EXPERIMENTAL AND CLINICAL TRANSPLANTATION

A kidney transplant program was started at Innsbruck University Hospital in 1974. This was followed by the first liver transplant in 1977 and the first combined pancreas-kidney transplant in 1979. Because these 3 programs were quite successful, the idea was born to try to establish a unit that could provide temporary and permanent replacement for the loss of all kinds of organ function. In 1993, a special unit for transplant was opened. Dialysis was incorporated as part of available treatment right from the beginning. The new ward made it possible to routinely treat patients in need of bioartificial livers, to provide ventricular assist devices and later total artificial hearts, and to provide extracorporeal membrane oxygenation. The first heart transplant was performed in 1983, the first heart-lung in 1985, the first double-lung in 1987, followed by the first multivisceral transplant in 1989, the first isolated bowel in 1994, and finally the first double-hand transplant was performed in 2000. Thus, our vision of such a unit has become true.

Key words : Multiorgan transplant, Organ transplant, Transplant program

In the early 1970s, when I was at an early stage of my career, an experienced surgeon invited me to help him develop a renal transplant program. Unfortunately, after I had organized tissue typing, brain death declarations, and organ preservation protocols, the colleague left the hospital, leaving me with the decision of whether to continue our plan. The decision was not an easy one since there were 2 other well-established departments (Urology and Vascular Surgery) that wanted to conduct kidney transplant procedures. An infrastructure virtually did not exist. There was only one 2-bed hospital room without a bathroom at my disposal. Transplants had to be performed during the night, since there were no available operating rooms during the day. Needless to say, there were no personnel, be it surgeons, administrators, or specially trained nursing staff. Despite all of these unfavorable preconditions, I finally decided to take up the challenge.

Kidney transplantation
In Innsbruck, the first renal transplant was performed in August 1965 and the second one in January 1967 by the same team. Although the transplant procedures were technically successful, both patients died from infection due to over-immunosuppression. Subsequently, no more transplants were performed until 1974, when the author initiated a kidney transplant program.¹ The number of transplants increased from year to year; in 1982, we for the first time performed more than 100 renal transplant procedures. Under conventional immunosup-pression with steroids and azathioprine, 1-year graft survival did not exceed 65%. As participants in the European Cyclosporine Trial, our group witnessed enormous improvements in patient and graft survival, namely to 99% and 86%, respectively.² A further improvement was achieved with the introduction of tacrolimus and with the reduction of calcineurin inhibitors.^3,4 After 2002, 1-year deceased-donor graft survival was never less than 95%. In the 1980s, our center had about 30 donors per million population in Austria, and it was not necessary to use organs from living donors. However, this favorable situation later changed, and we began to require kidneys from living donors in about 25% of cases, with 1-year graft survival of 100%.

Liver transplantation
It just so happened that Roy Calne was on a skiing holiday in Tirol. Because he was already in Austria, I asked him to do our first liver transplant in April 1977. Unfortunately, this patient, a 43-year-old woman, died, as well as 2 subsequent transplant patients. Our fourth recipient demonstrated long-term survival. He became the first successful liver transplant in Austria.¹ The number of transplants increased steadily over the following years, and the results improved. In transplant procedures conducted between 1995 and 2000, the 5-year patient survival rate was 88.3% and the 5-year graft survival rate was 84.8% in adults; for children, these figures were 93% and 82%, respectively.

Combined liver and autologous bone marrow transplant
In late September 1982, we performed our first liver transplant followed by high-dose cyclophosphamide, total body irradiation, and autologous bone marrow transplant for treatment of metastatic breast cancer.⁵ This kind of therapy was applied in 5 patients. All survived this complex procedure; the first patient had a life expectancy of no more than 6 months and survived by more than 6 years. Because none of these patients could actually be cured, we discontinued the program.

Liver-kidney transplantation
A combined liver-kidney transplant was performed for the first time ever in December 1983. The patient was a 27-year-old man with end-stage liver and kidney disease due to chronic glomerulonephritis and hepatitis B infection. Today, this patient is still alive with 2 normally functioning grafts.⁶ Until the author retired in 2009, a total of 46 such combined transplants were performed in Innsbruck, with a 15-year patient survival rate of 66%.

