Toledo celebrates Mike Rees

 Here's the announcement from the University of Toledo:

University Recognizes Faculty Members with Distinguished Honor 

"Rees joined the faculty of the then Medical College of Ohio as an assistant professor in the Department of Urology in 1999 and was promoted to associate professor in 2007 and to professor in 2008.

"His research interests include kidney-paired donation, transplant immunology, immunosuppression, xenotransplantation and value-based healthcare, and he has received numerous grants totaling millions of dollars including grants from the Echoes of Lasting Peace Foundation, the NIH, the Agency for Healthcare Research and Quality (AHRQ), the Stanford Impact Lab, Wyeth Pharmaceutical Corporation, Novartis, the Ohio Department of Development and the Ohio Center for Innovative Immunosuppressive Therapeutics.

Rees mentored three Ph.D. students in xenotransplantation immunology, all of whom have gone on to successful careers in the health sciences and he has trained more than 50 urologists. He has obtained four patents related to his work in transplantation methods, one of which has led to a 30% increase in the supply of deceased donor livers in Europe, and he has written more than 100 publications and book chapters. These publications include: “Nonsimultaneous Extended Altruistic Donors” an idea that has lead to an additional 20,000 living donor kidney transplants around the world, “Delayed Renal Transplant Function,” “Immunological Effects of Hepatic Xenoperfusion” and “Strategies to Increase the Donor Pool.”

His numerous awards and commendations include attending the 2012 Nobel Prize ceremony at the invitation of his mentor for his UToledo-sponsored 2016-2017 sabbatical, Nobel Laureate in Economics, Alvin Roth, the Medal of Excellence from the American Association of Kidney Patients, the Governor’s Award from the National Kidney Foundation, and he was named an American Society of Transplantation’s New Key Opinion Leader.

Rees has given lectures and seminars in France, the United Kingdom, Canada, Belgium, South Korea, Switzerland, Japan, Saudi Arabia, Germany, Hungary, the Netherlands, Italy, India and the Philippines, and he served a three-year fellowship at Cambridge University, where he trained as a multi-organ transplant surgeon under world-renowned surgeon and transplant pioneer, Professor Sir Roy Calne, as well as completing a Ph.D. in xenotransplantation immunology.

“I have been fortunate to be supported by The University of Toledo since 1996 when the Medical College of Ohio made it possible for me to obtain a Ph.D. in immunology and a fellowship in transplant surgery at Cambridge University prior to my arrival in Toledo in 1999,” Rees said. “Transplantation is the great team sport. I am honored to have been chosen for this award, and I am grateful to all those who have trained me, the University of Toledo and Medical Center, the teams that have supported me, and the grant agencies and philanthropists who have supported my dreams over the course of my career.”

 

Clinical trial of pig kidney transplants

 A clinical trial is good news.

The NYT has the story:

F.D.A. Approves Studies of Pig Organ Transplants for Kidney Patients
The research offers hope to tens of thousands of patients with kidney failure who are on a long waiting list for an organ transplant. By Roni Caryn Rabin  Feb. 3, 2025

"The U.S. Food and Drug Administration has given the green light to two biotechnology companies for clinical trials that will transplant organs from genetically modified pigs into people with kidney failure. If successful, these studies could lead to the broader use of cross-species transplantation, a dream of medical scientists for centuries.

One of the companies, United Therapeutics Corporation, will begin its trial with six patients, but that number could eventually rise to 50. The other, eGenesis, said it would begin with three patients and grow the study from there.

...

"Over the past three years, five patients have been known to receive organs from pigs engineered by these companies — two who received hearts and three who received kidneys. But these surgeries were not part of a formal clinical trial.

...

"The United Therapeutics study, which is expected to begin midyear, will start with six patients who have been on dialysis for at least six months but do not have other serious medical problems. There will be a three-month waiting period between each transplant so that doctors can learn from the outcomes.

If the first six transplants are successful, the trial will expand to include up to 50 participants in what is called a phaseless trial — a type of study that combines the traditional Phase 1, Phase 2 and Phase 3 trials and can lead directly to approval."

