Technological leaps make multiple, kidney-swapping surgeries more common

Chronic kidney disease affects 26 million American adults, with millions of those affected unaware because there are no symptoms until the disease is severe. When a person’s kidneys fail, they can go on dialysis or try to get a kidney transplant, which provides a better quality of life. The latter options requires that a friend or family member be willing to donate one. Otherwise, they face many years on a waiting list. 

But what if you have a donor who is not a match, which means the donated organ will be rejected by your immune system?  

The answer in Birmingham is UAB’s paired exchange and incompatible transplant programs. Ann Marie Reynolds, Gwendolyn Goldsmith and Frank Peters each needed a kidney and had a donor lined up that turned out to be incompatible. The swapping enabling them to be entered into a database that made all participants more likely to get a kidney, and this powerful story by UAB’s Tyler Greer describes their recent three-way transplant surgery.   

Their multiple, living-donor transplant has made it possible for each patient to live free of the constraints of dialysis for what doctors hope will be at least a decade and maybe two. Each of those who donated the kidney did so even though they knew their organ would be going to someone other than their family member or loved one. By the end of 2013, UAB is expected to complete perhaps 30 kidney swap transplants as part of the program.

A team of UAB surgeons, physicians and researchers in UAB’s Kidney/Pancreas Transplant Center has assembled and developed the technologies needed to make the multiple surgeries successful. We thought to talk to one of the UAB surgeons who oversaw the three-way transplant that day, Dr. Jayme Locke, and to ask her about this emerging field and what it means for patients. 

Show notes for the podcast:

1:52  The kidneys filter the blood, divert waste into urine and return useful proteins to the bloodstream. but can be damaged by diabetes, high blood pressure and cancer. 

3:00 As diseases progress, the kidneys become less and less able to function until they fail, at which points patients either go on dialysis, a mechanical system that filters the blood, get a kidney transplant or die. 

3:51 The field has shifted over the years from implanting kidneys from a stranger who recently died to organs donated by living people known to the recipient. In the United States there are about 100,000 people waiting for a kidney, but only 10,000 and 15,000 transplants done a year. The need far outweighs the supply, and those who have a family member willing to donate a kidney instead of going on a waiting list (ten-year wait in Alabama for some) has a tremendous advantage.  

5:12 It is important to note that about 35 percent of people who come forward and volunteer to donate a kidney to loved one are found to be incompatible with their would-be recipient. They have a blood type that means the recipient's immune system will immediately attack the donated organ and prevent it from functioning. Another 11 percent of willing donors will be found to be tissue incompatible. So almost half of would be donors cannot donate to their intended recipient. 

6:10  Paired exchange and incompatible transplant programs were born to address this problem, and to make it possible for many to get kidneys that would not otherwise happen.

6:37:  Paired exchange programs started in single hospitals, and now national databases have begun.  At UAB, the list of would be donors and patients is so large that the database locally is effective at making swaps possible in Alabama.

7:37: Ann Marie Reynolds, one of three patients in the transplant swap described above, has had three kidney transplants over the last 25 years. Some patients need more than one transplant because of rejection (sometimes years later) or because a systemic disease comes back in the new organ. Getting a second transplant is more difficult than the first because patients become sensitized. 

8:44 We all have labels on our cells that say self (made of a protein called human leukocyte antigen or HLA). Our immune system looks for this tag and spares self-labelled cells from immune attack, whereas those with other tags like bacteria are targeted. Thus, the goal is to find a transplanted organ made up of cells with an HLA that matches pretty closely with the patient's own tags. In the last ten years, researchers have developed the technology that enables patients to overcome some degree of mismatch if their blood and tissue types are close enough.  

10:30 Dr. Locke discussed the work of UAB's Dr. Roz Mannon, whose specialty is keeping the immune system from attacking a transplanted organ over the long term. While the field has gotten very good at preventing transplant rejection in the first year, gradual damage can cause the organ to fail five years later.

