Healthwatch- Better kidney transplants -- Interview

[okarol]

Healthwatch- Better kidney transplants

Friday, August 22, 2008 at 4:24 p.m.

BACKGROUND: End-stage renal disease is another name for kidney failure that is so advanced it can't be reversed. There are only two treatment options for patients experiencing end-stage renal failure -- dialysis or transplantation. The national kidney foundation estimates that about 350,000 people in the U.S. have end stage renal disease and about 67,000 people die of kidney failure each year. If a patient opts to have dialysis it may impose invasive limitations on his or her lifestyle because of the rigorous schedule, diet and side effects that accompany the treatment. A successful kidney transplant provides a better quality of life because it allows greater freedom and often is associated with increased energy levels and a less restricted diet. There are two types of kidney transplants, one that uses a kidney from a living donor, and one that used a kidney from a deceased donor. Because of a shortage of donor kidneys, each year only a small percentage of people who need a transplant actually receive a kidney. The wait for a donor kidney can take years.

COMPLICATIONS: A transplanted kidney may not be an immediate fix as complications can be associated with the transplant surgery. The most important complication that may occur after transplant is rejection of the kidney. The body's immune system guards against attack by all foreign matter, such as bacteria. This defense system may recognize tissue transplanted from someone else as "foreign" and act to combat this "foreign invader." Immune-suppressing drugs that prevent organ rejection are widely used to combat this complication; however they come with complications of their own. They raise the patient's risk for cancer and make them more susceptible to viruses and bacterial infections.

PREVENTING REJECTION: A new treatment being studied is showing promising results: preventing rejection without the need for immune-suppressing drugs. The treatment involves weakening the patient's immune system, then administering bone marrow from the donor along with the organ. When the patient's immune system reforms, it does so with the presence of both host and donor bone marrow cells, which teaches the immune system that both host and donor are "self."


In one experiment, four out of five kidney recipients were off immune-suppressing drugs up to five years later. The study involved five people who received kidneys from parents or siblings who had slightly different tissue types from the patients. Since many kidney transplant recipients and donors are similarly mismatched, there is hope more people might one day be spared from taking immune-suppressing drugs.


Researchers involved in the study say the next step is to take this trial to a larger population. They are also working on a procedure called xenotransplantation, the transplantation of organs from an animal to a human; in particular from a pig.   

 

David H. Sachs, M.D., an immunologist at Massachusetts General Hospital and a professor of surgery at Harvard School of Medicine in Boston, explains how a new discovery is making it easier for patients to tolerate a transplanted organ.



What does your recent discovery mean for transplant patients?


Dr. Sachs: The exciting thing about this new study is that it shows that we can fool the immune system, so to speak, into thinking that the transplant is self and therefore, the patient doesn't need to take immunosuppressive drugs to prevent rejection. There is no rejection because the transplant is considered by the immune system as part of the patient's own body.


How did this new method come about?


Dr. Sachs: The process is what we call immunologic tolerance and that means not reacting to -- not rejecting the tissue. The goal of being able to induce tolerance to transplants has been a goal of transplant immunologists for many years. It was shown first in animal models, first in mice and then in larger animals. And it's only recently that we have been able to take it to the clinic.


How did you come up with the idea to transplant bone marrow?


Dr. Sachs: It has been known for quite a few years that if the patient receives a bone marrow transplant for leukemia or lymphoma, and receives the bone marrow from a sibling, in general, it is very well matched. Then, if that same patient needs a kidney transplant years later and assuming the patient has remained on good enough terms with the sibling that gave the bone marrow originally, you don't need to use any immunosuppressive drugs. So we already know that bone marrow transplants, when successful, carry with them tolerance to any other tissue or organ from that same donor.


What do you mean by tolerance?


Dr. Sachs: Tolerance is the absence of rejection without exogenous immunosuppression -- that is without requiring drugs. So tolerance is acceptance of a tissue without the need for immunosuppressive drugs.


What is it about the bone marrow that allows that to happen?


