A genetically modified pig kidney has survived and functioned in a human recipient for 61 days, setting a record for this type of procedure and offering new hope to the nearly one million Americans living with end-stage kidney disease. The study, conducted at NYU Langone Health, showed that a pig organ with just a single genetic modification could sustain life-supporting kidney functions for over two months, even bouncing back from a serious rejection crisis.
Only about 3% of patients with end-stage kidney disease receive transplants each year. Many die before receiving an organ. Pig kidneys, capable of being produced on demand, represent one potential path forward.
Scientists transplanted a kidney from a 199-day-old female pig into a 57-year-old brain-dead man in July 2023. The pig had been genetically modified to remove alpha-Gal, a sugar molecule that humans lost millions of years ago during evolution. The human immune system now attacks alpha-Gal as foreign. Rather than using pigs with dozens of genetic changes, researchers opted for this simpler approach with just one gene edit.
A Month Of Success After Pig Kidney Transplant
Within hours of transplantation, the pig kidney began producing urine and filtering waste from the blood. A blood test measuring creatinine showed the organ was working very well. Creatinine is a waste product that builds up when kidneys fail. The recipient’s creatinine level dropped from 1.0 mg/dL before surgery to just 0.32 mg/dL within 12 days. For comparison, normal human kidneys maintain creatinine between 1.0 and 1.5 mg/dL.
For nearly a month, the transplanted kidney performed better than many human donor kidneys. It filtered blood at a rate of about 125 mL per minute per 1.73 m² of body surface.
Then on day 33, trouble struck. The kidney experienced antibody-mediated rejection, where the immune system mounts an attack against the foreign organ. The recipient’s kidney function declined as antibodies surged and immune cells swarmed into the organ. Microscope examination of tissue samples revealed inflammation in the tiny blood vessels and filtering structures, along with deposits of antibodies and immune proteins coating the kidney’s inner surfaces.
Doctors responded with treatments already approved for human organ transplants. They used plasma exchange, a process similar to dialysis that removes harmful antibodies from the blood. They added drugs that suppress the immune system and block complement, a component of immune defense that amplifies attacks on foreign tissue. The combination worked, and kidney function climbed back to normal levels. By day 60, the organ was filtering at well over 100 mL per minute per 1.73 m², similar to a healthy human kidney.
Tissue analysis on day 49 showed rejection had returned with immune cells now attacking blood vessel walls. Researchers added another round of plasma exchange and a powerful drug called rabbit anti-thymocyte globulin that eliminates T cells, a type of white blood cell that coordinates immune attacks. Once again, the kidney recovered. When removed at the planned end of the 61-day study, tissue samples showed no signs of rejection, no antibody deposits, and no damage to the filtering structures essential for kidney function.
T Cells Present Before Surgery Multiplied and Attacked Transplant
Researchers used sophisticated genetic sequencing to track immune cells throughout the study. They uncovered a troubling pattern: T cells capable of recognizing pig tissue as foreign were already present in the recipient’s blood before surgery. After transplantation, these cells multiplied explosively.
Before surgery, the five fastest-growing types of these pig-recognizing T cells made up just 3% of all circulating T cells. By day 49, they accounted for more than 30%. One particular T cell type ballooned from less than 0.1% to over 20% of the total population. These expanding cells transformed into activated killers, turning on genes that produce toxic proteins designed to punch holes in target cells.
When researchers examined kidney tissue samples taken during rejection, they found these activated T cells had infiltrated the organ alongside natural killer cells and other immune cells that amplify attacks. The finding suggests that simply suppressing the immune system after transplant may not be enough. Strategies to eliminate or control these pre-existing pig-reactive immune cells before surgery might be necessary.
Antibodies driving the rejection targeted an unknown pig protein found on blood vessel cells. Strangely, these antibodies attacked vessels from both minimally modified pigs and pigs with 10 genetic changes designed to eliminate foreign molecules that previous research had identified as problematic. The discovery means scientists still don’t know which pig molecules need to be modified or masked to prevent this type of immune attack.
