Carlos E. Marroquin, M.D., F.A.C.S., is Chief of Transplantation and Hepatobiliary Surgery at the University of Vermont Medical Center and a Professor at the Larner College of Medicine at UVM.

Carlos E. Marroquin, M.D., F.A.C.S., is Chief of Transplantation and Hepatobiliary Surgery at the University of Vermont Medical Center and a Professor at the Larner College of Medicine at UVM.

April is Donate Life Month. To learn more about organ donation and to register to be an organ donor, please visit www.donatelifevt.org.

As a Transplant Surgeon, I have seen both the good and the bad. Right now, there are a number of troubling trends impacting patients waiting for organ donation. There are also incredible advances in technology helping us better pair patient with organ for transplantation. Let’s examine both here.

The bad news: The incidence of end stage renal disease (ESRD) has increased over the last several decades. This is in part because of the obesity epidemic and the increased incidence of diabetes and hypertension. As a result, the number of patients who receive treatment for ESRD has increased. The majority of those patients receive renal replacement therapy in the form of dialysis. The dialysis population doubled from 225,852 in 1997 to more than 520,000 Americans on dialysis in 2010. Alternatively, some of these patients receive renal replacement therapy in the form of transplantation. Similarly, the number of patients receiving renal replacement therapy from a transplant also doubled during this time period from 86,488 to 178,806. This is due to advances in surgical technique, improvements in immunosuppression, and better control of the other associated medical conditions the patient may have.

As the dialysis population increases, so does the number of patients on the wait list for organ transplantation. There were 17,273 patients waiting for a kidney transplant in 1995, and 24,458 in 2005. This number increased to 36,458 in 2012. That means that of the more than 119,000 thousand patients waiting for a transplant, approximately 80 percent are waiting for a kidney transplant.

One effect of this increasing demand is that it increases the time period all patients wait for a transplant. The reason patients are waiting longer is due to a number of reasons. The organ supply has been relatively stable for many years. As the wait list continues to grow annually, we barely impact the rate of growth with our transplant rate. The total effect is that the disparity between supply and demand continues to widen dramatically with each decade.

One of the consequences of the huge disparity between the organ supply and demand is death while on the waiting list. In fact, from 1990 to 2005, the number of deaths on the waiting list has more than quadrupled for patients waiting for a kidney transplant. Another critical observation is that while the mortality on the waitlist has been declining for all solid organs, it has continued to increase for patients waiting for a renal allograft. While there are options for patients with renal disease such as peritoneal dialysis and hemodialysis, transplantation is the only one that is life saving.

One of the consequences of ESRD, is the development of cardiac disease. For patients who also suffer from diabetes, and hypertension, this is accelerated, but regardless, all patients with ESRD suffer greater cardiovascular complications than patients without renal disease. These cardiovascular complications are compounded once patients go onto dialysis. As such, these patients have a shorter life-span which is shortened even more once they initiate dialysis. This greater mortality is mitigated by a successful transplant. Hence, the life-saving nature of a successful transplant.

The problem is that while there are close to 120,000 people waiting for a life-saving transplant at any one point in time, there has never been more than 8,267 deceased donors in any one year.

The good news: One of the great historical events in transplantation was the contribution of laparoscopic donor nephrectomy to live donation. First performed by Ratner and Kavousi in 1995, laparoscopic donor nephrectomy addressed some of the disincentives of live donation. Specifically, decreased pain, improved cosmesis, decreased length of stay and decreased time out of work. Despite the impact, we have seen live donation plateau around 6,000 donors per year. The combination of deceased and live donor transplants results in approximately 14,000 to 16,000 total transplants per year. As such, we still see the list continue to grow disproportionately to the number of transplants we perform.

