Although Spain is a world reference in the field of transplants, every year thousands of people remain without receiving the donated kidney they need. The same happens with other organs. And globally the problem is much more serious, with millions of people affected and waiting lists continuing to grow due to an aging population. In the United States, seventeen people die every day waiting for a kidney transplant, and every nine minutes one more patient is added to the waiting list. The situation risks collapsing healthcare systems within a few years. Today, a biomedical advance led by Spanish researchers opens up a new way to ease transplant waiting lists using human mini-kidneys.
These organoids start as a mass of a few stem cells and then grow into balls a little smaller than the head of a pin. At that point they already possess a pattern of specialized cells that resembles that of the different organs of the body, a characteristic that makes them ideal for studying diseases or carrying out toxicological tests.
The new work takes a quantum leap to explore whether these structures can also be used for transplants in humans. Researchers developed kidney organoids from human stem cells, cultured them and, for the first time, demonstrated how to produce them in large quantities and cost-effectively, bringing their future application closer to patients.
The work was directed by the Barcelona biologist Nuria Montserrat, 47 years old, ICREA research professor at the Institute of Bioengineering of Catalonia (IBEC) until just over a year ago and current Councilor for Research and University of the Generalitat of Catalonia.
Before taking up his post in Salvador Illa’s government, Montserrat had been promoting the use of these cell cultures in regenerative medicine for more than a decade. Now, together with scientists from several Spanish bodies, including the National Transplant Organization, and researchers from the University of California, his team has managed to graft human kidney organoids into porcine kidneys for the first time thanks to normothermic perfusion machines, commonly used in the operating room to keep the organ alive and oxygenated outside the body before a transplant. This maneuver allows the integration of human cells into the animal’s organ. For the first time, researchers have retransplanted these kidneys into live animals from which they were taken, and have demonstrated their functionality and the absence of rejection. The study was published Friday in the specialized journal Biomedical Engineering of Nature.
The next step, Montserrat explains to EL PAÍS, will be to test the technique with the viscera of human cadavers. “Every year more than 1,000 kidneys are discarded that are not suitable for the transplant process. Now we have the opportunity to use them for research.” The ultimate goal is to reduce transplant waiting lists and increase the number of kidneys available for transplant.
The production of human organoids suitable for these uses is extremely complex. “10 years ago,” explains Montserrat, “our idea was to create an entire human kidney, from scratch, but it’s something very naive.” “The kidney is one of our most complex organs, with 23 different types of specialized cells,” he adds.
The new kidney organoids are barely visible when integrated into the pig’s organs – they must measure around 200 microns to fit into the arteries without blocking them – but they already contain 19 different types of specific cells. Thanks to collaboration with institutions spread across Spain, which form the framework of a future network (development of mini-organs in Barcelona, experiments and transplants on pigs in La Coruña using perfusion machines manufactured in Zaragoza and analysis of the immune response at the Carlos III Institute of Health in Madrid), this technique has been demonstrated “as a proof of concept”.
The global organ shortage has prompted the use of pork organ meats for human transplants. Until now, one of the most successful cases had been that of Tim Andrews, a 67-year-old American who had been grafted with a previously genetically modified pig kidney to eliminate viruses and make it more compatible with his body. The operation was successful until a few days ago, when doctors at Massachusetts General Hospital removed it because it was causing problems. Andrews lived 271 days with the implant, a world record. The first two patients who received these transplants died shortly after surgery, and the third was able to carry it for 130 days until his body rejected it. Other living patients have also received experimental heart and liver transplants from these animals, although their effectiveness is still very uncertain. For now, these types of interventions are seen as a bridge with which to buy time until the necessary human organ arrives.
Human organoids are now being added as a new avenue, says Jordi Ochando, an immunologist at Carlos III and Mount Sinai Hospital in New York and a co-author of the work. “In many cases a patient receives not one, but several kidney transplants due to rejection. These techniques could help make the grafts more compatible with the patient and avoid problems,” he explains. Furthermore, these analogues “can be used in human kidneys discarded for transplantation and increase the number of organs available, but they can also be used in the kidneys of transgenic pigs to make them more compatible with the recipient,” he explains.
It is the first time that quality mini-kidneys are produced in large quantities and with high reliability, underlines biochemist Elena Garreta, co-author of the study. “Until now, around 40 fabrics of this type could be made using conventional methods. Now, thanks to our system, we can produce 30,000 in a single experiment, also verifying that they are all of high quality,” he underlines. There are still years of work to be done, but in his opinion this progress opens many doors to therapeutic applications.
Nephrologist Beatriz-Domínguez-Gil, director of the Transplant Organization and co-author of the work, paints the background scenario in which this research is framed. “Every day in Europe there are more than 77,000 patients waiting for a kidney for a transplant, according to a recent study conducted in 40 countries. These are people condemned to long dialysis treatment, with the consequences this entails on their personal and professional development. This is completely transformed with the kidney transplant, which improves life expectancy and is also less expensive than dialysis. This situation is complicated by the progressive aging of donors, who have greater comorbidities. This makes it essential to look for solutions alternatives and organoids are one of the possibilities for the future,” he explains. The director of the ONT explains that there is already an agreement with hospitals in Barcelona, Madrid, Galicia and Cantabria to start using discarded human organs in these investigations, scheduled for next year.
Although the application of these human tissues is still a long way off, Domínguez-Gil believes, the doctor foresees two uses of this technology: being able to remove the kidney of a person suffering from kidney disease, treat it with a system similar to that used with pigs and reimplant it; and use this technique to regenerate donated organs that do not meet the requirements for transplantation.
Brazilian doctor Leonardo Riella was the director of the team that performed the pig kidney transplant on the American patient at the Massachusetts General Hospital. The kidney transplant manager and Harvard University professor, who was not involved in this work, praises it as a great first step. “This is an elegant and innovative proof of concept that demonstrates that human kidney organoids can survive and integrate within porcine kidneys for a short period. It is an exciting step towards the fusion of regenerative medicine and xenotransplantation (animal to human). The main challenges in the future will be to achieve long-term viability and demonstrate true kidney function from transplanted organoids. If the latter is achieved, it could ultimately lead to new treatments to restore kidney function in patients with chronic kidney disease,” underlines.
Marcos López-Hoyos, head of immunology at the Marqués de Valdecilla University Hospital, in Santander, warns that these techniques are still in the animal research phase, but are still “very interesting”. “Kidneys are currently already being recovered with ex vivo perfusion methods like those used in this study. Organoids, although they do not completely reproduce a real kidney, are capable of regenerating it and have enormous treatment possibilities,” he emphasizes.