Dr. Sachs: Well, all of us are continuingly making immune cells that can react against our own tissues. If something goes wrong, those cells will cause what we call autoimmunity or autoimmune disease. But in general any cell that reacts against self-antigens is eliminated in the thymus and it's eliminated by a process called negative selection. That process is based on the activity of cells from the bone marrow. So if there is bone marrow from both the recipient and the donor, then any new immune cell that forms that can react against either the donor or the recipient will be eliminated and what will be left is an immune system that is normal in every other respect, but it cannot react against the donor or the recipient.


By adding the bone marrow transplant, in essence what are you doing?


Dr. Sachs: First we have to eliminate the immune system that is already there and let it reform, but when the immune system reforms, it does so in the presence of both host and donor bone marrow cells and that is what teaches the immune system that both host and donor are self.


What precautions typically need to be taken to make sure a transplanted organ isn't rejected?


Dr. Sachs: In general, all the progress that has been made in the field of transplantation over the past several decades has relied on immunosuppressive drugs. Now these drugs are wonderful, they prevent the rejection of a transplant and allow people to resume a relatively normal life, but they all have side effects. They cause complications that are sometimes quite severe and in general if you have to take immunosuppression for the rest of your life then you have a much lower ability to fight infections and sometimes cancer.


As a doctor how do you feel knowing how successful it has been?


Dr. Sachs: Well, I think this procedure is not simple. It's a lot harder at the beginning than just taking an immunosuppressive drug to prevent rejection, but I think what you're doing is trading an initial harder procedure for a lifetime without having to take those immunosuppressive drugs.


From a personal point of view, how does it make you feel to know so many patients are doing so well?


Dr. Sachs: Well, it makes our whole team feel wonderful to see the success and to see these patients returning to a normal life. In particular some of these patients say this is the first time they've actually been normal since they had their disease.


How does it change a patient's life when they're not on immunosuppressive drugs?


Dr. Sachs: The same immunosuppressive drugs that have kept people alive with the transplant also have caused problems. Everybody has a weaker immune system and therefore, is more susceptible to infection, to viral or to bacterial infections, as well as to cancer. But in addition, different patients have different side effects from these drugs and some of them have renal failure, some complain of warts, some of them will have problems with loss of bone. It depends on the drug and it depends on the patient, but none of these drugs are without side effects.


Explain to me what happens during a bone marrow transplant?


Dr. Sachs: The reason the procedure is more difficult up front is that we have to eliminate the existing immune system first in order to train the new immune system to consider the donor as self. During that period between eliminating the mature cells that were already there and new cells forming, the patient is quite susceptible to infections for a couple of weeks. We keep the patients in a very clean environment to be sure they don't get infections, and we haven't had any problem with infections, but that's probably the most difficult part of the procedure.


Do you do the kidney transplant before the bone marrow transplant?


Dr. Sachs: No, we do them at the same time.


Do you have two different teams of doctors?


Dr. Sachs: That's right.


What does the process involve?


Dr. Sachs: Well, first what we do is give an antibody that eliminates the cells of the immune system that otherwise would reject the donor cells. Then we give bone marrow at the same time as the kidney, from the same donor. There are still host stem cells in that recipient, since we haven't eliminated all of the cells, just the mature cells. So new cells form from the recipient that now react against both host and donor cells as though they were self.


So it's almost like a third party cell, is that right because you're mixing them?


Dr. Sachs: We are all tolerant of our own tissues. We don't react against our own self. Why is that? That's because as T cells form in the thymus that can react against self, they are eliminated, because they react with a cell from the bone marrow that eliminates any cell that reacts strongly to self. If we have bone marrow from both recipient and donor, then any new T cell that forms that reacts either to self or to donor will be eliminated. So we are left with all the cells that can react against other problem antigens like bacteria and viruses, but none that react against either the host or the donor.


What's next for this research?


