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.

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"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.

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"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."

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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.

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"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.

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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

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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.”

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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.

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"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."