Leonardo V. Riella, MD
Dr. Riella is an Assistant Professor of Medicine at Harvard Medical School and the Assistant Medical Director of Kidney and Pancreas Transplantation at Brigham and Women’s Hospital. He is currently exploring the role of the Notch pathway in T and B cell activation/differentiation in alloimmunity; developing novel assays to characterize alloantibodies; and investigating the coinhibitory pathways that suppress T cell activation and promote tolerance. Follow him @LVRiella.
Competitors for the Transplantation Region
We have really a strong Transplantation region this year! Of course, the most exciting team here is The Untransplantables.
Dialysis outcomes remain poor and very little progress has been made in the past 50 years. For me, one of the clearest ways to demonstrate this issue is by comparing dialysis outcomes with cancer survival rates. As we can see in the graph, patients that remain on dialysis have a survival rate of 35% in 5 years, significantly worse than many malignancies (stage III for comparison). Furthermore, patients that are even briefly on dialysis, prior to transplantation, have a significantly worse survival outcome.
Therefore, for the sake of our patients, our goal as nephrologists should be to avoid dialysis and transplant all reasonable candidates with ESRD, irrespective of immunological barriers. Unfortunately, the high sensitivity of new DSA assays have started to exclude potential recipients, even though only half of patients with DSA develop antibody-mediated rejection (AMR). Even among those who develop early AMR (different than late AMR), aggressive early management is yielding successful outcomes.
The Untransplantables team has had many exciting achievements in the past few years. Transplantation across ABO-incompatible donors was a significant advancement with strategies that do not require splenectomy and use alternative approaches such as rituximab. In addition, certain blood groups have significantly disadvantage on the waiting list, in particular blood group B candidates with 3.92 years on the waiting list (compared to A = 2.8 years and AB = 2.2 years) in our US transplant region. Not only that, blood group B candidates are primarily from ethnic minorities.
Fortunately, kidney donors that are A2 or A2B were shown to be good donors for B recipients since A2 antigen has little expression in the kidney and in the absence of high titers (>1:8), B recipients are capable of getting A2/A2B kidneys without any additional immunosuppression. In this way, the disadvantaged position of candidate recipients of blood group B could be overcome, meaning earlier transplantation for these patients.
Furthermore, the expansion of local, regional, and national kidney paired exchange programs increases the pool of donors for those with an incompatible living donor available. Lastly, while the presence of DSAs with a positive XM was generally considered a contraindication for transplantation, the use of complementary aggressive strategies targeting B cells, antibody, and complement has led to transplanting patients that before would have stayed on the list for 10 years or longer.
If you are a nephrologist and care about your patients with ESRD, The Untransplantables should be your team. To further boost this category, we have the potential of xenotransplants to overcome the organ shortage. Dr Tector from UAB and Dr Church at Harvard among others have been leaders in manipulating pigs’ genes using CRISPR/CAS technology to remove unwanted genes that may prevent transplantation across species as well as to excise viral genes that may carry infectious risk (PERVs – porcine endogenous retrovirus). Soon human trials may start and although I am cautious about the long-term survival of these grafts, in the face of poor outcomes on dialysis, potentially using these pig kidney grafts as bridges for patients with no living donors could be a great strategy. Bring it on!!!
– Post written by Leonardo V. Riella. Follow him @LVRiella.
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