Most Kidney Functions Worked, Some Didn’t
Beyond just surviving, the pig kidney needed to perform the complex chemical balancing act that kidneys carry out every moment. Researchers monitored whether the organ could respond to human hormones, regulate electrolytes, filter drugs, and handle the intricate calcium-phosphate system that keeps bones healthy. Most functions worked well, though not perfectly.
The pig kidney responded correctly to vasopressin, a human hormone that signals kidneys to conserve water. This was not guaranteed to work because pigs produce a slightly different version of the hormone. When researchers briefly stopped the vasopressin being used to manage the brain-dead recipient’s water balance issues, urine output shot up to over 1,000 mL per hour, sodium levels climbed, and urine became watery. Restarting the hormone quickly reversed everything, proving cross-species hormone signaling could work.
Blood levels of sodium, potassium, and magnesium stayed relatively stable throughout the study with only occasional need for supplements. The kidney filtered and cleared drugs appropriately, including the antibiotic vancomycin. Calcium and phosphate levels were managed, though the kidney held onto more phosphate than expected, requiring medications to bind excess phosphate in the digestive tract.
One hormonal system didn’t work as expected. The kidney’s part of the renin-angiotensin-aldosterone system, which regulates blood pressure and salt balance, appeared nonfunctional. No pig renin enzyme could be detected in the recipient’s blood. Previous lab studies had shown pig renin doesn’t work well on human proteins, so this mismatch was somewhat expected. Yet blood pressure remained normal for over two months with only standard care, suggesting the body found workarounds.
The pig kidney also didn’t produce erythropoietin, a hormone that tells bone marrow to make red blood cells. Blood transfusions were needed to keep red cell counts adequate, though lab tests showed the bone marrow was trying to compensate by producing immature red cells at elevated rates.
Despite these limitations, the kidney’s core filtering function remained intact. No excess protein leaked into the urine throughout the study, and microscope images showed the delicate cellular structures responsible for filtering blood stayed healthy even after two rejection episodes.
No Dangerous Pig Viruses In Patient
A major safety question about using pig organs has been whether viruses that naturally infect pigs might jump to humans and potentially spread to others. Researchers tested extensively for known pig viruses throughout the 61 days, examining blood, the transplanted kidney, and various tissues.
Porcine endogenous retroviruses, which are permanently embedded in pig DNA, showed up in some blood samples from the recipient. However, these viruses appeared only when pig mitochondrial DNA was also present, pointing to the presence of a few circulating pig cells rather than actual infection of human cells. No pig viruses were replicating in human tissues.
The heavy immunosuppression needed to prevent organ rejection did allow some human viruses to flourish. The recipient developed norovirus and showed rising antibody levels against Epstein-Barr virus. Tissue from the removed kidney showed signs of post-transplant lymphoproliferative disorder, an abnormal immune cell proliferation that sometimes happens when transplant patients take strong immunosuppressive drugs.
Hope For Solving The Organ Shortage
Researchers included pig thymus tissue attached to the kidney as an experimental approach. In animal studies, donor thymus tissue can train the recipient’s immune system to tolerate foreign organs. Human immune cells were developing in the pig thymus when examined at study’s end, and lab tests showed recipient T cells responded less vigorously to pig cells by day 49 compared to day 28. But the explosive expansion of pre-existing pig-reactive T cells suggests more aggressive strategies will be needed to control immune responses that exist before surgery.
The success with minimal genetic modification defies earlier expectations. Primate studies had suggested more extensive changes might be necessary. The pig used here, with just one gene knocked out, lacked human genes for proteins thought important for preventing rejection. Yet it performed well for two months. Single-gene-edit pigs can be bred normally rather than cloned individually, making them more practical for producing organs at scale.
Brain-dead recipients offer both advantages and limitations as test subjects. Unlike primate studies, researchers can use the full range of treatments available for humans, including plasma exchange and sophisticated molecular monitoring difficult to perform in animals. Brain-dead individuals maintain working immune systems and normal physiology. But the model can’t show what would happen in living patients with kidney disease, who face different immune challenges and medical complications.
Source : https://studyfinds.org/pig-kidney-functions-normally-in-brain-dead-human/
