Abstract
From the very start of his surgical career, Jan Lerut was involved in organ transplantation. This interest resulted in transplantation fellowships at the University Paris-Sud – Centre Hépatobiliaire under the lead of Professor Bismuth and at the Pittsburgh Medical Center under the lead of Professor Starzl. He was director of the abdominal transplant program at the Inselspital University of Bern from 1987 to 1991. Currently, he is Professor of Surgery, Director of the Starzl Abdominal Transplant Unit of the University Hospitals Saint Luc of the Université Catholique de Louvain and director of the Université Catholique de Louvain Transplant Center in Brussels. He is also director of the department of Abdominal and Transplantation Surgery at the same university. He has served as president of the Belgian Society of Transplantation, chairman of the Eurotransplant Liver Allocation Committee and president of the European Society for Organ Transplantation. Under his presidency over the Eurotransplant Liver Allocation Committee, the Model for End stage Liver Disease system was introduced. His presidency at the European Society for Organ Transplantation was devoted to the broadening of the European transplant community and to the development of a master educational program in the field of transplantation. He has published over 250 peer-reviewed articles, authored 24 book chapters and 24 scientific films. His research interests focus on the development of technical refinements in liver transplantation and on the use of minimal immunosuppression and tolerance induction in liver transplantation.
■ Can you briefly describe how you became interested in immunosuppression in liver transplantation?
I have now spent almost 35 years in the field of transplantation, with a particular focus on liver transplantation. Immunosuppression in liver transplantation caught my interest after I saw many patients over the years with heavy immunosuppression whose quality of life was impaired as a result of the various side effects of therapy. Quality of life is an important topic in transplantation. Steroids influence an array of different organ systems in the body. Slowly but surely I began to research ways to follow-up and treat these patients. My interest was also triggered as a consequence of my training by Thomas Starzl at the University of Pittsburgh School of Medicine (PA, USA) who is credited with performing the first liver transplants and also has worked on a large number of transplant tolerance projects.
■ What do you consider to be the biggest breakthroughs in the field in the past 5–10 years?
First, I believe the fact that we can now perform not only liver transplants but seemingly all organ transplants without the requirement of steroids is a significant breakthrough. This is because steroid use is of course the main culprit of many side effects in transplantation. Second, we now know from clinical experience that some patients have independently stopped immunosuppression outside of a medical environment and have fared well without therapy. So it now seems possible to perform a transplantation without life-long immunosuppression. In my opinion, it is not necessary for a patient to be completely off all immunosuppressive therapy; however, this finding is important as, if you can reduce an organ recipients’ immunosuppression dose to a very low level, you can substantially improve their quality of life.
■ Some of the literature suggests that liver allografts have a lower likelihood of rejection than other transplanted organs, with 20% of liver recipients being ‘operationally tolerant’. Do you consider this to be true?
I think we must be very careful not to jump to conclusions here. Our research group has worked on this in depth, and we also have several immunosuppression-free patients; however, a figure of 20% of recipients being operationally tolerant is a misleading statement. This figure was put forward after several groups wrote articles, including myself together with Alberto Sánchez-Fueyo (Hospital Clinic Barcelona, Barcelona, Spain) regarding tolerance in liver transplantation. However, if you look closely at the relevant literature, there has been no systematic evidence-based medical approach to evaluate this. Approximately 10–15 papers have been published that present the experiences of groups who report a number of patients to be immunosuppression-free. Summing up, all of the patients described in these few articles – approximately 500 patients – result in a figure of 20% being operationally tolerant. However, one must be careful not to extrapolate this to all patients because these studies represent a very driven selection of patients. So, 20% is not an accurate reflection of the real situation.
■ What is the rationale for steroid-free immunosuppression after liver transplantation?
Steroids are responsible for a wide range of side effects that greatly impact the quality of life of transplant recipients. Of all the immunosuppressive drugs, steroids clearly cause the most organ damage. They are understood to provoke the following problems: cardiovascular problems; bone problems, including fractures and muscle wasting; many gastrointestinal problems, such as ulcer formation and gastritis; skin conditions including bruising; and ophthalmological conditions such as cataracts. They are also undoubtedly linked to diabetes and impact upon patients’ physical appearance with conditions such as lump formation, moon face and obesity. In addition, steroids also influence the psychological status of the patients, with mood swings being a severe complication of long-term use. In children, the impact of steroids can be even more profound, manifesting as crowd trepidation or retardation of sexual development. Considered together, no other single immunosuppressive therapy can lay claim to all of these damaging effects. A patient receiving calcineurin inhibitor such as tacrolimus (a commonly used macrolide immunosuppressant) or cyclosporine can expect to experience nephrotoxicity and cardiovascular problems such as hypertension, but they will not suffer destruction of bones, muscles or skin.
Taking these side effects and their influence on quality of life into consideration, succeeding in reducing or omitting steroid therapy from their immunosuppressive regimen is evidently a major concern for patients. Patients receiving steroids are increasingly approaching their outpatient clinics because they know of other recipients who no longer take steroids and ask for an alternative to steroid therapy. Some transplant specialists still believe that successful organ transplants cannot be performed without steroids. This is no longer true for the majority of organ recipients, but it remains important to consider each patient individually because this may not apply to all organ transplant recipients.