In November 1984, the first pediatric liver transplant in Innsbruck was performed. The 2-year-old girl is still alive, as is our first living-donor liver transplant patient. This procedure was performed in October 1997 in an 8-month-old girl with biliary atresia.¹

Pancreas transplantation
The first combined pancreas-kidney transplant in Austria was performed in December 1979. This transplant failed, as did the next 4 transplant procedures. Only patient 6 has remained free of exogenous insulin for many years. In our first 5 patients, we used pancreatic segments, the ducts of which were occluded with an alcohol-prolamin solution before implantation. In our first patient, the pancreas was placed extraperitoneally. However, in our second patient and the next 3, the pancreatic graft was placed intraperitoneally. In the next 13 procedures, the segment was anastomosed to the bowel. After our group experienced a number of serious complications with this technique, we introduced delayed duct occlusion. This technique turned out to be safe but caused a number of local complications that prompted us after 17 such transplants to switch to bladder drainage, although still with a pancreatic segment. From patient 6 on, a drain was inserted into the pancreatic duct, which provided us with pancreatic juice and allowed us to develop pancreatic juice cytology.

This turned out to be a reliable diagnostic tool with regard to rejection. After our group performed 101 procedures with this technique, we finally began to use the whole organ and attach the graft duodenum to the second loop of jejunum, with attachment to the bladder only in 3 patients. In a series of 87 transplant procedures between 2004 and 2008, the 1-year patient survival rate was 100%, with rates of 96% for kidney survival and 92% for pancreas survival.⁷

Later, we began to perform pancreas transplants in patients with type 2 diabetes mellitus. In 22 patients, the 1-year graft survival rate was 80%, which was somewhat less favorable than results for patients with type 1 diabetes.

Other developments in our transplant program
After we had successfully established the kidney, liver, and pancreas transplant programs, we realized that the problems experienced by recipients of various organs are much the same: all patients require appropriate immunosuppression (that is, prophylaxis or treatment of rejection) and prevention or treatment of infections. Organ-specific monitoring was quite easy to learn for the nursing staff. This experience gave us the idea to build a single unit that would provide temporary or permanent replacement of every organ function.

As far as temporary replacement of renal function is concerned, all patients, if necessary before transplant, or for those with delayed or no graft function, dialysis was provided at the beginning of our activities by our own staff. Before new employees could work within our unit, they had to be trained in various forms of dialysis treatment.

Patients with liver failure either before or after transplant were treated with devices that were available at the various times. We designed a new type of bioartificial liver that prolonged survival of pigs with fulminant hepatic failure.⁸

After we finally had a department sufficiently large enough for transplant procedures of any kind of organ failure, in 1993, we started to routinely use ventricular assist devices and later total artificial hearts, as well as extracorporeal membrane oxygenation. Thus, our first target had been reached.

At that time, we tested a new rotary blood pump that was based on the Wankel principle. This model offered several advantages compared with pneumatic pumping devices and impeller or pusher plate pumps. Our pump had no valves and therefore no dead space, had a gap seal that guaranteed only little backflow, and permitted blood cells to concentrate in the middle where they are not traumatized. Because the piston moves in only one direction, the pump’s energy requirements are much less than for all other pumps.⁹

Heart transplantation
In Austria, the history of heart transplant began in October 1983 when we transplanted a heart in a 52-year-old man with end-stage ischemic cardio-myopathy. Because of excessive pulmonary vascular resistance, the graft was placed in a heterotopic position. This patient survived, as did our next patient, a 28-year-old man with idiopathic cardio-myopathy who received a transplant in February 1984. He is still alive and thus is the patient who has been living for the longest time with a grafted heart in our country.¹

Although our results with cardiac transplant procedures in the 1980s were quite satisfying, we had to cancel an increasing number of transplants due to lack of capacity in our intensive care unit. In 1993, when a unit with intensive care facilities was opened for transplant for any kind of organ failure, we resumed our activities in this field. Until then, all kinds of transplants were performed by only one team. Because this new situation led to a significant increase in our transplant activities and we were frequently forced to do 2 organ transplant procedures with short ischemia tolerance in parallel, I changed the structure insofar as thoracic organs were from now on transplanted by our cardiac surgeons. The post-operative care of these patients, however, was still performed by the transplant unit.

