乌鸦传媒

A pig-to-human xenotransplant demonstrated successful kidney function in a deceased human with chronic kidney disease, representing a potential solution to the organ shortage crisis, researchers said.

In a brain-dead 52-year-old man, crossmatch-compatible pig kidneys with 10 genetic modifications were transplanted with pig vasculature anastomosed to the decedent's right-side common iliac artery and distal inferior vena cava, with the pig ureters anastomosed to the man's bladder, reported Jayme E. Locke, MD, MPH, of the University of Alabama at Birmingham Heersink School of Medicine, and colleagues.

The xenografts made urine within the first 4 minutes of reperfusion and continued to produce more than 37 L within the first 24 hours, they noted in a research letter published in .

This dropped down to a median urine volume of 14.1 L on postoperative days 1-3 and 5.1 L on postoperative days 4-7. Average living is about 1-2 L per day.

These findings "firmly established the ability of the xenografts to produce urine to provide life-sustaining kidney function by clearing creatinine," Locke told 乌鸦传媒. "This has never been shown before in a human."

"These data ... are going to be critical as [the FDA] evaluates whether or not this should move forward into living persons in the form of a phase I trial," Locke noted. "We're very hopeful that these data will provide further evidence that xenotransplantation is not only a viable, but an immediate, solution to the organ shortage crisis that really causes thousands of preventable deaths each year because the gap between supply and demand is that vast."

These results are a big leap forward from Locke and team's first preclinical study published early last year. In a similar scenario, two pig kidneys with 10 genetic modifications were transplanted into a brain-dead human. Though this study wasn't specifically designed to "optimize renal performance or immunologic outcomes," the team noted that the right kidney started making urine within 23 minutes and made 700 cc of urine within the first 24 hours. However, the other kidney only produced a scant amount of urine.

Furthermore, while normal serum electrolytes were maintained during the few days post-op, creatinine clearance never recovered.

With the current study's xenotransplant, serum creatinine decreased to 1.9 mg/dL within the first 24 hours after an initial pre-op level of 3.9 mg/dL after cessation of dialysis and bilateral native nephrectomy. Serum creatinine normalized to 1.1 mg/dL at 48 hours post-op and remained within normal limits throughout follow-up. On postoperative day 7 (study completion), serum creatinine was 0.9 mg/dL.

Creatinine clearance also improved from 0 mL/min right after transplant to 200 mL/min on postoperative day 7. The biggest jump was seen right after postoperative day 1.

There was no evidence of thrombotic microangiopathy by the end of the study.

This isn't the only group trying to solve the organ shortage crisis via pig xenotransplantations. Last month, Robert Montgomery, MD, DPhil, of the NYU Langone Transplant Institute in New York City, and colleagues conducted the fifth xenotransplant procedure at their institution, in which a genetically modified pig kidney was transplanted into a 57-year-old brain-dead man on ventilator support.

As of now -- 32 days later -- the kidney is still functioning without rejection. This marks the longest period that a gene-edited pig kidney has function in a human. The team plans to observe kidney functioning through mid-September. These results have not yet been published in a journal.

Regarding her group's experience, Locke said, "We know that a human being without kidneys and in the absence of dialysis cannot be sustained for 7 days. They would ultimately succumb to that by not being able to clear various toxins from their body."

"These xenografts not only made urine, but they cleared these toxins and maintained normal renal function, and really stability, in this model for a full 7 days," she added. "And, in fact, at study completion, the kidneys were still working ... they were still making about 275 cc per hour of urine."

The "patient" had a history of hypertension and stage 2 chronic kidney disease, and suffered from an acute kidney injury around the time of death.

"His serum creatinine peaked at 13.8 mg/dL and he ultimately actually had to be started on dialysis," Locke explained. "This presented a really unique opportunity for us to not only test these xenografts, but to actually do this in an individual who really reflects the kind of individual that we are ultimately hoping to transplant one day."

With informed family consent, the decedent received cardiopulmonary support in a critical care setting throughout the study. He underwent bilateral native nephrectomy and stopped dialysis after being crossmatched with xenotransplants.

Created with a total of 10 genetic modifications, the pig kidneys had four gene knockdowns and knockouts (GTKO, CMAH, B4GALNT2, GHR) and six human transgene insertions (CD46, CD55, CD47, THBD, PROCR, HMOX1). The kidneys were harvested from living pigs under general anesthesia who were then humanely euthanized.

One day prior to xenotransplant, the decedent received eculizumab (Soliris), followed by standard induction therapy, which involved a solumedrol taper, antithymocyte globulin (6 mg/kg total), and rituximab (Rituxan). Maintenance immunosuppression included a combination of tacrolimus – with goal levels (8-10 ng/dL) reached by postoperative day 2 -- mycophenolate mofetil, and prednisone.

Locke said that her team is working with the FDA to obtain an investigational new drug application -- the next step needed to test this procedure in live humans in a phase I adaptive clinical trial.

Montgomery noted that he and his team believe "using a pig already deemed safe by the FDA in combination with what we have found in our xenotransplantation research so far gets us closer to the clinical trial phase."

Locke also extended her gratitude to the decedents' families, "who have so graciously honored the desire of their loved one to give back."

"It is through their efforts that we will move the needle and solve one of the most lethal crises in modern healthcare," she said.

Comment