Dr. Sachs: This is only a small study. It's really just the beginning, just four of the first five patients who have now become tolerant of their kidneys. We have to treat more patients to be sure this is reproducible and we would like to extend the procedure to other organs, not just to the kidney. Eventually, even if this works really well and works for other organs, it will solve some of the problems that we have in transplantation today with regard to the quality of life of the patients, but it won't do anything for the fact that we've run out of donor organs. We just don't have enough to save the lives of all the people whose lives could be saved with a transplant. So we are hoping that this kind of procedure may also some day be used for xenotransplantation; that is the transplantation of organs from an animal to a human, in particular from the pig.


How would that work?


Dr. Sachs: Well, we've been working on special pigs that are exactly the same size as humans and have genetics that are very similar to humans with regard to transplantation. So we are hoping that eventually we'll be able to use this procedure there too. Now you have to remember that if you're going to cross a species, the immune reaction is even greater. So the idea of tolerance, of eliminating the immune response, will even be more important than for human transplants because that way we won't have to give much greater amounts of immunosuppressive drugs. I think that is the long term future for this field, and its also something we're working on.


http://www.krcgonline.com/news/news_story.aspx?id=179221

[stauffenberg]

He conveniently 'forgets' to mention lethal graft-versus-host disease which can result from this procedure, but then again, what scientist wants to spoil his own party?

[Wallyz]

potential gvh vs. potential rejection- interesting discussion possible there.

[pelagia]

He conveniently 'forgets' to mention lethal graft-versus-host disease which can result from this procedure, but then again, what scientist wants to spoil his own party?

No research, no progress. 

[Zach]

Many medical scientists are utter nerds, who waste research money on entertaining their curiosity with minor theoretical problems related to the disease which have no relation to a potential cure.  Other researchers are lazy time-servers, who research and publish in the most conservative, unimaginative, repetitious way they can, because this is the easiest way to ensure publication, grant money, a Ph.D., and university promotion, given that everyone regards imaginative and revolutionary thinkers as suspect.

I guess you're wrong, again.

[stauffenberg]

On the contrary, I think the opening research report of this thread proves my theory correct.  Since everyone who graduates from medical school knows that graft-versus-host disease would make this entire line of research pointless for curing anyone of anything, only a science nerd wasting precious research funds to sustain his playing around in lab would come out with anything like this 'spectacular result.'

[pelagia]

It just so happens that one of Sachs' research interests is "prevention of graft versus host disease."  By the way, Sachs, who is the director of the Transplant Biology Research Center at Mass General, is a medical doctor.  The Center is "a multi-disciplinary research group working at the interface between basic science and clinical applications in transplantation immunology."  Oh and he's on the faculty of Harvard University, too.  I think I'll take his word on the subject for now.

http://www.mghtbrc.org/about/education.html
http://www.mghtbrc.org/index.html

[Zach]

I think I'll take his word on the subject for now.

But stauffenberg's theories are always correct.
 

[pelagia]

And here's just a little more from Dr. Sachs' website:

"Dr. Sachs has published over 650 articles in scientific journals. His research achievements include: 1) discovery of Ia (Class II) antigens in 1973; 2) development of monoclonal anti-bodies to MHC antigens; 3) development of a unique large animal model for transplantation using miniature swine; 4) use of mixed marrow reconstitution as a means of inducing specific transplantation tolerance; and 5) studies of specific transplantation tolerance to allografts and xenografts in murine, swine and primate models. Dr. Sachs is a member of the Editorial Board of several journals in his field, including: The Journal of Experimental Medicine, Immunological Reviews, Bone Marrow Transplantation and Clinical Transplantation, and is Editor of Transplantation and founding Editor of Xenotransplantation."