Heart-lung transplantation
Our first heart-lung transplant was performed in September 1985. The recipient was a 36-year-old man with obstructive lung disease. He survived, as did the next 3 patients.

In August 1987, the first double-lung transplant was performed in a 51-year-old male patient with end-stage emphysema. Unfortunately, the patient died a few days later from bleeding problems.¹ The introduction of cytomegalovirus prophylaxis for 100 days was able to significantly improve the results to 75% patient survival at 5 years.

Multivisceral transplantation
The first attempt at multivisceral transplant, namely, transplant of 3 or more abdominal organs en bloc, was made by Dr. Starzl in Pittsburgh in 1983. However, the patient, a 6-year-old girl, bled to death during surgery. In 1988, another child underwent multivisceral transplant in Pittsburgh. Two such transplants were also reported by Dr. Williams from Chicago. His first patient lived 4 days, whereas the second child transplanted in Pittsburgh and the second one in Chicago lived 190 and 100 days, respectively. However, they had not been discharged or had been fed orally.

In late December 1989, we performed a multi-visceral transplant in a 49-year-old male patient; this was the first such procedure in an adult patient. After an initially stormy course, the patient was able to leave the hospital on enteral nutrition only.10 Altogether, we performed 12 such transplants, with the procedure extended to the colon, vascular structures, or ureter in some patients. Some of these patients lived up to 15 years.

Intestinal transplantation
In Innsbruck, the first isolated intestinal transplant was performed in late November 1994 in a 51-year-old male patient with familiar idiopathic visceral neuropathy. After resection of the entire small bowel together with the great gut down to the sigmoid colon, the small bowel was implanted together with the right hemicolon. To meet the concerns of the patient’s underlying disease, the upper part of the stomach was, after transection, anastomosed to the proximal end of the graft, whereas the distal part of the stomach was simply closed. Although this surgical technique had never been described before, it worked well. At the time that the patient was discharged, he was on enteral nutrition only.¹

For safety reasons and to provide easy access to the graft, the distal end of the bowel is usually brought out as a stoma that is closed whenever the graft is felt to be immunologically safe. To keep endoscopic monitoring simple, we began to leave the stoma in place as a sentinel tissue after restoration of bowel continuity.¹¹

Islet cell transplantation
Optimistic reports from leading centers in the field in the mid-1990s prompted us to start such a program. We performed our first islet cell transplant in mid-January 1995 in a 31-year-old patient with type 1 diabetes who had already received a kidney some time earlier. A total of 450 000 islet cells isolated for us by the San Raffaele team were injected into the portal vein. After our center established an isolation facility, the subsequent years until 2005 included a total of 17 transplants performed by our team. In all patients, we achieved at least a temporary reduction in exogenous insulin of up to 70%. Unfortunately, none of these patients became independent of insulin. They would have needed at least a second injection, which all patients declined. On the other hand, patient selection was not ideal in all cases. Because of these disappointing results, we decided to stop these activities.¹

Hand transplantation
We performed our first double-hand transplant 7 weeks after the first such transplant was conducted in Lyon in January 2000 in a 49-year-old police officer who had lost both hands while trying to defuse a pipe bomb. These hands still function well without any signs of chronic rejection.¹² In February 2003, for the first time ever, a double forearm transplant was performed in a 41-year-old man. He had lost both forearms in a high-voltage current accident.¹³ Today, these grafts are still in place. Altogether, we performed 3 double-hand and 1 single-hand transplant procedure as well as the double-forearm transplant. Except for the single hand, all grafts are still functioning. The single hand had to be removed after 8 years for chronic rejection, which was possibly induced by continuous traumatization in his work with Christmas trees.

Performing temporary as well as permanent replace-ment of loss of function of every vital organ in one single unit is not only possible but also provides excellent results, is economical, and is diversified, thus producing a lot of excitement for the medical and nursing staff. It is certainly a challenge to run such a unit because it requires knowledge of the basic pathology of every organ, as well as knowledge of the diagnostic and therapeutic possibilities (Figure 1). Needless to say, one also must be familiar with the various immunosuppressive regimens. The fact that only one team can transplant all organs is certainly an exception, however my vision was realized.

Volume: 17 Issue: 1 January 2019 - Supplement - 1

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