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In View: People in Transplantation

James Southard, PhD, Professor of Surgery (Emeritus), Pioneer in Organ Preservation, Co-inventor, UW Organ Preservation Solution

Southard, James H.

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doi: 10.1097/TP.0000000000003293
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Organ preservation as a topic is as hot today as it has been at the start of clinical organ transplantation. What attracted you as a PhD into the field?

JS: I had finished a postdoctoral fellowship at the Enzyme Institute, University of Wisconsin, and was working there in a research position. I knew little about opportunities in organ preservation. Dr Belzer had recently (1974) become Chair of Surgery at Wisconsin. A fellow surgeon whom I knew told me Dr Belzer had a position for a PhD biochemist. I interviewed with him in 1976, he liked my approach to improving organ preservation and hired me to direct his newly obtained National Institutes of Health grant to improve long-term kidney preservation by machine perfusion.

Folkert Belzer, the long-term chair of surgery had already done pioneering work in organ preservation at University of California San Francisco, before moving to the University of Wisconsin. He has been a surgical powerhouse, you commented on his laboratory methods as “unorthodox.” Can you share the details?

JS: Dr Belzer was conventional in his appreciation of the value of basic research. When something caught his attention that he thought would improve kidney preservation; however, he wanted to test it immediately. This led to some bizarre experiments with many different preservation solutions containing many different additives. We used such things as coffee creamer to serve as a method to keep fatty acids in solution in the cold, a larger serum albumin molecule we made by cross-linking the albumin with glutaraldehyde, and a perfusate containing many of the trace elements found in plasma. This became known as the kitchen sink perfusate, because it contained so many compounds. Most of these experiments failed. But Dr Belzer was always thinking of ideas to try.

He would also study the Merck Index of chemicals while in the laboratory and would say to me that the answer to improved preservation was in this book, if only we could figure what chemicals to use. We knew that in the cold, cells swelled because the membrane ion pumps were relatively inactive and the chloride anion in most solutions would leak into the cell down a concentration gradient. We replaced chlorine with a more impermeable anion, added gluconate into the perfusion solution, giving us 3–5 days of successful canine kidney preservation. Next, we turned our attention to liver and pancreas preservation by simple cold storage. In the absence of perfusion, however, the preservation was not effective for prolonged intervals (3 d).

While pursuing the Merck Index, Dr Belzer came across lactobionic acids and thought this a catchy name. He asked me what it was, and I said it was similar to gluconate but of larger molecular size and might be better in preventing hypothermic-induced cell swelling. He asked me to get some and try it in liver and pancreas preservation. The solution I made became the University of Wisconsin solution and worked almost immediately to give 3-day pancreas preservation, 2-day liver preservation, and 3-day kidney preservation.

The combinatorial efforts of a PhD and MD can, at least in theory, be ideal in moving clinically applicable pioneering work forward. Can you share some details of your relationship with Dr Belzer?

JS: We had an ideal working relationship. I knew my role and his expectations of me. I knew Dr Belzer expected me to run the day-to-day operation of his laboratory. Thus, I was to obtain funding for the laboratory in his name, train surgical residents and students, review manuscripts or grants he received, supervise our technical staff, direct the budget, direct the research of visiting surgeons, and create research approaches that would advance the field and produce publishable results.

In return, Dr Belzer encouraged me to develop a national and international presence in the field and helped me to do this. He gave me departmental and university responsibilities necessary to advance my career. He placed me on the tenured professorial track, secured me a joint position in a basic science department so I could teach and take on graduate students, and saw that departmental funds were available if needed.

He was busy clinically as Department Chair and Division Chief of Transplant. Yet, he talked with me almost daily about our research. He knew what the laboratory was doing and would keep us focused. He showed genuine interest in our work and provided encouragement and motivation. This involvement and interest in my work and the work of the laboratory was a critical factor that drove us all to succeed. He set high standards for work ethics by how he himself worked, was fully engaged, and knew what was going on in the laboratory and in the department. He was genuinely highly respected for his skills, leadership, and loyalty to his staff.1

The composition of (any) organ preservation solution including that of UW appears, at times challenging to comprehend for those who are not deeply involved in the field. Can you share some of the thoughts and rationale the went into the composition of the UW solution?

JS: The rationale for the UW solution was based upon ideas of how anoxia and hypothermia adversely affected cells and how injury on rewarming and reperfusion of the organ at normothermia (ie, transplantation) would exacerbate further preservation injury.

Based upon previous studies, we thought it necessary to prevent hypothermic-induced cell swelling due to the loss of adenosine triphosphate (ATP) and inhibition of the electrolyte membrane pumps. Thus, we replaced the anion chloride with the impermeant anions (gluconate or lactobionate), which have a larger size, remain outside of the cell preventing the influx of water. In the cold, potassium leaks out of the cell in exchange for Natrium. This, we thought, would be unfavorable to the cell and that much energy would be required after transplantation to establish a normal cellular ionic concentration. The solution was to increase the concentration of potassium and decrease the concentration of Natrium in the preservation solution. To further prevent cell swelling, we made the solution slightly hypotonic with a trisaccharide (raffinose), which would remain outside the cell. Because cold storage is done anoxically, the lack of oxygen leads to a loss of ATP, which breaks down to end products that are permeable to the cell membrane (adenosine, adenine, and phosphate). The cell, in turn, needs to regenerate ATP rapidly upon reperfusion and requires these chemicals. Thus, we used adenosine or adenine and phosphate in the solution. Phosphate was used as a hydrogen ion buffer to maintain the pH around 7.4. Additionally, we aimed to suppress oxygen-free radical generation during reperfusion and used glutathione to help reduce the concentrations of oxygen-free radicals or their end product in the cell. In addition, we added allopurinol to inhibit 1 source of oxygen-free radicals, xanthine oxidase. We showed that the combination of glutathione and adenosine resulted in the rapid regeneration of ATP in canine renal tissue after preservation and simulated reperfusion.

