Safety and feasibility of pig-to-human kidney transplantation was established in a new clinical-grade surgical study by scientists at the University of Alabama Birmingham (UAB), where the pig organs were transplanted into a 57-year-old man upon brain death.

The study was published on January 20 in an article in the American Journal of Transplantation titled, “First clinical-grade porcine kidney xenotransplant using a human decedent model.”

Jayme Locke, MD, is senior author of this study.

Patients in dire need of kidney transplants inspired this work, said Jayme Locke, MD, senior author of the paper and professor in the department of surgery, transplantation division, at the UAB Marnix E. Heersink School of Medicine. “Kidney failure is a formidable disease and dialysis is not the answer. Kidney transplantation is the cure, yet we do not have enough kidneys available for transplant. Radical solutions are needed to overcome the unmitigated crisis of organ shortage. Xenotransplantation offers the hope of a new donor source and a cure for the hundreds of thousands of Americans in need of a lifesaving kidney transplant.”

In the current study, the authors reported that the transplanted kidneys turned a healthy pink and started producing urine within 23 minutes following the restoration of blood flow and remained functional until the experiment was stopped 77 hours after the surgery.

Brain death creates an inherently hostile environment for transplantation, the authors admit, and restricts the tests that can be performed to assess kidney function. Despite these drawbacks, conducting xenotransplantation on a brain-dead human allows assessments for multiple risk factors such as hyperacute rejection of the transplanted organ through crossmatching assays, surgical complications, and potential viral transmission from the donor to the recipient. Overcoming these major hurdles is a significant step toward the first Phase I clinical trial in living humans, that will be needed for the widespread availability of the procedure.

“Our study utilized a novel model for the study of the human condition by leveraging brain death as a preclinical human model and demonstrated how pig-to-human kidney transplantation can be implemented in a safe and systematic fashion,” said Locke. “Importantly, the novel preclinical human model allowed us to test critical elements without risking a living person. The promise for the future is tremendous.”

Earlier proof-of-concept studies that carried out transplantations from pigs to nonhuman primates (NHP) had identified a major immune barrier to xenotransplantation—the presence of carbohydrate antigens on the inner lining of blood vessels in pigs that are not expressed NHPs and humans and can therefore cause rejection of the donor organ.

Later studies removed these vascular antigens to overcome hyperacute rejection in pig-to-NHP transplantations. Over the years, additional genetic changes were included in donor pigs to prevent complement-mediated cytotoxicity and thrombosis upon xenotransplantation.

The kidneys used in the current study were obtained from genetically engineered pigs grown by Revivicor. These pigs have ten genetic modifications (10-GE pigs) including targeted insertions of two human complement inhibitor genes (hDAF, hCD46), two human anticoagulant genes (hTBM, hEPCR), two immunomodulatory genes (hCD47, hHO1), and deletions of three pig carbohydrate antigens and a growth hormone receptor gene. Effectively, the lack of red blood cell antigens in the 10-GE pigs makes them universal donor blood type.

“We were able to procure kidneys from a donor 10GE pig—a clinical-grade pig designed for human transplantation—at a pathogen-free facility, package and transport the pig kidneys to the recipient hospital, and transplant the organs,” said Locke. “We replicated every single step in the transplant process and demonstrated this was feasible using a pig donor source.”

The researchers also tested serologic compatibility between the donor pig and the human recipient before the transplant through a novel flow cytometric crossmatch assay where the recipient’s serum was tested against 10-GE lymphocytes.

“We developed and tested a pig-to-human specific flow crossmatch that determined tissue compatibility prior to transplantation. This is a necessary and important step as no such test existed prior to our study,” said Locke. “Pre-transplant crossmatch testing is a federal regulatory requirement for human-to-human transplantation.”

Since pigs and NHPs have lower blood pressures than humans, another key question that the current study addresses is whether the pig organ can withstand the elevated pressure in the human environment. In addition to vascular integrity of the donor organ that the current study established, the researchers said, the relative hemodynamic stability of the decedent recipient upon reperfusion indicated that washout of inflammatory mediators from the xenograft did not cause cardiovascular collapse.

The xenotransplant recipient was tested daily for the presence of pig endogenous retroviruses in the blood. “We also demonstrated that no disease transmission of pig endogenous retroviruses occurred,” said Locke. In addition, chimerism was assessed by measuring the expression of the gene for a pig ribosomal protein (pRPL4) in the human blood and was found negative at all tested time points, indicating pig cells did not transport into the human blood.

“In general, this is a very positive step forward and the authors should be commended not only for the manner in which the procedure was performed (technically and with great respect for the deceased recipient) but also for the fact that it was published in the peer-reviewed literature and opened to the scrutiny of formal review,” said Allan Kirk, MD, PhD, FACS, professor, chair and surgeon-in-chief at the Duke University School of Medicine, who was not involved in the study and has written an editorial on the paper in the American Journal of Transplantation.

Kirk added, “The study clearly demonstrates that the barrier of hyperacute rejection is controlled with the genetic manipulations in the donor pig, and from a technical standpoint, the field can reasonably begin to contemplate clinical trials. This, combined with another similar experience reported in the lay-press from NYU and the evolving experience with a heart xenotransplant recipient at UMD, (also in the lay-press) make a strikingly positive statement about the feasibility of xenotransplantation for patients with kidney and heart failure. There is still a long way to go and there are many unanswered questions, but regardless, this is a big deal.”

Although the grafted pig kidneys produced variable amounts of urine, creatinine clearance—a measure of kidney function—did not recover. The authors noted that it remains unclear whether the recovery of kidney function was affected by the condition of brain death in the recipient or by microvascular injury, or both.

The researchers monitored the health of the kidneys through daily biopsies and revealed the formation of microscopic blood clots, the cause and significance of which remains unclear and is one of the questions the team is still trying to answer.

“We need to figure out many things, including whether pig kidneys will be rejected or harmed by a human immune system over a long period of time. The longevity of a pig kidney xenotransplant will help us figure out how best to use this cure. For example, this information will help us understand whether xenotransplantation will be a bridge to allotransplant (human-to-human transplant) or whether it will last the lifetime of the recipient and become a destination therapy, as opposed to a bridge,” said Locke.

“Our hope is that pig xenografts are a destination therapy, as we know pigs have a life expectancy of around 30 years. The only way for us to know for sure is to test this in living human beings,” Locke added.

To test xenotransplantation in living humans, the scientists will need to acquire FDA approval. The team is in the process of initiating this process and believe pig-to-human kidney transplantations could become a clinical option in the next 5–10 years.

[Source: UAB]
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