How Death Becomes Life

by Joshua Mezrich

  One piece of advice I’ve always liked is that every surgeon needs to have a metaphorical “box” into which he places all his complications. He should be able to access that box each time he sees the patients with complications and their families, and when he presents a case at an M and M conference. At the same time, a surgeon should be able to close that box and put it away when he goes home to his family. Those who fail to maintain access to the box become cavalier and lose their compassion. Conversely, those who don’t have a box can struggle to keep their sanity, can’t stop thinking about all the bad things that may have happened or they may have caused, even after hours. Such surgeons often leave the profession entirely, or never really get started once they finish their training. Others limit themselves to small procedures, and call partners in to help at the slightest turn of a hair. Whatever the right strategy, we surgeons have to find a way to live with complications, to learn from them, to help patients get through whatever we may have caused or at least been a part of, and to move on.

  Sometimes in surgery things happen even though you did nothing wrong. And these cases test you like nothing else in our field. I remember one winter, a few years ago. I was doing a kidney transplant on a young woman—a girl, really—with IgA nephropathy, an autoimmune disease characterized by deposits of antibody in the kidney, leading to inflammation and ultimately kidney failure. She was about nineteen years old and otherwise totally healthy. She was receiving a good deceased-donor kidney, and I remember it was a right kidney. I know this because right kidneys have short renal veins and are always a bit trickier than left ones. When they come from deceased donors, they are usually procured with a cuff of vena cava attached to the right vein, which allows you to extend the vein if needed. I decided not to extend it in this case because the recipient was small, and I figured it was unnecessary. I remember noting that the vein was quite thin as it entered the kidney; but then, right veins always are. I flushed some fluid into the vein to distend it and noted that it was watertight. There were no major branches to tie, no little bleeders to fix. Jake, an impressive resident, and I started at around 9:00 p.m. The case went really well—once we sewed it in, the kidney reperfused beautifully and started making urine right away. I had that incredible feeling of satisfaction as we were closing, and even though it was almost midnight when we finished, we took our time and gave her a nice plastics closure, with dissolvable sutures.

  Later, as I pulled into my driveway and turned off the car’s engine, I reached over for my phone. I usually keep it in the cup holder next to me, but it wasn’t there. I fumbled around in my jacket pocket; it wasn’t there, either. I looked over at my house, where all the lights were off, and pictured my daughters sleeping soundly inside. It was already around 12:30 a.m., but as I started to climb out of the car, I had second thoughts. What if I were needed and couldn’t be contacted?

  I started the car back up, drove the five minutes to the hospital, and made my way to the OR locker room on the third floor. As I entered, I could hear the faint sound of my phone ringing inside my locker. I pulled it out and saw that I had ten missed calls from Jake. Oh shit.

  As I tapped open the text app, I started hearing my name being announced on the hospital’s overhead pager. I was being summoned urgently to the OR. My heart jumped to my throat.

  I ran to the back of the locker room, pulling off my street clothes on the way, grabbed some scrubs, and started changing rapidly, all the while calling Jake back. He answered and started yelling, “She’s bleeding. I couldn’t get hold of you!”

  I ran into the OR just as Jake and the team were pouring betadine over her exposed belly, which was so distended that she looked pregnant. I also noted how the parts of her that didn’t have betadine on them looked pale, like a cadaver’s. I looked up at the monitors and saw that her blood pressure was in the 60s, and her heart rate was 150. Several anesthesia residents and staff were squeezing bags of blood through the large IVs they had jammed in her neck.

  I turned to the circulating nurse, who was frantically getting the room set up, and told her to set up a back table and start making some ice, just in case we had to pull the kidney out. That way, I could flush the blood out and cool the kidney down to be retransplanted back into the patient if possible. Then I went out to the scrub sink and took a deep breath. As we were scrubbing, Jake filled me in on what had happened.

  Shortly after hitting the recovery room, the patient’s pressure had started dropping. She got confused, and her belly became distended. It was obvious she was bleeding internally. I couldn’t decide whether to yell at him for going to the OR on his own or hug him for taking the initiative.

  I cut Jake off in midsentence and started rehearsing with him the steps we would take once we got back in there. I was picturing the rivers of blood we would see. I told him to make sure he had some eye protection, then we smashed through the OR doors and walked over to the scrub table, where the tech gowned and gloved us. We threw some drapes on the patient, and I told the tech to get a bunch of laparotomy pads ready. Then we tore through the patient’s beautiful skin closure and cut the sutures holding her fascia closed. I told anesthesia that her blood pressure was probably about to drop even more, and then we cut through the second layer. Blood shot out and nearly hit us in the face. We rapidly opened the whole incision and packed a bunch of lap pads in to stop the bleeding temporarily. Anesthesia started to make a little progress on her pressure. It was still low, but at least we’d avoided an arrest. I was dying to pull out the laps that were soaking up her blood and figure out what was going on, but I waited until her pressure went back up.