Another transplant of a pig kidney

A very highly sensitized patient, even one with lots of priority on the deceased donor waiting  list (a prior donor) may not find a compatible human kidney.  Right now pig kidneys are still very experimental. The Washington Post has the story:

Years after donating a kidney, Alabama woman receives one from a pig
She became the third human to receive a genetically engineered pig’s kidney, raising hopes for thousands of Americans on the waiting list for organ transplants. By Mark Johnson

"Twenty-five years after donating a kidney to her mother, an Alabama woman became the third human to receive a genetically engineered pig’s kidney, raising hopes for thousands of Americans on the waiting list for organ transplants, officials at NYU Langone Health announced Tuesday. She is the first live patient to receive a pig’s kidney with 10 gene edits designed to reduce the risk of organ rejection.

...

"In March, doctors at Massachusetts General Hospital performed the first transplant of a gene-edited pig’s kidney, implanting the organ in Richard Slayman, a 62-year-old worker for the Massachusetts Department of Transportation. He lived for 52 days.

"Lisa Pisano, a 54-year-old grandmother, was the next to receive a gene-edited pig’s kidney, the first time such a kidney had been transplanted in a person also receiving a heart pump; the two procedures were performed on different days in April. She survived 86 days, though the gradually failing kidney had to be removed after 47 days.

...

"The gene-edited pig used in Looney’s transplant was developed by Revivicor Inc., a subsidiary of United Therapeutics Corporation.

"The 10 changes to the pig’s genetic code included the removal of three immunogenic antigens, molecules that can trigger an immune response. A growth hormone receptor, which can regulate growth and metabolism, was also removed.

"In addition, scientists gave the pig six human transgenes, pieces of DNA that have been experimentally constructed, and were intended to make the pig organ more compatible to the human body.

"Doctors received permission to perform the procedure under the Food and Drug Administration’s compassionate use program, which allows the use of investigational medical products outside of clinical trials when a patient has a life-threatening condition."

The first four patients who received transplants of organs from genetically modified pigs

 NBC reports on the four patients who have so far received organ transplants from genetically modified pigs.

Their loved ones died after receiving pig organ transplants. The families have no regrets. Four people have received hearts or kidneys from pigs. Some of their relatives recount a roller coaster of hope and uncertainty. By Aria Bendix

"David Bennett Sr., had severe congestive heart failure and wasn’t a candidate for a human transplant. He knew he would likely die soon. There was nothing more to do — other than take a chance on a novel, cutting-edge surgery. Bennett Sr. and his son agreed it was worth the risk.  

"The achievement made headlines around the world after the transplant surgery in January 2022.

...

"But two months later, Bennett Sr.’s body rejected the heart and he died at age 57. In a paper, his doctors at the University of Maryland Medical Center explained that his body had likely produced too many antibodies that fought off the new organ.

...

Three other patients have followed in Bennett Sr.’s footsteps and received pig organs, most recently a pig kidney transplant in April. Together, they represent the pioneer patients of the burgeoning field of xenotransplantation. For their families, three of which spoke to NBC News about the experience, the journey came with a roller coaster of emotions, from uncertainty to blind hope — and, ultimately, admiration for their loved one’s decision. 

...

"None of the patients survived more than three months. To the public, that might seem like failure. But to the families, the transplants accomplished their goals: to buy their loved ones more time and advance research that could potentially save lives one day."

Increasing the supply of transplantable organs, in the long term, and sooner.

 Here's an article on the website of The American Council on Science and Health, on technologies that might eventually replace the need for human organ transplants, and on policies to increase their supply while still needed.

We Urgently Need More Organs For Transplantation. Science And Policy Can Come To The Rescue. By Henry I. Miller, MS, MD and Sally Satel, MD

"Both scientific and policy advancements could provide desperately needed organs for transplantation. For example, there have been some promising early studies using kidneys from pigs genetically engineered to prevent rejection, but a policy change – paying human donors for donating organs – could be implemented immediately and would be a game changer.

...

"[A] sector of medicine that desperately needs breakthroughs is the transplantation of solid organs, which are in severely short supply. Currently, more than 100,000 Americans are waiting for transplants, and due to a shortage of hearts, lungs, livers, and kidneys, at least 17 die each day. Donor organs — from a living person or cadaver — must match the rejection recipient’s tissue type and size; they are often not perfect. By one estimate, approximately half of transplanted organs are rejected by recipients’ bodies within 10-12 years, despite a constantly expanding understanding of what causes rejection. Another obstacle is that the organ procurement system in the U.S. is inefficient, inconsistent, and unaccountable – in short, a mess that causes preventable deaths.

"We are making progress, but too slowly. Two new high-tech approaches to providing organs for transplantation might ultimately both eliminate the need for organ donors and reduce the risk of tissue rejection. And there is also a low-tech approach that would require only a tweak in healthcare policy.