In the perfusion fluid, we also used a modified form of hydroxyethyl starch (pentastarch) replacing serum albumin as an osmotic colloid to counteract the pressure generated by the perfusion pump. We continued to use starch in the UW solution that was not used for perfusion. The idea was to create a single preservation solution that could be used for either simple cold storage or machine perfusion.

Our development of these solutions was based on the idea that preservation-reperfusion injury is multifactorial. Thus, it was conceivable that each of the injuries must be prevented or corrected nearly simultaneously after transplantation or the organ would not function well. Cell swelling, mitochondrial injury, lack of ATP, generation of oxygen-free radicals, activation of lysosomal enzymes, membrane injury, endothelial cell injury, or other events could all cause serious organ injury and delay recovery or cause nonfunction.

Machine devices have been around during the early days of organ preservation. One kidney had even been shipped from San Francisco to Leiden, the Netherlands, facilitating the first successful “intercontinental” kidney transplant. Do you recollect details of the story?

JS: Dr Belzer told me that the clinic had received a kidney, and no suitable recipient was found. The successful preservation time for the kidney (3 d) was running out. Dr Belzer, being of Dutch origin, and with many Dutch surgeon connections, flew the machine and kidney to Leiden. He told me he sat in first class with the portable mini-Belzer machine in a seat beside him. The flight crew paid rapt attention to the machine and the human kidney inside. They continually brought Dr Belzer ice to put in the machine and for him Martinis. The kidney was successfully transplanted.

The link between metabolism and immunity has recently emerged as a most relevant topic. You have already touched upon this subject 30 years back by characterizing the effects of fasting on organ quality. Can you speculate how we would utilize changes of metabolism to improve organ preservation?

JS: There has been some evidence that organs could be “preconditioned” to tolerate ischemic-reperfusion-induced damage. For that reason, we did an experiment in which dogs were fasted before harvesting and this maneuver seemed to improve outcome in the transplant model.2 Also, we were interested in how hibernators conditioned their organs to tolerate life at 4°C (the ground squirrel). We showed that the liver from a hibernating ground squirrel was significantly less injured after 72 hours of cold storage in the UW solution compared with a liver of a rat. I have thought that understanding the biochemical changes that allowed this preconditioning could provide strategies to improve organ tolerance to hypothermic storage. Another idea we considered was pretreatment of the donor with drugs or agents that could increase its tolerance to the trauma of harvesting, preservation, and transplantation. This would require a knowledge of the mechanisms of injury.

How would you characterize the future of organ preservation today?

JS: Interestingly, research directions have not changed substantially in the field over the last 40 years. There was always an interest in resuscitation of the injured organ, warm blood–based perfusion for preservation and for viability assessment before transplantation, debate over the use of simple cold storage versus machine perfusion as the best method, attempts to make a better preservation solution, ways to pretreat the donor to stabilize the organ and suppress ischemic-reperfusion injury, suppression of oxygen-free radical-induced injury, and the development of better portable preservation machines.

I think the key to progress in organ preservation is using the right model, one that mimics the clinical situation, incorporating factors such as brain death, ischemic times, fatty livers, and so on. Dr Belzer believed that in the laboratory, we must be able to preserve the canine organs for twice as long as the clinical need to give assurance that the method of preservation would be safe for clinical use.

Results obtained with high-quality organs seem to be very good with solutions that have been successfully used for over 20 years. Organs of limited quality are probably going to need machine perfusion, and new solutions for these are a worthwhile pursuit in the laboratory. I think that for any new solution, to claim superiority to the UW solution, it should be shown to achieve what the UW solutions can achieve in the laboratory, which is 3–5 days of successful machine perfusion of kidneys, 3 days cold storage of the pancreas, 3 days cold storage of the kidney, and 2 days preservation of the liver. These preservation times were obtained with high-quality organs and remained a yardstick for preservation solution development.3,4

Do you foresee that the development of organ preservation will allow us to implement transplantation as an elective procedure?

JS: Dr Belzer had no problem with doing livers and kidneys as semielective surgeries and if the liver arrived late at night, he would have the team schedule the transplant for the next morning as a scheduled procedure. Also, since his clinic used machine perfusion for kidneys, and still do mostly, Dr Belzer did not have concerns with doing the procedure as a scheduled procedure.

Can you share some insights into your “Emeritus” life?

JS: I retired from the university in the fall of 2008. Mainly I am a grandpa, husband, and father. And these roles bring me great joy. I stay busy with hobbies, reading, guitar practice, and work for my church. I follow, but not too closely, developments in the field of organ preservation and transplantation. Still living in Madison gets me to see some of my work colleagues periodically, and this is enjoyable.

REFERENCES

1. Southard JH. Coffee creamer, the bionic man, and organ preservation. Surgery. 2002; 131:228–229
2. Boudjema K, Van Gulik TM, Lindell SL, et al. Effect of oxidized and reduced glutathione in liver preservation. Transplantation. 1990; 50:948–951
3. Belzer FO, Southard JH. The future of kidney preservation. Transplantation. 1980; 30:161–165
4. Schilling M, Saunder A, Southard JH, et al. Five-to-seven-day kidney preservation with aspirin and furegrelate. Transplantation. 1993; 55:955–958
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