  Telling Jake to grab a sucker, I pulled the kidney up a bit and peered in. Torrents of blood were coming from the side of one of the vessels. I could actually hear it: audible bleeding. I could tell it was venous. I reached my finger down and somehow got it right on top of the hole in the vein—just as Lillehei told a young Christiaan Barnard to do more than fifty years before.

  As Jake suctioned vigorously, I managed to gently place a couple of Allis clamps on the side of the renal vein without obstructing the entire vessel. The side wall had blown out of this thin, short right vein. I’m still not sure why it happened, but whatever the cause, we had the bleeding controlled. And amazingly, the kidney still looked pink and perfused. It was no longer making urine, but that seemed the least of our problems at the moment.

  While anesthesia continued to resuscitate her, I considered my options. After much thought, I decided it would be okay to sew up the side of the vein. I did so. And once we had the sutures in place and the clamps off, I relaxed. The kidney was still pink, and the vein was soft. Everything was okay. As I dropped the kidney back down into her belly, I asked anesthesia how we were doing. They were back down to one resident and one staff, so that was a good sign. They had rapidly given eight units of blood, probably her entire blood volume. I looked around the room. Bloody sponges littered a floor smeared all over with blood. I looked down at my scrub pants; I could see and feel the sticky blood against my legs under my gown.

  Over the next few days, we watched this young woman like hawks. She had come out of the OR with a breathing tube and was brought to the ICU. I went and talked to her family, who had been summoned by the nursing staff back to the OR waiting room after having been told everything was fine the first time around. They were concerned but understanding. Her kidney was a bit slow kicking in, but ultimately it came back to life. After the patient woke up, she was pissed that I had put staples in—I hadn’t thought it appropriate to spend time on a nice closure after the second surgery. Her recovery was tough, quite a bit more than she was expecting, but when I saw her in my clinic about six weeks later, her color was better than I had ever seen it. She was back to normal—a radiant, beautiful young woman who now had a working kidney.

  She asked me how close she’d come to dying. I told her she was about as close as she could be without being dead. She thanked me, and even gave me a hug. She told me that she didn
’t blame me for the complication. She felt great and was excited to live without dialysis. She even pulled her shirt up to reveal her staples and said she was proud of her battle scar.

  Did I do anything wrong there? Probably. Have I made any changes since that case? Well, I probably now make an extra effort to slow down on the back table, take my time to make sure everything is perfect before I start the implant. I also may be quicker to extend the vein, as this allows me to pull up less on the kidney, sew onto the thicker vein as it gets farther from the kidney, and see better.

  One other thing: I never, ever forget my phone. Thanks, Jake, for saving my patient’s life. If things had played out just a little differently, she might have died. I would have felt like shit, and she would have missed out on an entire life that she now gets to enjoy—hopefully forever off dialysis.

  17

  Xenotransplantation

  From One Species to Another

  Xenotransplantation is the future of transplantation, and always will be.

  — NORM SHUMWAY

  Xenotransplantation is just around the corner, but it may be a very long corner.

  — SIR ROY CALNE, 1995

  New Orleans, January 1964

  When thirty-eight-year-old surgeon Keith Reemtsma first met Edith Parker, he must have known she was going to die. A twenty-three-year-old black schoolteacher from a small town in Louisiana, Parker was making almost no urine by that point, having developed renal failure from primary kidney disease. She would spend more than two months in the hospital, being maintained on peritoneal dialysis, a new and temporary technique at the time. This was not a long-term solution for her. Unfortunately, she had no potential living donors. Reemtsma did have one option for her, but it was pretty risky: he would offer her both kidneys from a chimpanzee.

  The charismatic Reemtsma had already gained a reputation as a risk taker. He had gone to medical school at the University of Pennsylvania and completed his residency at Columbia. After his internship, he joined the military, serving with the navy and marines in the Korean War. In fact, many who knew him personally continue to think he was the model for the Hawkeye Pierce character in M*A*S*H. He showed up in Korea with a footlocker full of scotch and was known for his wise cracking and for mixing topnotch martinis. In 1957, he arrived at Tulane, by this point fully trained, and motivated to make his mark on the world.

  Not much is written about how Reemtsma got involved in transplantation prior to his experiences with xenotransplant. But on October 8, 1963, in a rarely reported case, he placed both kidneys from a rhesus monkey into a thirty-two-year-old-woman in renal failure. Although the surgery went well, the woman’s body rejected these kidneys, and they were removed ten days later, two days before she died from untreatable kidney failure. Still, Reemtsma wasn’t deterred. He knew that chimpanzees share a high percentage of genes with humans (some studies have estimated 96 to 99 percent of DNA), higher than with rhesus monkeys (likely closer to the low 90s). So, when a forty-three-year-old dockworker named Jefferson Davis was diagnosed with end-stage renal disease secondary to hypertension, and peritoneal dialysis was begun, Reemtsma knew the clock had started. Davis was suffering from heart failure secondary to massive fluid overload that couldn’t be controlled with the short-term dialysis and fluid restriction. Reemtsma had many conversations with Davis over several weeks, in which they discussed the possibility of a transplant from a chimpanzee. Davis agreed to proceed. He had no other options.

