Glimmers of hope for intestinal transplantation

Main Body / Editorial

This edition of the AJT features a study from France entitled “Beyond 10 years, with or without an intestinal graft: present and future?” with promising results for the field of intestinal transplantation (ITx) (1). The authors studied children who received an ITx at their center between 1989 and 2007, analyzing 10-year post transplant outcomes in a cohort with and without a functional graft (26 and 9 patients, respectively). The overall 10-year patient and graft survival rates were 53% and 36%, respectively, and all patients in the group with a functional graft were weaned off parenteral nutrition and exhibited mostly normal physical growth and minimal abnormality in biopsies. Improved graft survival was associated with a concurrent liver transplantation as well as the use of a three-drug regimen including sirolimus or mycophenolate-mofetil, which prevented graft rejection.

While at first glance a 10-year patient survival rate of 53% might not sound like good news, it is heartening to see that ITx can give those suffering from intestinal failure a chance at a normal life, free from the morbidity of total parenteral nutrition (TPN). Indeed, the field of ITx has contracted in recent years, and if it is to survive, something must change in the current trend. Consider that in 2019, only 81 ITx were performed in the United States, compared to 8,896 liver and 23,401 kidney transplants. This means that on any given day, there were nearly as many kidney transplants performed as intestinal transplants that entire year. While liver and kidney transplants have increased almost every year since 2005, ITx have been on a declining trajectory (Figure 1A). It wasn’t always this way. In 2007 there were nearly 200 ITx performed in the US, across 21 centers. In 2019, only 15 centers (less than 6% of all centers) performed ITx, and only 3 centers performed 12 or more ITx, i.e. at least one ITx every month (Figure 1B). This means that few centers have a critical mass of cases to study ITx, making it increasingly unlikely for research breakthroughs to occur.

Figure 1:

Trends in intestinal transplantation in the United States (US). A) Relative levels of intestinal, kidney, and liver transplants performed in the US since 2005. Data from UNOS for number of intestinal, kidney, and liver transplants performed were analyzed for the years 2005 to 2019. 2005 levels were pegged at 100% for each organ. B) Number of intestinal transplants (ITx) performed in the US and number of centers performing ITx since 1990. Data from UNOS on the number of intestinal transplants performed and the centers performing those transplants were analyzed for the years 1990 to 2019.

Hesitancy by centers to offer ITx is understandable, as ITx is associated with high rates of rejection and treatment-related secondary complications due to the complex immunological milieu of the gut (2). Since rejection is more common than with other solid organ transplants, higher levels of immunosuppression are typically employed, which can lead to life-threatening secondary complications, such as infections, malignancies, and renal failure. As a result, historically reported one- and five-year survival rates for ITx are low (77.2% and 50.5%, respectively) and lag behind those for liver (89.6% and 72.8%) and kidney (94.7% and 78.5%) transplants (2). However, outcomes are improving at high volume ITx centers. For example, at the nation’s three highest volume ITx centers as of 2019, 3-year ITx graft survival for adults transplanted between 2014 and 2016 were 70%, 64%, and 58% (versus 54% nationally) as per SRTR data (https://www.srtr.org). One of our center’s pediatric patients has even become the nation’s first operationally tolerant ITx recipient (case report forthcoming).

There is reason to be optimistic that diagnostic and therapeutic breakthroughs are possible in ITx. For example, in the aforementioned study from France, the use of a three-drug regimen including sirolimus or mycophenolate-mofetil was associated with improved graft survival, which confirms other’s positive experience with sirolimus (3). Moreover, if rather than viewing ITx rejection through the lens of other solid organ transplants, the field applies insights from inflammatory bowel disease (IBD), it is possible to make advances in early detection of rejection as well as treating patients who are not responding to conventional therapy (4). Specifically, IL-17 and TNF-α producing memory Th17 cells in the graft have recently been identified as key culprits in rejection refractory to traditional therapy, which could pave the way for new treatment options leveraging medications that have been successfully used in treating IBD. Furthermore, elucidating the role of tissue resident immune cells, such as innate lymphoid type cells, and their potential as predictive biomarkers could also accelerate our field’s ability to improve outcomes in ITx.

The potential need for ITx is growing. There are thousands of Americans whose daily life is constrained by TPN. The incidence of gastroschisis, a common cause of pediatric short bowel syndrome, is increasing. A recent study found that non-white children with intestinal failure were significantly more likely to die and less likely to receive ITx than white children (5). Moreover, while IBD has historically been viewed as a disease mainly affecting Caucasians, over the last two decades its reported incidence and prevalence is increasing among minorities. Right now, ITx is only offered as a salvage therapy if TPN fails. Imagine if ITx could instead become an alternative to TPN, allowing people to live a more fulfilling and productive life? Results such as the ones from the study in France can hopefully help rejuvenate our field.

Abbreviations:

IBD

inflammatory bowel disease

ITx

intestinal transplantation

TPN

total parenteral nutrition