"Organs produced by 3D bioprinting"

...

"Organs from genetically modified pigs"

...

"The low-tech policy approach

"Although friends and relatives and even the occasional “good Samaritan” donor can donate kidneys, they must be given without compensation. Under section 301(a) of the National Organ Transplant Act of 1984 (NOTA), it is a federal crime for “any person to knowingly acquire, receive, or otherwise transfer any human organ for valuable consideration for use in human transplantation if the transfer affects interstate commerce.”  Therefore, we propose a federal tax credit for living donors willing to save the life of a stranger. The value of the reward should be between $50,000 and $100,000, which physicians and others who endorse donor compensation believe would be sufficient to address the organ shortage. An economic analysis published in 2022 estimated that a reward of $77,000 could encourage sufficient donations to save 47,000 patients annually.

"The credit would be universally available—refundable in cash for people who do not owe income tax, not phased out at high-income levels, and available under the alternative minimum tax. NOTA’s restriction on payments by organ recipients and other private individuals and organizations would not change—it would still be illegal for recipients to buy organs.

"A qualified organ donation would be subject to stringent safeguards. As all donors are now, prospective compensated donors would be carefully screened for physical and emotional health. A minimum six-month waiting period before the donation would filter out impulsive donors and donations by financially desperate individuals seeking instant cash.

"In addition to saving lives, the credit would save the government money, perhaps as much as $14 billion per year, by reducing expenditures on dialysis. Thus, donors would receive financial compensation from the government for contributing to the public good and bearing the risk of a surgical operation to remove the organ.

"This would be a compassionate and pragmatic policy. Moreover, it could be implemented immediately, rapidly clearing much of the backlog of Americans waiting for organs in advance of the longer-term high-tech approaches.

"The organ shortage kills thousands of Americans every year. We must do all we can to alleviate it now."

HT: Frank McCormick

Richard Slayman: first recipient of pig kidney transplant dies after two months. (RIP)

 Here's the story from the Guardian:

Pig kidney ‘xenotransplant’ patient dies two months later. No indication that Richard ‘Rick’ Slayman’s receipt of genetically modified kidney caused his death, says Massachusetts transplant team

"The first recipient of a genetically modified pig kidney transplant has died about two months later, with the hospital that performed the surgery saying it did not have any indication the transplant was the cause.

...

"In a statement, Slayman’s family thanked his doctors. “Their enormous efforts leading the xenotransplant gave our family seven more weeks with Rick, and our memories made during that time will remain in our minds and hearts,” the statement said.

"They said Slayman underwent the surgery in part to provide hope for the thousands of people who need a transplant to survive. “Rick accomplished that goal and his hope and optimism will endure forever.”

"In April, New Jersey woman Lisa Pisano also received a genetically modified pig kidney as well as a mechanical pump to keep her heart beating.

########

I'm not aware of any medical journal reports so far on these transplants--reporting has just been by press release...

Before pig kidneys can be transplanted into human patients...

 Here's a paper in the Lancet suggesting some of the work that remains before pig kidneys can be transplanted into human patients:

Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study, by Prof Alexandre Loupy, MD PhD, Valentin Goutaudier, MD MSc, Alessia Giarraputo, PhD, Fariza Mezine, MSc, Erwan Morgand, PhD, Blaise Robin, MSc, Karen Khalil, PharmD, Sapna Mehta, MD, Brendan Keating, PhD, Amy Dandro, MSc, Anaïs Certain, MSc, Pierre-Louis Tharaux, MD PhD, Prof Navneet Narula, MD, Prof Renaud Tissier, DVM PhD, Sébastien Giraud, PhD, Prof Thierry Hauet, MD PhD, Prof Harvey I Pass, MD, Aurélie Sannier, MD PhD, Ming Wu, MD, Adam Griesemer, MD, David Ayares, PhD, Vasishta Tatapudi, MD, Jeffrey Stern, MD, Prof Carmen Lefaucheur, MD PhD, Prof Patrick Bruneval, MD, Massimo Mangiola, PhD, Prof Robert A Montgomery, MD PhD, August 17, 2023 DOI:https://doi.org/10.1016/S0140-6736(23)01349-

"Background: Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach.

...

"Interpretation: Despite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results."