  So, on the morning of November 5, 1963, Reemtsma went over to Charity Hospital, next door to Tulane, “and shaved a chimpanzee that had been discarded, because of irascibility, by a circus.” He was large enough and shared a compatible blood type with Davis. Reemtsma then brought the ape over to Tulane and proceeded, under anesthesia, to remove both his kidneys en bloc, meaning both were still connected to the aorta and vena cava. He then proceeded to sew these into Davis, the lower end of the aorta and vena cava onto the external iliac artery and vein, and then the ureters separately directly into the bladder (using the same technique Alexis Carrel developed fifty years before, and the same technique we still use when transplanting pediatric en bloc kidneys from a baby into an adult). Davis was treated with azathioprine, steroids, and radiation, which was all the immunosuppression available at the time. He had a rejection crisis four days after transplant, but it responded to treatment with radiation and more steroids. He recovered kidney function and was discharged on December 18, a month and a half after transplant. Sadly, he was readmitted just two days later with pneumonia, which ultimately killed him sixty-three days after his transplant; at the time of his death, his kidneys were functioning fine, with no rejection.

  Just a week after Davis’s death, Reemtsma performed an identical transplant operation on Edith Parker, again giving her two kidneys from a single chimp. The kidneys functioned right away, making seven liters of urine in the first day. Her blood pressure quickly normalized, as did her labs. Her leg swelling dissipated. She suffered a rejection crisis twenty-three days after her initial transplant, but it responded to treatment. Parker was ultimately discharged home, and returned to her life, resuming her job as a teacher. At six and a half months she was determined to have normal kidney function. Sadly, a full nine months after her transplant, she died suddenly, possibly due to an electrolyte imbalance. An autopsy revealed no evidence of rejection or any other problem with her new kidneys.

  Over a two-year period, Reemtsma and his team performed a total of thirteen chimpanzee kidney transplants, with survival generally recorded between nine and sixty days. By 1965, as chronic dialysis was now available, and outcomes with cadaveric transplantation (now called “deceased-donor transplantation”) were improving, Reemtsma discontinued xenotransplantation in humans but continued to research it in the laboratory.

  Reemtsma’s success inspired others to toss their hats into the ring. Thomas Starzl quickly performed six kidney transplants from baboons, with a survival of nineteen to sixty days. Most of his patients died of infection, possibly due to the increased immunosuppression required to maintain these more genetically disparate organs in humans. Numerous other single attempts were performed around the world, perhaps the most famous being the case of baby Fae, who received a baboon heart as an infant at the Loma Linda University Medical Center, in California, in 1984; she survived twenty-one days, and died of rejection. The original plan had been to use this heart as a bridge until a compatible human heart could be located, but an appropriate heart couldn’t be found in time.

  By the 1990s, researchers had called for a moratorium on clinical xenotransplantation until there could be more discussion and understanding of the risks of transmission of infectious agents, the complexities of informed consent (which seems a bit odd, given that it is hard to imagine a primate or pig consenting), and animal welfare issues. While the FDA issued no official moratorium, it made clear that it would have to approve any future trial of xenotransplantation in humans.

  TODAY, NO ONE in the xeno world is thinking about primates as a source for organs for transplant. There are numerous reasons for this. For one, chimpanzees are an endangered and protected species. Also, the limitations of primates as organ donors are several, including the small size of many of their organs (which was what necessitated both kidneys being used for a single recipient) and the fact that these animals are difficult to breed, have only one off-spring at a time, are expensive to procure and care for, and are too much like humans for us to get our heads around trying to raise a colony of them just to provide us with organs. Another limitation, one that has gotten a lot of press (although it may be overstated), is that exposure to these animals so genetically close to humans may introduce xenoviruses or other infections that could pose a public health hazard. Perhaps our immune systems would not be ready to fight off the endogenous viruses or other infections found in primates.

  Virtually everyone in transplantation now believes that pigs (specifically, miniature pigs) will serve as organ donors if xenotra
nsplantation becomes a reality. They are easy to breed (each litter might have four to eight piglets), their size is appropriate for their consideration as organ donors (twenty to seventy kilograms), there is a fair amount of genetic homology to humans (although nothing in the range of primates), they are cheap, and maybe most important, it is already socially acceptable to breed them for consumption.

  Perhaps the biggest challenge in considering pigs as donors for humans is the presence in them of the alpha-gal epitope, a protein on the cells of nonprimate mammals. This protein is absent in humans, apes, and Old World monkeys (due to evolution), and in fact, we have natural antibodies to it, which leads to rapid rejection of grafts from these animals. In 2002, researchers cloned the first mini-swine lacking alpha-gal, a major step forward in the effort to make xenotransplantation a clinical reality. However, it wasn’t a magic bullet. Transplants into primates using organs from these pigs survived longer than ever before, but graft function was still measured in days or months rather than years, and extremely severe immunosuppressive regimens were required.