What’s new in paediatric transplantation?

by Mr Nizam Mamode, Consultant Transplant Surgeon (pictured) – Children are not just small adults; an aphorism which paediatricians are fond of quoting, but one which perhaps has not yet reached the transplant community. Many of those who are involved in paediatric transplantation are accustomed to simply applying knowledge gained from studies in adults, partly because so few trials are performed in children. But children are different: the immune system is stronger, viral infections (and associated malignancies) are more common, and most importantly, the benefits of transplantation may be even greater when compared with adult populations.

Although in the recent past, a diagnosis of renal failure in early life meant certain death, we have now reached the stage where paediatric renal transplantation is essentially routine, even in small children. One year graft survival rates are now 95% after deceased donation and 97% after living donation (NHSBT 2011). It is also clear that transplantation is particularly important in children to avoid significant physical and mental developmental delay, and indeed the risk of death is halved if a child reaches the age of 18 with a transplant rather than on dialysis.

This article considers three areas where opinion has recently changed in paediatric renal transplantation: blood group incompatible transplantation, laparoscopic procurement and maintenance of long-term graft survival.

Despite the fact that many adult units now have blood group incompatible transplant (ABOi) programmes, there has not been a similar interest in paediatric ABOi. There are several reasons for this; firstly, in the UK, the deceased donor organ allocation system favours children. This means that waiting times are relatively short and organs tend to be well-matched. Furthermore, normally at least one parent will be willing to donate, and will tend to be relatively young and fit, unless there is a familial condition. Finally, the active immune system in children has led to concerns that the risk of rejection after ABOi might be higher.

Recently, however, attempts have been made to transplant across blood group barriers in the young. This has been helped by the fact that isoagglutinnin antibodies tend to be lower in children – around a third of children have antibodies which are low enough to allow an ABOi without any additional treatment (Barnett ESOT 2011). This is due to the fact that anti-A or anti-B antibodies arise from a cross-reaction with gut bacteria, and the exposure of young children has been limited, resulting in lower titre levels. Indeed, NHSBT is currently exploring the possibility of listing some children on the deceased donor list for ABOi, based on these low levels. Typically, the Japanese have reported most success with paediatric ABOi, with one study of 16 children (who were treated aggressively with cyclophosphamide, ALG and splenectomy) resulting in a 1 year graft survival rate of 87%.¹ In Sweden, nine children have been transplanted using the adult rituximab-based protocol, with a 100% graft survival, and in the UK five paediatric ABOi have been performed (at Guys-Evelina/Great Ormond Street and Newcastle) again with all grafts surviving.

A second area that has caused much concern in recent years is laparoscopic procurement of kidneys for paediatric recipients, following a study which showed that the risk of rejection was significantly increased when compared with organs procured from open operation.² This was particularly important in the under 5 age group and the hypothesis was that an insult to the kidney during laparoscopic nephrectomy (due to the pneumoperitoneum or longer warm ischaemic time) coupled with the haemodynamic issues in young children, where hypoperfusion of the organ is common in the perioperative period, led to poorer outcomes. It may be that this study represented the learning curve in laparoscopic donor nephrectomy, since two recent studies, including one utilising NHSBT registry data, have shown that outcomes are at least as good, and often better, in paediatric recipients of laparoscopically procured kidneys and that this benefit persists in the longer term.^{3, 4} Given the importance of a quick recovery when the donor is also the care-giver, these are welcome data.

Finally, it has become clear that long-term outcomes are problematic in paediatric renal transplant recipients. There is a high incidence of chronic rejection, and increasing evidence suggests that this is due to non-compliance, particularly during the adolescent period.⁵ Yet the lifetime risk of malignancy may be high (20% after 10 years), and this is often associated with EBV viraemia, leading to PTLD. Two strategies have been advocated to deal with these issues; firstly, an aggressive programme of support and intervention for adolescents, with adequate counselling, the use of smartphones and other technologies to promote compliance, and combined transition clinics with adult services.⁶ Secondly, in those patients who qualify, minimisation of immunosuppression. The use of conversion to monotherapy (either calcineurin inhibitors or mycophenylate mofetil) has recently been described in a small cohort of patients with excellent results and reduced viraemia⁷ and the TWIST study showed that early steroid withdrawal improved growth without significantly worsening outcome.⁸

In summary, it would seem that we can use laparoscopically procured kidneys for children and can consider blood group incompatible transplantation and minimisation protocols in some. Further data are needed in these groups and larger studies with novel immunosuppressive strategies in children must be carried out. Highly sensitised children are an increasing problem, as more are transplanted early and succumb to graft failure whilst still in childhood; strategies for these will be challenging but necessary. But, if we can recall that we are not simply dealing with small adults, we will continue to improve on one of the greatest successes in transplantation.

 

References:

1. Shishido S, Asanuma H, Tajima E, Hoshinaga K, Ogawa O, et al. Transplantation 2001; 72(6): 1037-1042
2. Tropmann C, M^cBride M, Baker T, Perez R. Am J Transplant 2005; 5: 175-182
3. Chandak P, Kessaris N, Durkan A, Owusu-Ansah N, Patel J, et al. Neph Dial Transplant 2011; First published online June 28 2011.  DOI: 10.1093/ndt/gfr315
4. Mamode N, Johnson R, Hadjianastassiou V. Transplantation 2011; 91(9): 1005-1009
5. Debray D. Curr Opin Org Transplant 2010; 15(5): 588-589
6. Fredericks E, Dore-Stites D, Lopez M, Well A, Shiek V, et al. Ped Transplant 2011; 15(4): 414-424
7. Sinha R, Tse Y, Mark S. Ped Transplant 2011; 15(1): 119-120
8. Grenda R, Watson A, Trompeter R, Tonshoff B, Jaray J, et al. Am J Transplant 2010; 10(4): 828-836