I put the bold in for emphasis.  The Class II antigens include DR, which is one of the most important antigens for determining compatibility between donor and recipient.  I'm willing to trust this fellow with my tax dollars.

http://www.mghtbrc.org/about/staff_sachs.html

[stauffenberg]

If 99% of the M.D.s working in medical research were not simply research nerds idly entertaining themselves forever in their labs without producing any useful results, do you think that the central problem of renal patients today would still be the same as it was in 1942, which is that dialysis is a terrible form of treatment?  Or that transplant patients are still in the same situation today as they started out in back in 1954, which is that the drugs that have to be taken to prevent rejection are toxic?  How much progress has there been in treating diabetic since Banting and Best developed insulin in 1922 and openly admitted that it was a pitifully inadequate way to treat the disease?  The dialysis machine was also recognized as inadequate when it was first developed, which was way back at the same time the Germans developed the world's first military jet.  Now we are more than 30 years past sending a man to the Moon and back in aerospace science, and we are still stuck with dialysis in renal medicine and with muliple daily insulin injections in diabetes medicine, a treatment developed five years before Lindburgh flew across the Atlantic.  Name a single major disease that has been cured since polio was effectively eliminated as a threat to health a half a century ago.  There has not been a single one!  Recently even the ultra-conservative FDA issued a panic bulletin because the number of new patents being issued in medicine is starting to decline for the first time in history, and even most of the patents granted over the last 20 years are just minor tinkerings with existing treatments to get around some other corporation's patent protection.  Medicine is stagnating, and the inertia is due to exactly the sort of 'going nowhere' science posted in this news thread.  If you don't believe me, just do some research on graft-versus-host disease, which affects even identical twins.

As for all the credentials the good doctor has for himself, they simply prove he belongs to the nerd's treehouse club for boys, since they are awarded by others of his type.  They don't impress me because see them every day where I work.  If you gave the average medical research scientist a model of a doorknob and a schematic diagram of it, it would take him a century to re-invent it.

As for his long list of publications, that is also utterly meaningless, since everyone in the lab, even the person who makes the cup of coffee and says "Golly gee Dr. X, how did you get to be so smart?" gets his or her name on every piddly publication, no matter how short or trivial it may be.  I have read medical journal articles two pages in length but with eight author names on them.

[Zach]

Here we go again.

[okarol]

Earlier this year this story came out. It has more info about the 5 patients who were transplanted.

Rejecting defeat
Scientist triumphs after setback in kidney transplant method

By Patricia Wen, Globe Staff  |  January 24, 2008

Dr. David H. Sachs was full of optimism when the third patient in his $1 million study was wheeled into the recovery room at Massachusetts General Hospital after an experimental kidney transplant.

The first two patients had thrived, adding credibility to an unorthodox idea that Sachs had pioneered over his career, that transplanting a donor's bone marrow along with the kidney could solve the problem of organ rejection, sparing patients a lifetime of powerful antirejection drugs.

But 10 days after the third patient's surgery, Sachs's phone rang at his spacious lab overlooking Boston Harbor. A colleague reported that William Andrews, a 43-year-old father of two, was rejecting the kidney.

Sachs and his research team remember the darkness of the ensuing months in 2003, when they abruptly suspended their transplants for nearly two years. Andrews was demoralized and on dialysis, his sister's donated kidney seemingly wasted. Over and over, Sachs paced the corridors of his lab asking himself, "What did we miss?"

Today, capping a comeback from the crisis, Sachs and his team are reporting that they unraveled the explanation for Andrews's rejection. After they tweaked their protocol, adding a drug to avert what happened to Andrews, two new patients have thrived without the long-term need for antirejection drugs, according to a paper published in the New England Journal of Medicine.

Overall, four of Sachs's five patients have experienced no organ rejection, a particularly striking accomplishment because they all received kidneys that were different from their own tissue type. Transplants of such mismatched organs are the most common and the most likely to be rejected, even when patients take immunosuppressive drugs.

"I had confidence we would figure it out," said the 66-year-old Harvard Medical School professor, who has dedicated more than three decades to conquering organ rejection. He said the results restored his faith that his once-radical idea will eventually become mainstream, making organ transplants safer and more available.

Transplant surgeons said Sachs's study represents a pivotal moment in organ transplantation, demonstrating that it is feasible to eliminate immunosuppressive drugs with their debilitating side effects, such as skin warts, cataracts, and increased risks of heart disease, diabetes, and serious infections. If the results are borne out in a larger group of patients, the Mass. General technique has the potential to help transplant recipients live longer. Within 10 years, half of all transplanted organs fail because of chronic rejection, a bleak predicament in this era of organ shortages.