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Yesterday:

Wednesday, August 23, 2023

Transplanted pig kidney functions for a week in brain dead patient

Transplanted pig kidney functions for a week in brain dead patient

 Here's a report on a kidney from a genetically engineered pig, that was transplanted into a brain dead patient maintained on a ventilator, and which functioned successfully for seven days.  I'm beginning to think it's possible that xenotransplants of pig kidneys may be available for living patients in my lifetime.

Locke JE, Kumar V, Anderson D, Porrett PM. Normal Graft Function After Pig-to-Human Kidney Xenotransplant. JAMA Surg. Published online August 16, 2023. doi:10.1001/jamasurg.2023.2774

"Thirty-seven million adults in the US have chronic kidney disease (CKD), many of whom will ultimately progress to end-stage kidney disease (ESKD). Kidney transplant is the gold-standard therapy for patients with ESKD, yet annually, only 25 000 individuals receive a kidney. The gap between supply and demand is so vast that 40% of listed patients die within 5 years while waiting for a kidney transplant. Although xenotransplant represents 1 potential solution for the kidney shortage, previous reports of pig-to-human kidney xenotransplant using a preclinical human brain death model have shown xenograft urine production but not creatinine clearance, a necessary function to sustain life.1,2 Thus, no study to date has shown the ability of a xenograft to provide life-sustaining kidney function in a human.

...

"Discussion | The findings from this case series show that pigto-human xenotransplant provided life-sustaining kidney function in a deceased human with CKD. Future research in living human recipients is necessary to determine long-term xenograft kidney function and whether xenografts could serve as a bridge or destination therapy for ESKD. Because our study represents a single case, generalizability of the findings is limited. This study showcases xenotransplant as a viable potential solution to an organ shortage crisis responsible for thousands of preventable deaths annually."

FDA Contemplating Clinical Trials of Pig-Organ Transplants (WSJ)

The WSJ has the story:

FDA Planning to Allow Clinical Trials of Pig-Organ Transplants. Move could be an important step in effort to ease the shortage of human donor organs.  By Amy Dockser Marcus and Liz Essley Whyte

"The Food and Drug Administration is devising plans to allow clinical trials testing the transplantation of pig organs into humans, a person familiar with the matter said.

"If the agency follows through, the trials could be a key step in an effort to ease the deadly shortage of human donor organs. The planning comes in the wake of a handful of experimental surgeries involving the transplantation of pig organs into a critically ill man and in brain-dead patients.

"It is unclear when the trials would begin, the person said, adding that proposals from researchers would be handled case by case."

Xenotransplantation and pork chops

 There's been recent news about xenotransplantation, with attempts made to transplant kidneys or hearts from genetically modified pigs into humans.  Those haven't been successful yet, but the organs weren't immediately rejected, because the special pigs involved don't have the alpha-gal sugar molecule on their cells that non-human mammals have and that immediately alerts human immune systems to reject the organ.

But while pig organs aren't ready for transplant yet, it turns out that there are some people who are allergic to the alpha-gal sugar, and hence to meat. But they can eat the meat of these almost-transplant-ready pigs.

The Atlantic has the story:

A Tick Bite Made Them Allergic to Meat. And an organ-transplant company has an unexpected solution. By Sarah Zhang

"It just so happens that the same molecule—a sugar called alpha-gal—that causes the human immune system to reject pig organs also causes the tick-associated red-meat allergy, known as alpha-gal syndrome. To make a pig whose organs could be harvested for transplant, Revivicor first had to make an alpha-gal-free pig. And when it did, the company realized that transplant surgeons weren’t the only ones interested.

"Since last fall, Revivicor has been quietly sending refrigerated packages of alpha-gal-free bacon, ham, ground pork, chops, and pork shoulders to people in the alpha-gal-syndrome community. These packages were free, but Revivicor has told the FDA it is exploring a mail-order business. And so a biomedical company has found itself an accidental purveyor of specialty pork products."

************

In the background of this story is Revivicor part of the public benefit corporation United Therapeutics, founded by the remarkable Martine Rothblatt.

 

David Bennet Sr., who lived for two months with a transplanted pig heart, RIP

 Xenotransplants from pigs are probably here to stay, but are also not quite here yet, and may not be for some time.

Yesterday's NY Times has the story:

Patient in Groundbreaking Heart Transplant Dies. David Bennett Sr. had received a heart from a genetically modified pig, a procedure that may yet offer hope to millions of Americans needing transplants.  By Roni Caryn Rabin, March 9, 2022

"The first person to have his failing heart replaced with that of a genetically altered pig in a groundbreaking operation died Tuesday afternoon at the University of Maryland Medical Center, two months after the transplant surgery.

