE inhibitors can cause a reversible rise and hyperkalaemia, especially with tacrolimus, which also raises potassium), and add a calcium channel blocker such as amlodipine if needed. I would avoid beta-blockers as first-line unless there is a cardiac indication, and I would avoid NSAIDs entirely." [1]

Q: His HbA1c has risen to 8.1 per cent since transplant. What is going on and what will you do? [1]

A: "This is a combination of his longstanding type 2 diabetes and the diabetogenic effect of tacrolimus and corticosteroids — the syndrome of new-onset diabetes after transplant superimposed on pre-existing diabetes. Tacrolimus impairs beta-cell insulin secretion and steroids cause insulin resistance. I would intensify his insulin regimen, reinforce dietary input from a diabetes educator, and aim for an HbA1c of around 7 to 7.5 per cent, balancing the microvascular benefit against the harm of hypoglycaemia. If the diabetes proved very difficult to control, I would discuss with the transplant team whether converting tacrolimus to a less diabetogenic agent (such as belatacept, or ciclosporin in selected cases) is appropriate, weighing the higher rejection risk." [1]

Q: What malignancy surveillance does this patient need? [1]

A: "Annual dermatological review is mandatory, because squamous cell skin cancer is the most common post-transplant malignancy and is 65 to 100 times more common than in the general population, related to immunosuppression, HPV and ultraviolet light. I would maintain age-appropriate colorectal, and for men prostate, screening. I would maintain a low threshold for investigating any new symptom, because post-transplant lymphoproliferative disorder (EBV-driven, highest in EBV-seronegative recipients) presents with fever, lymphadenopathy and extranodal masses, and is managed first by reduction of immunosuppression [8]. If he develops recurrent or high-risk skin cancers, I would consider switching from a calcineurin inhibitor to an mTOR inhibitor, which has anti-tumour activity."

Q: What would you do differently if his biopsy had shown C4d staining and donor-specific antibodies? [1]

A: "That would indicate concurrent antibody-mediated rejection, which changes the management entirely. I would treat the AMR with plasmapheresis (3 to 5 sessions), intravenous immunoglobulin (around 2 g/kg in divided doses), rituximab (375 mg/m2) and intensification of maintenance immunosuppression, while still reducing the immunosuppression enough to control the BK load — a genuinely difficult balance that requires close collaboration between the transplant physician, the pathologist and the infectious diseases team. The lesson is that the biopsy and the donor-specific antibody testing make the diagnosis, and the treatment follows the diagnosis." [1]

Q: What is the standard immunosuppression regimen and how was it established? [1]

A: "The global standard is tacrolimus plus mycophenolate plus prednisolone, after induction with basiliximab for low to moderate risk or anti-thymocyte globulin for high risk. 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]. This established tacrolimus as the standard calcineurin inhibitor and the triple regimen as the global default."

Outcome

Mr K's mycophenolate is halved to 250 mg twice daily. At two weeks his BK viral load has fallen to 28,000 copies/mL and his creatinine is stable at 185. At six weeks his viral load is 6,000 copies/mL and his creatinine has fallen to 155. His tacrolimus trough is maintained at the lower end of target (around 6). His blood pressure is controlled to 132/80 on uptitrated ramipril and amlodipine, and his insulin regimen is intensified to bring the HbA1c toward 7.5 per cent. He is booked for annual dermatological review and reinforced adherence education. The transplant team continues monthly BK surveillance to 9 months, then quarterly to 2 years, with a low threshold to re-biopsy if the creatinine rises again [7].