Advances in immunosuppressive therapy for liver transplantation have paved the way for other organ transplants. In the field of liver transplantation, the first group to trial steroid withdrawal schemes was led by JM Neuberger, E Elias and P McMaster from Queen Elizabeth Hospital (Edgbaston, Birmingham, UK), over 20 years ago. Their work caught my attention and I visited them several times, but when I returned to my university hospital and relayed what I had seen to my colleagues, they were very sceptical and I felt as if I was ‘preaching in the desert’. It was also initially very difficult for the Birmingham group to convince others that it is possible to perform liver transplantation entirely without the use of any steroids, but eventually other groups began to concur and the initiative gained momentum. As I see it, the emphasis for steroid-free immunosuppressive therapy today should be on the ‘how’; how can we omit steroids from immunosuppressive therapy after transplantation and how can we perform transplantation without steroids at all?
When implementing any changes to immunosuppressive therapy regimens, the principal concern is the health of the patient; there must be no long-term harm as a result of the therapy change. Therefore, we took the next logical step, namely performing a liver transplant while avoiding the use of steroids. We performed a prospective randomized double-blinded study to compare the tacrolimus placebo versus tacrolimus plus short-term steroid use in 156 liver transplantation cases Citation[1]. This initial study suggested that there was zero difference in terms of survival. This conclusion has been supported by the results of biopsies at the 5-year follow-up stage. I consider the results of this study to be the sufficient rationale for steroid-free immunosuppression. Evidently, if this strategy works out to be successful in the long term, the next step would be passage to monotherapy immunosuppression, followed by an infratherapeutic monodrug therapy, which is also called almost (or ‘prope’) tolerance. This can be achieved without risk to the patient when using tacrolimus-based immunosuppression.
■ You mentioned that the issue is now ‘how’ to go about changing therapy regimens to move toward steroid-free therapy. What would be your preferred method?
If you look at the literature, there are many different ways to achieve steroid-free immunosuppression. The approach depends on a combination of factors such as the preference of the center and the age of the patient. Pediatric regimens tend to administer steroids on alternate days because this is believed to impact less upon the growth and development of the child.
In my experience, a steroid-avoidance or almost-avoidance protocol is the best therapy option as it would prevent breakthrough rejection of the allograft and this approach also avoids interference with the tolerogenic process. Indeed steroids, even if given for only a short period, can break the tolerance-induction process. Experiments have demonstrated that the immune system behaves differently depending on whether the individual has ever received steroid therapy, in other words, they have a steroid-adapted immune system. It should also be noted that if steroids are prescribed and the dose is subsequently reduced, the patient can switch to rejection of the transplant during the tapering period.
The almost-avoidance steroid protocol is what we have adopted in our transplant center in Brussels. We only prescribe 1 g of hydrocortisone during the immediate perioperative period, mainly to prevent ischemia reperfusion injury of the allograft and to allow delayed introduction of tacrolimus. We then aim for a tacrolimus monotherapy strategy through progressively building up the dose to suit the clinical situation of the recipient. In doing so, we follow the ‘Terasaki Drugs Added When Needed concept’, meaning that drugs are only added when needed Citation[2].
■ Would it be of benefit to achieve consensus on how to accomplish steroid-free immunotherapy?
Reaching consensus on how to achieve steroid-free immunotherapy would be useful, but it is difficult to attain because people need to believe in it. Furthermore, it is challenging to achieve statistical significance when one scheme shows 90% success, a second 92% and a third 89%; many thousands of patients will be needed to prove the superiority of one immunosuppressive scheme over another.
In order to collate adequate data to generate a consensus, all transplant patients should be documented with biopsies for long-term follow-up. It should be acknowledged that in terms of achieving a complete overview of the health of a transplant patient, biochemistry, clinical judgement and pathology in isolation are not sufficient; all three must be considered together. This would enable unification of patient care and a ‘global approach’ to the follow-up of transplant recipients. Currently, many patients who are transplanted are eventually ‘lost,’ not to medical follow-up but to the transplant center, owing to the vast numbers of patients who have been successfully transplanted at each center. These patients will attend regional or peripheral centers instead, meaning they are often not followed up by specialists, leading to a loss of uniformity in treatment.
As an example, I recently had a patient who was in good health and his liver biopsy and liver tests were fine. He then moved house to a different city and subsequently changed his hepatogastroenterologist. At his first appointment, the hepatogastroenterologist observed very low levels of calcineurin inhibitor in the serum so his first action was to increase the daily dose!
■ What do you think the next 5 years will hold for the field?
Results of liver transplants have become so good in recent years that the field should now be focusing on long-term outcomes for patients. ‘Long-term’ for a liver transplant patient no longer means 5–10 years; it can be 10, 15 or even 20 years, therefore presenting a challenge for follow-up. I advocate regular biopsies for all patients; however, performing biopsies at the 5-, 10- and 20-year stage would create a considerable workload for transplant centers. Another hurdle to such universal follow-up would be reluctance of healthy patients to undergo the potentially risky biopsy procedure. A greater degree of structure among transplant centers would be needed to successfully achieve this and dedicated biopsy clinics would need to be established.
Financial & competing interests disclosure
Lerut has received an unrestricted grant from Fresenius Biotech and Astelellas for an investigator-driven study. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Lerut J, Mathys J, Verbaandert C et al. Tacrolimus monotherapy in liver transplantation: one-year results of a prospective, randomized, double-blind, placebo-controlled study. Ann. Surg. 248(6), 956–967 (2008).
- Terasaki PI, Everly ML, Kaneku H et al. A ‘new’ road to tolerance: clonal deletion and drugs added when needed (DAWN). Clin. Transpl.253–260 (2010).