ESOT 2015: Tailor-made immunosuppression and post-transplant follow-up

by Maria Dalby: Advances in diagnostic techniques, genetic testing and immunosuppressive protocols allow clinicians to tailor interventions to the individual patient’s needs to a greater extent than in past years. Whilst most transplantation centres may still be some way short of delivering personalised medicine, transplant recipients are increasingly stratified according to genotypes phenotypes in an evidence-based way. A state-of-the-art session entitled Decision tree or lottery: allocating grafts and therapies included presentations on tailor-made immunosuppression early post-transplantation and as part of the long-term follow-up.

 

Professor Teun van Gelder (Erasmus Medical Center, Rotterdam, the Netherlands) began by pointing out that a completely tailor-made approach to immunosuppression at the time of transplantation may not be the best alternative – in transplantation, fully individualised therapy is going to be very complex and the risk of errors will increase – a standard protocol for all patients may actually be preferable. Evidence based clinical practice guidelines issued by Kidney Disease: Improving Global Outcomes (KDIGO) state that the initial maintenance immunosuppressive regimen should include a calcineurin inhibitor (CNI) and an antiproliferative agent, with or without a corticosteroid, and that the tacrolimus should be the CNI of choice.¹ There are as yet a limited number of subgroups identified for the purpose of stratified medicine; the KDIGO guidelines refer somewhat vaguely to ‘low risk’ and ‘high risk’ patients.¹ However, in his presentation Professor van Gelder drew attention to two important patient groups where immunosuppression should be adapted: elderly patients and patients who express CYP3A5.

 

Patients aged over 65 years who undergo kidney transplantation are likely to have a less vigorous immune response and be at increased risk of developing side effects due to their age.² Whilst they will be at less risk of developing acute rejection, their risk of dying from an infection will be higher than in younger patients. Professor van Gelder speculated that elderly patients may not require any induction therapy and that it may be possible to avoid corticosteroids; prospective clinical trials are needed to confirm this. There is data in the literature to show that elderly patients require a lower tacrolimus dose to achieve therapeutic trough levels,³ and the starting dose should therefore be lowered to avoid over-exposure.

 

The CYP3A5 enzyme has a pronounced effect on tacrolimus pharmacokinetics; transplant patients who express CYP3A5 are known to require up to 50% higher doses of tacrolimus to reach target levels.^4-12 The TACTIC trial investigated the impact of genotyping patients for CYP3A5 status prior to initiating tacrolimus and found that this significantly increased the number of patients achieving the target trough level; however, more than half of the patients were still outside the target range and there was no difference in patient or graft survival or other outcomes between patients who received an adapted dose and those who received a standard dose,¹³ and Professor van Gelder concluded that further studies are required to determine the role of genotyping in clinical practice.

 

Professor Bryce Kiberd (Dalhousie University, Halifax, Canada) reminded the audience that premature death with function still accounts for a sizeable part of adverse long-term outcomes after transplantation¹⁴ and the long-term post-transplant follow-up should include monitoring the patient for cardiovascular disease (CVD), cancer and infections, and optimising immunosuppression. The major targets for monitoring CVD are blood pressure, lipids, blood glucose and lifestyle, with little tailoring required. Not all forms of cancer increase post-transplantation; for example, the cancers that are most commonly screened for in the general population, breast and prostate, are not increased in transplant recipients. In contrast, the risk of developing skin cancer, lymphoma or kidney cancer is five times higher in transplant patients compared with the general population and there is a rationale for screening for these cancers routinely or in high-risk patients. Infections are best prevented by maintaining a high degree of general suspicion and adhere to prophylaxis, vaccination and screening protocols. Optimising long-term immunosuppression based on individual pharmacokinetics and genomics remain ‘pie in the sky’ according to Professor Kiberd; what clinicians can do is be vigilant for signs of non-adherence as this is a risk factor that can be modified. When it comes to longer-term follow-up, it will not be feasible to do ‘everything for everyone’ – instead clinicians must choose wisely, do simple things well and focus on providing high-value care.

Professors Teun van Gelder (Rotterdam) and Bryce Kiberd (Halifax, Canada)

 

References

1. Kidney Disease: Improving Global Outcomes Transplant Work G. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.
2. Lehner LJ, Staeck O, Halleck F, et al. Need for optimized immunosuppression in elderly kidney transplant recipients. Transplant Rev (Orlando) 2015.
3. Jacobson PA, Schladt D, Oetting WS, et al. Lower calcineurin inhibitor doses in older compared to younger kidney transplant recipients yield similar troughs. Am J Transplant 2012;12:3326-36.
4. Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 2004;75:422-33.
5. Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics 2004;14:147-54.
6. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003;74:245-54.
7. Macphee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation 2005;79:499-502.
8. MacPhee IA, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 2004;4:914-9.
9. Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003;76:1233-5.
10. Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004;78:1182-7.
11. Zhao W, Elie V, Roussey G, et al. Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther 2009;86:609-18.
12. Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 2003;3:477-83.
13. Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther 2010;87:721-6.
14. USRDS. Annual Report.  2013.