...

"Mr. Bennett’s transplant was initially deemed successful. It is still considered a significant step forward, because the pig’s heart was not immediately rejected and continued to function for well over a month, passing a critical milestone for transplant patients.

**********

The Times story also made mention of the complicated discussion about organ donation, in this case having to do with the recipient's checkered history, as discussed in this earlier story from the Washington Post:

The ethics of a second chance: Pig heart transplant recipient stabbed a man seven times years ago By Lizzie Johnson and William Wan, January 13, 2022

**********

And while we're thinking of ethical objections, don't forget the pig, or the gene manipulation involved in raising a suitable pig. Here's a rundown from the BBC:

Three ethical issues around pig heart transplants By Jack Hunter, 11 January, 2022

First pig-to-human heart transplant (and some background on the trials with non human primates)

 Xenotransplants, of pig organs into humans, may be closer than I thought. A dramatic step was taken last Friday when a pig heart was successfully transplanted into a man who was still being kept alive by the heart yesterday when the NY Times reported it.  Following the news story, I'll link to a recent summary of the increasing success of transplanting pig hearts into non-human primates.  In the near term, the idea is that a pig heart might keep a patient alive until a human organ becomes available.

Here's the NY Times story:

In a First, Man Receives a Heart From a Genetically Altered Pig. The breakthrough may lead one day to new supplies of animal organs for transplant into human patients.  By Roni Caryn Rabin

"A 57-year-old man with life-threatening heart disease has received a heart from a genetically modified pig, a groundbreaking procedure that offers hope to hundreds of thousands of patients with failing organs.

"It is the first successful transplant of a pig’s heart into a human being. The eight-hour operation took place in Baltimore on Friday, and the patient, David Bennett Sr. of Maryland, was doing well on Monday, according to surgeons at the University of Maryland Medical Center.

“It creates the pulse, it creates the pressure, it is his heart,” said Dr. Bartley Griffith, the director of the cardiac transplant program at the medical center, who performed the operation.

“It’s working and it looks normal. We are thrilled, but we don’t know what tomorrow will bring us. This has never been done before.”

****************

And here's a just-published paper that gives some background:

Shu, S., Ren, J. & Song, J. Cardiac xenotransplantation: a promising way to treat advanced heart failure. Heart Fail Rev 27, 71–91 (2022). https://doi.org/10.1007/s10741-020-09989-x

Abstract: Cardiac xenotransplantation (CXTx) might be a promising approach to bridge the gap between the supply and demand of a donor heart. The survival of cardiac xenograft has been significantly extended in pig-to-nonhuman primate (NHP) CXTx, with records of 195 days and 945 days for orthotropic and heterotopic CXTx, respectively. ...

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Earlier:

Sunday, December 5, 2021

Organ shortages for transplantation: Pig kidneys won't be transplanted into people soon

Organ shortages for transplantation: Pig kidneys won't be transplanted into people soon

 Here's an article in Medpage Today by the chief medical officer at UNOS, pointing out that xenotransplantation is not going to substitute in the near term for other efforts to increase organ transplants. (The article goes on to discuss recent progress in other directions.)

A Look at Pig Kidneys in the Broader Transplantation Puzzle— Advancements across the field are accelerating in real time  by David Klassen, MD November 29, 2021

"Last month's breaking news that the kidney of a pig functioned normally when attached for 54 hours to the body of a brain-dead patient was hailed as an eventual solution for more than 100,000 people nationwide who are waiting for life-saving organs. While xenotransplantation, or animal-to-human transplantation, has been undergoing study and experimentation for quite some time, this was a huge step in the right direction.

As first reported on October 18, the team at NYU Langone Health obtained consent from the ventilated donor's family to attach a pig kidney to her upper leg and monitor the results. They reported that the organ, which came from an animal whose genes had been modified to avoid early rejection by a human host, began to work almost immediately and produce urine and function as would a human kidney. The pig kidney functioned normally throughout the 54-hour trial.

...

"Unfortunately, the next steps remain incredibly complex. Routine xenotransplantation of non-human organs into human bodies is many years away. One of the greatest hurdles is immunological: getting non-human organs to survive long-term, not just for a 54-hour trial. Due to the need for additional research and testing, it is unlikely that xenotransplantation will arrive in time to help most of those currently on the transplant waitlist, including more than 90,000 kidney transplant candidates."