11:10 One approach to preventing long-term rejection, says Dr. Locke, is to find people better blood and tissue matches in donated organs in the first place. By carefully testing the expanded pool of potential donors and recipients in a swapping system, the chances increase that each patient will not only get a kidney, but a better matched kidney.  

11:45 The transplant researcher community also continues to work urgently to improve immunosuppressive medications such that they stop immune attack on a transplanted organ without making patients overly vulnerable to infections. UAB is a national leader in this regard, participating in several, ongoing clinical trials. 

12:57 A unique team at UAB makes multiple swap transplant operations possible. In some cases, six operations are underway at the same time, which requires skilled support by teams of nurses, anesthesiologists, pharmacists, etc., both in preparation and follow up to surgery. This tremendous and coordinated effort by UAB Nursing is led by people like Katie Stegner who runs the operating rooms and Debbie Sparks, the nurse manager on the kidney floor. 

15:35 The living donors that make the swapping system possible are willing to sacrifice part of themselves for their loved ones, a choice that has Dr. Locke's respect. Beyond that are those that chose to donate an organ into the system in honor of a family member or friend, hoping the swap system can give an organ back to that loved one. 

17:28  Dr. Locke would like to see a truly national swapping system develop, one that was not for profit. The huge size of such a database would make a great difference for many more patients in need of transplant. 

 

Goal: keep your transplanted organ permanently

Unless you have an identical twin, needing an organ transplant comes with a serious problem even beyond the fact that you need a transplant. Assuming the surgery goes well, the minute the new organ is grafted into your body, your immune system will recognize it as foreign, akin to invading bacteria, and seek to destroy it.

Taking the kidney for an example, there was a time 25 years ago when half of kidney transplant recipients lost their transplant due to immune rejection. The field of transplant immunology has in recent years become very good at preventing this during the first year after transplant using drugs that turn down the immune response, but long-term rejection remains commonplace.

The immune systems of many organ recipients eventually destroy transplanted kidneys over ten to 15 years. Worse yet, patients live through those years with a suppressed immune system; making them vulnerable to viral infections, some of which cause cancer.

Research efforts to solve these thorny, remaining problems in transplant immunology continue, but the field is under duress thanks to cuts in federal research funding, says UAB's Rosyln Mannon, M.D., director of research at the UAB Comprehensive Transplant Institute and a kidney transplant specialist. She was among the organizers of a recent transplant immunology symposium held by the institute.

Dr. Mannon sat down with The Mix to talk about research frontiers in transplantation, including efforts to design drugs that precisely turn down the activity of immune cells involved in transplant rejection, while ignoring those that fight infection.


Show notes for the podcast:

1:05  As we develop in the womb, special proteins are built on the surfaces of all our cells that serve as tags that say "self," and thus keep our immune cells from attacking them.  A transplanted organ obviously has different cell-surface, protein labels.

1:31  When surgeons put in a transplanted organ, the proteins labels on the organ surfaces are picked up and carried by immune cells to nearby lymph nodes, where they trigger the building of an army of cells designed specifically to attack the new organ. Several sets of immune cells are swept up into the effort to destroy the transplanted organ (also called a graft), including T cells and antibodies, two workhorse cells of the adaptive immune system.

1:47 Thus, the response to a transplanted organ that immunologists must deal with when preventing transplant rejection includes a mix of proteins, including antibodies that glom onto and remove foreign cells,    and cells that swarm to the transplant site and release destructive chemicals (e.g. cytokines).

3:15 The field of transplant immunology has been "incredibly successful" at preventing acute transplant rejection in the first year after the transplant using a subtle, powerful mix of drugs that damp down the immune system to protect transplanted organs.

3:39  The average person who receives a kidney this year from a diseased patient can expect the graft to last ten years. If the organ came from a living donor, the transplant may continue to function for 15 years, and especially if the organ came from a well matched family member. Despite these advances, all patients see their transplants fail eventually. About half of them "fail" because the patient dies, some from heart disease. Others organs fail because the medicines taken to suppress immune systems leave patients vulnerable to infection.