"This is landmark work," said Dr. Joshua Miller, an organ transplant researcher at Northwestern University's Feinberg School of Medicine in Chicago.

Other researchers cautioned that only the healthiest patients may be able to endure the rigorous treatments, including chemotherapy and radiation, that precede the transplant.

Andrews said that going through the experimental protocol was not easy and that being an example of a failed case was even harder. But he sees his difficult experience as a contribution to medical research, saying how impressed he was that the Mass. General staff worked tirelessly on his case.

"They did not want to accept defeat," said Andrews, who ultimately received a replacement kidney in 2004 using conventional treatment with antirejection drugs.

Sachs is no stranger to the emotional roller coaster of experimental medicine and the intellectual nimbleness required to overcome setbacks. Since he was a young Harvard medical student in the mid-1960s, hearing his first lecture on organ transplantation, Sachs has set out to tackle "the most important problem that could be solved." In his mind, that was the persistent problem of organ rejection.

Sachs, director of the Transplantation Biology Research Center at Mass. General, had faith that a donor's bone marrow, from which immune cells originate, could play a pivotal role in giving transplant patients "induced tolerance" to a donated organ.

Under Sachs's approach, five days prior to transplant surgery, patients begin to undergo low-dose chemotherapy to kill off some of their marrow cells and make room for injection of the donor's bone marrow.

The patients also receive a drug and radiation to the thymus to eliminate a type of immune system cell, known as a T cell, that typically attacks any tissue perceived as foreign.

On the day of the procedure, surgeons attach the new kidney while injecting the donor's bone marrow into a blood vessel in the patient's arm. The donor's bone marrow mixes with the patient's, creating a temporary state called mixed chimerism. This tricks the patient's immune system into recognizing for years - and possibly forever - the donated organ as part of the self.

After the surgery, the immune system is still in a period of adjustment, and doctors give patients antirejection drugs that are gradually tapered off. Most patients were off the drugs by the ninth month.

Sachs first tried this approach successfully on mice, pigs, then monkeys. In 1998, he won approval to try his treatment on a select group of Mass. General patients with severe kidney failure, all of whom were offered matching kidneys from close relatives. When these six patients did well, Sachs moved on to the most ambitious test of his method, trying it out on patients with mismatched donors.

Starting in 2002, the method worked nearly flawlessly on Jennifer Searl, 28, a librarian from Peabody, and Christopher McMahon, 26, a retail store manager from Tewskbury.

Sachs and his colleagues felt something close to restrained euphoria. At a New Year's Eve party in 2002, Sachs and the chief surgeon on the research team, Dr. Benedict Cosimi, who share a small boat that they years ago named "Tolerance," gave a toast to the initial success of the experiment.

Then in October 2003, Andrews, a software engineer with polycystic kidney disease, went in for his experimental procedure. When the surgery was complete, spirits were high.

"Everybody thought it was a success," Andrews recalled.

But within two weeks of the surgery, Dr. Tatsuo Kawai, one of Sach's research colleagues, was handed test results showing that Andrews's urine output had dropped and that his blood contained high levels of toxins. An ultrasound scan showed the new organ was losing blood flow.

"The kidney's rejecting," Kawai remembered saying to himself.

He phoned Sachs, who was in his lab at one of Mass. General's research facilities in the Charlestown Navy Yard, with the news.

"It hurt," Sachs recalled. "You want to see everyone succeed."

For several months, Sachs and his team tried various drugs on Andrews, hoping to reverse the rejection. But by spring 2004, doctors began dialysis, conceding defeat in saving Andrews's new kidney. Because of the failure, Andrews was no longer eligible for another try with the experimental treatment.

The outcome for Andrews hit everyone on the research team hard.

"It was the lowest moment," Sachs recalled.

He said these studies put "people's lives in your hands" and are full of unpredictability.

