Kidney transplantation in children: SAQ

This boy has end-stage kidney disease from congenital renal hypodysplasia, a leading cause of paediatric transplant, and is approaching dialysis. A preemptive living-donor transplant from his mother is the optimal plan because it offers superior graft survival and avoids the morbidity of dialysis entirely. The estimated glomerular filtration rate of 12 mL per minute per 1.73 square metres places him at the threshold where dialysis is imminent, so the donor workup should already be complete. [2]

Question 1 (10 marks)

Outline the rationale for a preemptive living-donor transplant, the standard maintenance immunosuppression regimen, and the role of therapeutic drug monitoring. [3]

The rationale for a preemptive living-donor transplant rests on two independent advantages. First, a living-donor kidney, especially from a parent, gives the best long-term graft survival because the kidney is healthy, the surgery is elective, and the cold ischaemia time is short. Second, performing the transplant before dialysis begins avoids the growth failure, neurodevelopmental harm, cardiovascular damage and infectious risk that dialysis itself causes, and graft survival after a preemptive transplant is superior to that after a dialysis-first transplant. The practical trigger is the eGFR: once it approaches 10 to 15 mL per minute per 1.73 square metres, dialysis is imminent, so the living donor should be worked up in advance so the child never starts dialysis. [2]

The standard maintenance immunosuppression is a three-drug regimen: tacrolimus, a calcineurin inhibitor that blocks T-cell activation by suppressing interleukin-2 transcription; mycophenolate mofetil, an antimetabolite that inhibits lymphocyte proliferation; and low-dose prednisolone, a corticosteroid that is minimised and, in selected low-risk recipients, withdrawn to protect growth. Induction at the operation uses basiliximab for a low-risk recipient such as this boy, or a lymphocyte-depleting agent such as antithymocyte globulin for a sensitised or higher-risk recipient. [3]

Therapeutic drug monitoring of tacrolimus is essential because tacrolimus has a narrow therapeutic window. The trough whole-blood level is kept around 5 to 10 nanograms per millilitre in the early post-transplant period, then lowered to a long-term target to limit chronic nephrotoxicity. The level is affected by drug interactions: azole antifungals and macrolide antibiotics inhibit cytochrome P450 3A4 and raise the level toward toxicity, while rifampicin, phenytoin and St John's wort induce the enzyme and lower the level toward rejection. The level is therefore checked frequently and the dose adjusted to the result rather than to a fixed prescription. [4]

Question 2 (10 marks)

Three months after a successful transplant, the boy's creatinine rises from 78 to 135 micromoles per litre over one week. His tacrolimus trough is 16 ng per mL. Describe your differential diagnosis, your investigation plan, and how the management differs between acute rejection and calcineurin inhibitor toxicity. [5]

The differential diagnosis of a creatinine rise in a transplanted child is approached systematically as pre-renal, intrinsic graft, and post-renal causes. Pre-renal causes include volume depletion from dehydration. Intrinsic graft causes include acute tubular necrosis, acute rejection (T-cell-mediated or antibody-mediated), calcineurin inhibitor nephrotoxicity, recurrent disease and BK virus nephropathy. Post-renal causes include ureteric obstruction. In this boy the high tacrolimus trough of 16 ng per mL raises calcineurin inhibitor nephrotoxicity as a leading possibility, but acute rejection remains in the differential because the two can coexist. [5]

My investigation plan begins with the non-invasive tests. I would check serum creatinine and its trend, electrolytes, a full blood count, urinalysis and the urine protein-to-creatinine ratio, and repeat the tacrolimus trough. A graft ultrasound with Doppler excludes ureteric obstruction, a peri-graft collection and vascular thrombosis. I would send donor-specific antibodies by single-antigen bead assay and a BK virus blood PCR. The definitive investigation is a graft biopsy read against the Banff classification. [4]

The management differs sharply between the two. If the biopsy shows calcineurin inhibitor nephrotoxicity (arteriolar hyalinosis, striped interstitial fibrosis, no tubulitis), the treatment is to reduce the tacrolimus dose and recheck the level, because the drug is injuring the graft. If the biopsy shows acute T-cell-mediated rejection (tubulitis, interstitial inflammation, intimal arteritis), the treatment is to increase the immunosuppression with high-dose intravenous methylprednisolone, with antithymocyte globulin added if it is steroid-resistant. Treating the wrong diagnosis causes harm: lowering immunosuppression for rejection accelerates graft loss, while escalating immunosuppression for toxicity deepens the injury. This is why the biopsy is done before changing the regimen. [5]

I would also consider BK virus nephropathy, which mimics acute rejection clinically and histologically and is distinguished by a high BK viral load and SV40-positive staining on biopsy; its treatment is to reduce immunosuppression, the opposite of rejection management. Throughout, I would address adherence, because missed doses and erratic levels are the commonest cause of late rejection in children and adolescents, and I would arrange long-term follow-up with a structured transition plan as the boy approaches adolescence. [6]