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In View: People in Transplantation

Dr. Sue McDiarmid, UCLA

Advancing Outcomes After Pediatric Liver and Vascular Composite Tissue Transplantation

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doi: 10.1097/TP.0000000000001361
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Transplantation: You are a foreign medical graduate. What made you move from New Zealand to the US?

SMD: Curiosity! New Zealand is a delightful, small country—but actually a long way from the rest of the world. I was very curious as to what the wider world of medicine might offer. Most of my contemporaries would make a visit of a year or 2 visits to the United Kingdom to satisfy this curiosity, but I was intrigued by the innovation, free spirit, and can-do attitude of the people I came across from the United States. I have not been disappointed!!

Transplantation: You have a broad clinical experience and a wide range of interests. How many hours does your day have?

SMD: 24 like everyone else—and it never seems enough—but I must say that during the week I do work long hours, 12 to 14 often—but I try to keep weekends for family and friends.

Transplantation: What would you consider critical factors determining the outcome in pediatric liver transplantation?

SMD: Still our biggest challenge is getting donors in time—although we have the option of living donors (LD), I personally think that we need to be very mindful of the ethical responsibility of taking a perfectly healthy person—usually a parent in my field—and subjecting them to a major operation with a known mortality risk. The ethics of this dilemma do change with geography—and in countries with a very small number of deceased donors (DD) the reliance on LD clearly saves the lives of many children—and also adults. While I endorse LD, I have spent quite some time over the years trying to change national policies to prioritize children for appropriate DD—without harming adults also waiting on the list. For me, the death of a child on the waiting list always seems like a failure of our system.

Reducing surgical complications appear as the most important factor to improve short-term outcomes—during the first 6 months or so. Thus, the training of surgeons in pediatric liver transplantation when the volumes are low appears critical, particularly as many programs may only do a few children a year.

In the long term, the most critical aspect will be the knowledge to individualize immunosuppression, thus reducing long-term complications from immunosuppression while maintaining long-term excellent graft function.

I am very worried about what we are seeing in children with 20+ years of graft life—unexplained fibrosis, and graft loss in pediatric recipients who are now in their young adult years. We could in fact be under immunosuppressing some—and over immunosuppressing others. The search for the right so-called tolerance assay to help us determine long-term immunosuppression needs is still elusive. Along with this anxiety over the long-term outcome for children is the concern about how these young adults will be cared for in adult programs. Many become lost to follow-up or they are unable to transition to the style of care of an adult health system. Of note, we have no databases that are attempting to capture in detail—outcomes from infancy through adulthood. Who knows what 40 years of immunosuppression will look like?

Another important concept that has not received much attention in pediatric transplantation—and this is also relevant to VCA—relates to a realistic expectation of transplant half life. The erosion of graft function for no obvious reason that we are seeing in our children with graft lives over 20 years is very concerning—incipient and progressive fibrosis appears to be the histologic correlate. It is looking as if the half life for liver grafts in pediatric recipients might be in the order of about 15 years (it is about 10 to 12 years for adult liver recipients).

What is the mechanism of these histologic finding? Is this a smoldering chronic rejection process? What do the small intra graft vessels look like? What role do donor specific HLA antibodies have? Is this what will happen in VCAs?

Transplantation: Adolescent transplant recipients are particularly challenging. How can we improve outcomes in this patient population?

SMD: A very hard question, transition clinics and teen clinics with teams of physicians and nurses, social workers and psychologists are very important concepts but often difficult to put into practice for lack of institutional resources. I think that we very much underestimate the prevalence of depression and anxiety in our teen transplant patients—I have often said that ideally every one of them should be in counselling at about age 11 to 12 years—but again the problem of resources—and sometimes even the willingness of parents or the youngster—to recognize the problem.

The issue of noncompliance with medicines (and just about anything else an adult person recommends!) in this population is very well known. How can we change the “normal” developmental pattern of teens to question and rebel? I have no good answer—except to try our best to maintain a close relationship between the teen and the medical team and hope that we can continue to keep the trust that has been built—before the storm of the teen year's hits.

Transplantation: You have a very detailed insight into long-term side effects of immunosuppression. What aspects have you identified as particularly relevant? What improvements do you suggest?

SMD: From the pediatric perspective, the problem of gradual erosion of renal function in a young child who entered transplant with healthy kidneys—even with well-managed immunosuppression that relies on calcineurin inhibitors—is a very important concern. As yet, I still do not think we have a current candidate drug—or one in the pipeline—that can systematically replace our reliance on calcineurin inhibitors especially early after transplant. Certainly, there are choices we can make about substituting other agents in more stable patients, and this can be helpful.

The long-term risk of malignancies is another very important concern. As the years after transplant become longer, we will need to be very mindful of what our recommendations should be for prevention and screening. Current surveillance recommendations for the most common cancers in the general population may not be appropriate for patient with lifelong immunosuppression. For example, for my older teen-aged girls, I have no good evidence to guide me in advising them about routine breast cancer surveillance. I already know that they have an increased incidence of atypia and dysplasia on cervical smears—and for most of them, I am recommending a routine PAP smear every 6 months.

Finally—as I alluded to above—I think the greatest improvement we could hope for to decrease risks of long-term immunosuppression is to be able to safely minimize and perhaps even withdraw immunosuppression in patients we could identify with so-called operational tolerance. The big caveat here is that this state of operational tolerance can be broken—just recently one of our late teen patients off all immunosuppression for 4 years—carefully monitored, and with protocol biopsies—presented with an acute episode of rejection. I am not sure we can ever let our guard down, at least with our current knowledge.

Transplantation: Vascular composite tissue transplantation has become a more recent interest for you. Where do you see the greatest future progress? What regulatory aspects do you consider of particular relevance?

SMD: Our future progress, I think, will depend on gradually and safely increasing the number of these procedures to build enough confidence in our insurance payers that these patients should be covered. It is going to be very difficult to build the experience we need in the field if we are mostly dependent on very small numbers being performed at institutions with the will—and the resources to support these endeavors.

The other enormous help to our field would be future progress in inducing tolerance, or if not that, being able to individualize, and hopefully minimize, immunosuppression. The risks of our current immunosuppression protocols are a major deterrent to many patients—and physicians—to go forward with a VCA.

As for the regulatory progress, trying our best to balance the need for transparency and oversight with the need to foster responsible innovation is still our biggest challenge. We must always remember that we serve the public safety and trust.

Transplantation: What advice do you have for young (female) clinicians and scientists entering the field of transplantation?

SMD: Be passionate, be determined, be persistent, think outside the box, dare to be different! Doesn't matter if you are a young man or woman (and if you expect to live your transplant career life by resident work hour rules—don't go into transplantation!)

Transplantation: What excites you outside of work?

SMD: A long run with no pain!

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