Last Friday, doctors in Turkey pushed the boundaries of modern medicine when they attempted to perform a quadruple limb transplantation in a 27 year-old man in Ankara, who had previously lost his extremities after being electrocuted. The procedure was not successful and the patient died on Monday. Transplantation of extremities is an evolving field, dating back to 1964 when surgeons in Ecuador made an effort to transplant a cadaveric donor hand without success. After years of research, the first successful hand transplantation was performed in 1999 by surgeons in Louisville, Kentucky. As of several years ago, the recipient of the 1999 transplant continued to exhibit some function in his hand. Since 1999, many single and double hand transplants have been performed in various countries.

The first successful limb transplantation took place in Malaysia in 2000 when a girl received an arm from her deceased identical twin. In 2008, surgeons in Germany performed the first double arm transplantation in a 54 year-old farmer after he had lost both of his arms in an accident. Transplantation of the lower limb dates back to 2006, when the leg of a conjoined twin with a fatal cardiac abnormality was transplanted to her sister. The first double leg transplant was performed in Spain in the summer of 2011, in a young man who reportedly took his first steps with his transplanted legs late last year.

As with solid organs, transplantation of extremities is surgically and medically complex. The procedure in any limb transplantation involves connecting the donor and recipient bones, tendons, nerves, arteries, and veins. Connection of the vasculature ensures proper blood flow while attachment of the nerves and tendons allows for partial restoration of function. One of the greatest challenges with transplantation is immune rejection: the immune system of the recipient recognizes the transplanted tissue as foreign and destroys it. In order to reduce the likelihood of rejection, various measures are taken. Prior to transplant, comprehensive blood and tissue typing is performed to check for donor and recipient tissue type compatibility. After surgery, the recipient is placed on a long-term regimen of powerful medications known as immunosuppressants, which weaken the immune system and decrease the odds of rejection.

Immunosuppression has serious side effects as it can increase the risk of infection, cancer and other diseases. Some of the newest research in the field of transplantation has focused on how broad immunosuppression can be replaced with immune regulation. The latter involves selectively suppressing the components of the immune system that are responsible for tissue rejection, and reducing the chance of adverse events such as infection and cancer. Thanks to advances in this field, several years ago, the first steroid-free hand transplant surgery was performed. Steroids are among the oldest immunosuppressants used in transplantation. Some of the newer agents used in place of steroids are agents such as Alemtuzumab, a monoclonal antibody that regulates immune system function. Another novel strategy is to introduce white blood cells from the tissue donor into the recipient’s blood stream prior to transplantation of the extremity. If these cells persist, they will incorporate into the recipient immune system and decrease the likelihood of rejection after the extremity has been transplanted.

Investigators have also focused on the science of nerve cell regeneration. As researchers have begun to understand how severed nerve fibers can regenerate after reattachment, they have applied these findings to the field of hand and limb transplantation. One new strategy involves enhancing the regeneration of axons or individual nerve fibers. Another approach is the augmentation of support cells in the nervous system known as Schwann cells, which can promote regeneration of neurons. In the future, stem cell technology and tissue regeneration may also enhance this process.

There may be advantages to performing quadruple limb transplant simultaneously and from the same donor, as was the case in last week’s procedure in Turkey. First, the patient does not have to undergo multiple lengthy surgical procedures. Secondly, extremities from a single donor will be better size matches and will exhibit similar immunogenicity profiles. However, some experts have argued that transplanting four limbs at once is a “bold” move. The team who performed the quadruple limb transplantation last week attributed their failure to “metabolic complications” and stated that the patient’s cardiovascular system was unable to sustain the transplanted limbs. Transplanting two arms and two legs at once requires the cardiovascular system of the recipient to suddenly ramp up its activity and perfuse significantly greater volumes of tissue. This may in part explain the unsuccessful attempt in this recent procedure. It also reaffirms the complex nature of limb transplantation and the deliberate planning that is required in such sophisticated surgeries.



References

Glaus SW, et al. Clinical strategies to enhance nerve regeneration in composite tissue allotransplantation. Hand Clinic, 2011 Nov;27(4):495-509

Shores JT et al. Composite tissue allotransplantation: hand transplantation and beyond. Journal of the American Academy of Orthopedic Surgeons. March 2010, Vol 18, No 3.