4:20 Physicians typically take a biopsy of a failing kidney to see why it has failed after working well for so long. In some cases, the slides will reveal that the immune system finally overcame immunosuppressive drugs to recognize the transplant as foreign and attack it. Interestingly, sometimes it will be one part of the immune system that finally tracks down the organ (e.g. antibodies), and sometimes another (T cells).  In still other cases, the biopsy may reveal that a longtime, undetected viral infection has destroyed the organ, or maybe it was fibrosis, the wear-and-tear scarring that comes with age.

5:15 The failure of organ transplants many years after implantation for these varied reasons is the central, remaining problem facing transplant immunologists and their patients.

5:43 The drugs used to suppress the immune system on the way to protecting a transplanted organ have evolved. In the old days, transplant recipients received steroids like prednisone (an anti-allergy drug) and drugs called anti-metabolites. In the mid-1980s, a set of drugs called calceneurin inhibitors arrived, including cyclosporin and then later Prograf. Most patients in those days got large doses of drugs like these, some of which themselves scar the kidneys. Other risks of such therapy included knocking the immune system thoroughly enough to encourage viral infections like the Epstein-Barr virus, cytomegalovirus and related cancers viruses.  The latter make random genetic changes in the cells they infect, some of which accidentally cause the abnormal growth seen in cancer. Presentations at the recent symposium talked about ways of fine-tuning immunosuppressive treatments to minimize damage related to their use.

7:47 Newer FDA-approved treatments appear to have fewer side effects, but still have the same problem as older drugs: they knock down the immune system broadly instead just the cells attacking the new organ. All physicians can do is gradually reduce the dose of immune suppressing medications over time under the assumption that the immune system has come to see the transplant as self, but doing so may result in the late-stage rejections currently observed five and ten years down the line.

8:53 Frontiers in the field include research efforts to design therapies that influence only the subsets of immune cells most associated with transplant rejection. Certain kinds of immune cells "remember" they have encountered a foreign protein, for instance.  Therapies may destroy most of those cells, but those that remain eventually become capable of re-launching the attack on the transplant.  On the other hand, one subset of T cells, called Tregs, are known to damp down the immune response in a careful way. What if engineers were able to deploy a person's own Tregs to damp down response to specific proteins on the surfaces of transplanted tissue?

10:11  Research efforts looking suppressing specific immune mechanisms, while the future of the field, are still in the early phases. Dr. Mannon hopes they suppress more surgically than the global suppression seen with older drugs.

10:45  The recent UAB transplant immunology symposium was timely, said Dr. Mannon, because UAB has been working to establish a collaborative consortium of transplant centers in the Southeast. UAB is one of the largest clinical transplant centers in the country, as is its partner in this symposium, the Emory Transplant Institute. Vanderbilt and the Medical College of South Carolina also have a strong interests in this area. The symposium was the first forum to identify and discuss the central, remaining problems in transplant immunology, and to launch joint efforts to solve them.

11:15 Among the research frontiers discussed was how best to arm patients with the ability to fight off infections without jeopardizing their transplants. One way may be to harness the bacteria that live in the human gut. What role do the bacteria that permanently colonize the body have in the immune system and transplant rejection? Can the interaction between our gut bugs and antibiotics for instance be manipulated to improve long-term outcomes of transplant patients by damping down system-wide inflammation?

14:24  Dr. Mannon is the newly elected president of the American Society of Transplantation, the second president in a row to come from UAB after Dr. Robert Gaston, M.D.  UAB has for years been recognized across the Southeast for the large volume of clinical transplant procedures done here, but having the presidency sends a message to the nation about the strength of the basic and translational research underway.

15:45 The society has been very active on Capitol Hill in terms of lobbying for the support of related research, and that stance will continue during Dr. Mannon's term. As for the group's legislative agenda, they have been trying for 12 years to get a bill passed that would provide coverage for immunosuppressive therapy for the life of those with kidney transplants. Currently, Medicare pays for such medications for three years after the transplant, after which medications the become prohibitively expensive for those without private insurance. Another bill would ensure that those who donate a kidney to another person cannot have their coverage dropped by an insurer after they give the gift of life.