Some patients develop antibodies as a part of our native immune system. These antibodies develop after exposure to foreign antigens or proteins.  Because these proteins are foreign, our body reacts to these by forming anti-bodies against the protein with the objective of protecting us with subsequent exposure. The effect is that the antibodies decrease any given patient’s ability to receive a life-saving transplant from donors that express these proteins as they would reject the transplant immediately. These patients are “sensitized.” Sensitizing events include blood transfusion, pregnancy with an Rh disparate pregnancy, and prior transplant. The greater the degree of sensitization, the harder it is to receive a transplant. The degree of sensitization is characterized in percentages and is termed panel reactive antibodies (PRA). Sensitized patients represent 20 percent of the waitlist.

Patients who have a PRA greater than 80 percent have traditionally been prohibitive transplant candidates; even if they had a potential live donor. We cannot calculate a median time to transplantation for these patients because fewer than 50 percent have been transplanted. Only approximately 2.8 percent of highly sensitized patients receive a kidney transplant annually.

In many cases, patients have a live donor who would like to donate to them, but they are incompatible from a blood group perspective or because they have developed antibodies against the potential donor. Blood group A expresses protein A and can donate to other As. Blood group B expresses protein B and can donate to other Bs. While blood group O can donate to anybody because they do not express A or B proteins, they can only receive a transplant from an O. This relationship is very stringent because we form antibodies against the major blood group we do not belong to; for example A forms antibodies against B, and B forms antibodies against A. Since O does not belong to either A or B, it forms antibodies against A and B. Blood group incompatibility (ABO incompatibility) has traditionally limited the desire of friends and families to help each other by donating. Approximately 30 percent of potential donors are ABO incompatible. Better than 50 percent of incompatible donors have 0 recipients; 30 percent of pairs have O donors. O recipients with non-O donors have ~15 percent match rates. Non-O recipients have ~50 percent match rates.

As a result of these incompatibilities, some groups began to perform exchanges between incompatible blood group pairs to create compatible donor and recipient pairs. Initially, exchanges involved simple, straightforward exchanges between incompatible donor/recipient pairs and involved two pairs who would donate to each other often at the same center. Exchanges grew to involve three or more pairs in essentially a closed loop as they all donated to each other’s recipient. The concept rapidly developed into large-scale exchanges with one donor initiating a chain and another donor down stream from the chain serving as a bridge donor initiating another chain with bridge donors serving to perpetuate chains.

In 2012, Alvin Roth and Lloyd Shapley were awarded the Nobel Memorial Prize in Economic Sciences for their application of computer modeling and game theories to the creation of a computer model that has led to the development of widespread and virtually limitless paired exchanges of incompatible transplants to compatible transplants. This application allows an infinite number of random exchanges incorporating more variables including blood type, degree of sensitization, age, and the inclusion of multiple pairs and compatible pairs allows computer optimization and generation of hundreds of thousands of combinations of highly compatible matches between strangers. This has the capacity to drive significantly better patient outcomes and has the potential of getting nearly all incompatible pairs transplanted.

Paired exchange allows the exchange of kidneys from living donors between two or more living kidney donor and recipient (D/R) pairs. The exchange allows complete or partial avoidance of immunologic barriers such as the antibody dilemma that forces highly sensitized patients to wait inordinate times. These exchanges have led to the transplantation of many who would previously have gone without. Exchanges may involve non-directed donors (NDD).

Exchanges can also involve compatible D/R pairs to optimize outcomes of each individual transplant from an immunologic perspective and also from age pairing perspective to optimize the durability of each transplant; for example… allow a younger donor to donate to a younger recipient and the older donor to donate to the older recipient in effect matching the expected lifespan. Greater age matching will have significant impact in the total life years saved per donor recipient pair from a patient perspective and a graft perspective. In turn, this will have significant economic impact by decreasing the number of re-transplants. The development of paired exchanges and the application of computer modeling is the latest among a series of historical events that contribute enormously to transplantation.

Carlos E. Marroquin, M.D., F.A.C.S., is Chief of Transplantation and Hepatobiliary Surgery at the University of Vermont Medical Center and a Professor at the Larner College of Medicine at UVM.

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