A matter of protocol

The use of the protocol transplant biopsy is a divisive topic: some units see a protocol program as necessary for proper management post-transplantation, whilst others deride the whole concept as unnecessary. So who is right?

Protocol biopsies are taken at predefined intervals after transplantation regardless of kidney function. Their use is based on the theoretical benefit of detecting acute rejection, chronic allograft injury, calcineurin inhibitor (CnI) toxicity, recurrent primary disease & BK virus infiltration where the presence of these diagnoses is not evident by a measurable decline in allograft function.

Most work to date has focused on sub-clinical rejection. I detect two relevant questions here: is sub-clinical rejection sufficiently common to be an issue and is detection and treatment beneficial? In answer to the first point; the KDIGO guidelines list seven studies (on pg S31) which have looked at prevalence of sub-clinical rejection providing estimates of 13-25% at 1-2 weeks, 11-43% at 1-2 months, 3-31% at 2-3 months and 4-50% at 1 year. A number of studies have shown that sub-clinical rejection is associated with reduced graft survival and chronic allograft injury and that treatment of sub-clinical rejection may improve long-term graft outcomes.

However, the majority of these studies have been performed with cyclosporine (CsA) and azathioprine (Aza) maintenance regimes. As a result, perhaps most relevant to current practice is an RCT that randomized 240 patients on tacrolimus & MMF to biopsies at 0,1,2,3,6 months or 0 & 6 months. Rejection rates were generally low with clinical episodes seen in 10% of biopsy arm patients and 7% in the control arm. Additionally, sub-clinical rejection was seen in only 4.6% of the biopsy arm and creatinine clearance at 6 months was identical between the two groups.

So, perhaps not surprisingly, KDIGO feels only able to state that 'based on very-low-quality evidence, the benefit of performing protocol biopsies in CsA/Aza patients without induction therapy may outweigh the harm' (pg S32). This strikes me as a vanishingly small proportion of incident transplants. Taking this together with the fact that the KDIGO authors could find NO data showing a benefit in detecting sub-clinical CnI toxicity, recurrent disease, BK nephropathy etc, I would suggest that perhaps the protocol biopsy has had its day.