Instructor, General Surgery
Specialty Areas: Transplant Urology, Kidney Transplantation, Pancreas Transplantation, Transplant Immunology, Transplant Immunosuppression, Transplant Surgery
Wake Forest Baptist Medical Center
Medical Center Boulevard, Winston-Salem, NC 27157.
MedicalResearch.com: What are the main findings of the study?
Dr. Orlando: Our study shows that we can use discarded kidneys from deceased human donors as platform for kidney regeneration investigations. As of now, we are using porcine models, after having developed smaller scale models (mainly in rodents, as it normally occurs in health science ie we need to provide the proof of concept in small animals before scaling up to larger animals which, for obvious reasons, are clinically more relevant). In regenerative medicine we know that cells do not survive if they are not seeded on supporting platforms which we call “scaffolds”. There are several types of scaffolds, but probably the most effective are the ones that we can produce from animal/human organs. Basically, every organ consists of a cellular component which is endowed within the framework of the so-called extracellular matrix. When we strip cells out of an organ, what remains is the acellular extracellular matrix. Quite strikingly, the acellular organ in question maintains the same shape and volume that it had before stripping. What counts is that the so-obtained scaffold contains most information that cells require to grow, be viable and exert their function. It looks like this happens also for discarded human kidneys which may represent the most promising platform for our research
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Orlando: That we are working very hard and with great hope in the intent to produce bioartificial organs, in this case the kidney. The human scaffold platform is interesting as is species-specific to humans and so all theoretical issues that may arise when you use material of an origin other than human, like rejection and the transmission of disease that so far have been restricted to non-human species, are basically ruled out. We do hope that our experience will convince the general audience of the importance of donating organs. In fact, organs may be used also for research purposes. It should however be emphasized that when organs are used for research purposes, this can happen because the organs in question are not suitable for transplantation for a myriad of causes. For the medical community, to waste an organ that had been procured for transplant purpose, is a tragedy if we consider the dramatic gap between the demand of organs and the offer. Just to give you an idea, 100k patients are waiting for a kidney transplant as we speak, each year; though, we will be able to perform only 16-17k transplant per year, no more than that! In the US, we waste 2600 kidneys each year. Unfortunately, in some cases the family of the donor does not grant research consent, and so we can not use part of this 2.6k kidneys. The audience should be aware that there is an alternative way to contribute to the society, and that is by granting also research consent when they consent to donate organs for clinical purposes. Somehow, as transplant operator, I do hope that our research may convince the community about the importance of organ donation, as well
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Orlando: We are now able to produce scaffolds from human kidneys. The next big step is the repopulation of the scaffold. This seems quite challenging as, as of now, no report is available on the successful repopulation of a large scale scaffold. There is still a lot of work to do, but we are investing a lot in this field, in terms of energy, asset and funds. Future – actually current research – should focus on the developmental/regenerative aspect of each specific tissue. But this is something that goes beyond the interest of the general audience, I think. What the general audience should be aware of, is that they may contribute to the advancement of our research with donations.
Author Interview updated May 23 2013
Study Suggests New Source of Kidneys for Transplant
Rejected Organs have Potential to be “Recycled” for Patients
WINSTON-SALEM, N.C. – May 20, 2013 – Nearly 20 percent of kidneys that are recovered from deceased donors in the U.S. are refused for transplant due to factors ranging from scarring in small blood vessels of the kidney’s filtering units to the organ going too long without blood or oxygen. But, what if instead of being discarded, these organs could be “recycled” to help solve the critical shortage of donor organs?
Researchers at Wake Forest Baptist Medical Center and colleagues, reporting in the journal Biomaterials, found that human kidneys discarded for transplant can potentially serve as a natural “scaffolding material” for manufacturing replacement organs in the lab using regenerative medicine techniques.
According to the authors, more than 2,600 donor kidneys are discarded each year in the U.S. “With about 100,000 people in the U.S. awaiting kidney transplants, it is devastating when an organ is donated but cannot be used,” said Giuseppe Orlando, M.D., Ph.D., lead author, a Wake Forest Baptist transplant surgeon and regenerative medicine researcher. “These discarded organs may represent an ideal platform for investigations aimed at manufacturing kidneys for transplant.”
The research involved pumping a mild detergent through kidneys that were refused for transplant. The goal of the process, called decellularization, is to remove all cells – leaving only the organ structure or “skeleton,” known in regenerative medicine terms as a scaffold. Ultimately, the patient’s own cells could be placed in this scaffold, creating a customized organ that the patient theoretically would not reject.
In fact, an analysis of the decellularized organs revealed that antigens likely to cause an immune response were removed in the cleaning process. “This finding has significant implications,” said Orlando. “It indicates that transplantation of such customized kidneys could be performed without the need for anti-rejection therapy. In addition, these kidneys maintain their innate three-dimensional architecture, their basic biochemistry, as well as their vessel network system. When we tested their ability to be transplanted (in pigs), these kidneys were able to maintain blood pressure, suggesting a functional and resilient vasculature.”
While the project is in its infancy, the idea represents a potential solution to the extreme shortage of donor kidneys. According to the authors, the probability in the U.S. of receiving a kidney transplant within five years of being added to the waiting list is less than 35 percent, and people age 60 or older who are placed on the waiting list only have a 50 percent chance of ever receiving a kidney.
The science of regenerative medicine has already had success in engineering skin, cartilage, bladders, urine tubes, trachea and blood vessels in the lab that were successfully implanted in patients. Most of these structures were able to receive oxygen and nutrients from nearby tissues until they developed their own blood vessel supply. However, more complex organs such as the kidney, liver, heart and pancreas are larger with dense cellular networks and must have their own oxygen supply to survive. The need for a blood supply is why scientists are exploring the possibility of using donor organs and “seeding” them with a patient’s own cells.
As the research continues, the scientists will need to assess whether discarded organs with certain defects can be used to benefit patients. For example, some kidneys are rejected because of fibrosis (scarring) in the tiny vessels throughout the organ. Can these organs be recycled? Orlando said that time will tell but that early clinical data suggests that fibrotic lesions are reversible and that the human body has the ability to remodel kidney fibrosis and restore normal anatomy.
The research was supported in part by a grant from the state of North Carolina.
Co-researchers were Christopher Booth, B.S., Zhan Wang, Ph.D., Christina L. Ross, Ph.D., Emma Moran, B.S., Marcus Salvatory, M.D., Yousef Al-Shraideh, M.D., Umar Farooq, M.D., Alan C. Farney, M.D., Ph.D., Jeffrey Rogers, M.D., Samy Iskandar, M.D., Ph.D., Frank Marini, Ph.D., Robert J. Stratta, M.D., and Shay Soker, Ph.D., Wake Forest Baptist; Giorgia Totonelli, M.D., Ph.D., Panagiotis Maghsoudlou, M.S., Mark Turmaine, Ph.D., Alan Burns, Ph.D., Paolo De Coppi, M.D., Ph.D., University College London; and Ginger Delario, Ph.D., Carolina Donor Services.