Sachs and his dozen colleagues on the project began brainstorming about what went wrong, trying to salvage a lesson, if not Andrews's kidney. After intensive study, they concluded that another type of immune cell, the B cells, played a critical role in his organ rejection. They theorized that Andrews's body harbored B cells that ultimately produced antibodies against his sister's kidney, a scenario they did not anticipate because B cells had played no role in organ rejection in any of their previous studies.

To prevent rejection in new cases, the team revised the protocol to give all patients a drug prior to surgery that depletes B cells. Before they could proceed with the study, they had to win approvals from several regulatory agencies, which ensure patient safety.

Meanwhile, Sachs was delighted when he heard that Andrews's cousin had stepped forward to offer a kidney.

In August 2004, that conventional transplant surgery went smoothly, and Andrews went back to work "feeling great," while accepting his fate of being on antirejection drugs.

By 2005, the regulatory agencies approved the revised plan. In February 2005, surgeons operated on Derek Besenfelder, 28, a communications specialist from Los Angeles, and then in January 2006, they did transplant surgery on Matthew Knowles, 48, of Marshfield. Both have returned to their normal lives.

"I'm in perfect health," said Knowles, a supervisor for a gas company. "I don't take a pill a day. It's a miracle."

The four successful transplant patients have so far lived between 15 months and nearly five years without antirejection drugs.

Other researchers are also experimenting with ways to create permanent tolerance to donated organs, using slightly different approaches. Today's New England Journal includes two case studies from these other groups.

Sachs hopes to expand the study to include 20 new patients with mismatched donors. His greatest hope is that someday his novel treatment will extend to other organs.

"It's a wonderful feeling when you see people returning to their normal lives," he said.

Patricia Wen can be reached at wen@globe.com.

http://www.boston.com/news/local/articles/2008/01/24/rejecting_defeat/  GRAPHICS BELOW

[pelagia]

If only someone could get Stauffenberg to use his energy and smarts to work on a cure...

[Wallyz]

I think that the field needs better critics.  There is little accountability in many research fields outside of "Publish or Perish".  The JDRF has been a tool of the strip manufactuers for years, and are still fighing the use of CGM's even though the trials show that it works 2006, you knew it works you had a big trial, and are still fighting the manufacturers?

Stauffenberg appears to be treated as a kook, but when we accept that large companies, and large institutions get to dictate to us what gets funded, and we are uncritical and unvocal, we will get steamrolled.

I would encourage you guys to look at his information and past his curmudgeiosity  (is that  a word? it is now) and dig as deep as he does into the issues.

[pelagia]

Little accountability?  When was the last time you tried getting a paper published in a high quality journal or research funding?  The peer-review system used by the scientific community is not perfect, but it's pretty darn good (remember what Churchill said about democracy? - see below).  The same can be said for most of the systems that govern the working lives of scientists.  Should we strive for ever more accountability in the system? - sure, but we also need to be careful to ensure that we leave a little room for "risky research" which might open new frontiers.

As a research scientist at a major university for the last 20 years, and someone who has successfully competed for over $3 million in federally-funded research and science education programs, I can assure you that I know how to dig deeply on an issue.  While I am not trained in the medical field, I appreciate the insights and information we get from those who are.  But, I am also highly wary of those who repeatedly take very negative positions on virtually everything having to do with research.  That tells me that their minds are not open and their assessments could be biased.  The very best scientists I know are, in fact, very "critical" in their thinking, but they are not "negative." There's a difference.

I will repeat my stance - no research, no progress.

I think this is a most interesting thread in which to have this discussion because it highlights my points.  Some can not even give Sachs the credit he deserves. 

"Many forms of Government have been tried and will be tried in this world of sin and woe. No one pretends that democracy is perfect or all-wise. Indeed, it has been said that democracy is the worst form of government except all those other forms that have been tried from time to time."  -Winston Churchill

[pelagia]

Addendum -

I also want to add that when someone mixes science or medical research findings in with a strongly held personal position based on personal beliefs, they are crossing a line from science or medicine to advocacy.  There is nothing wrong with advocacy, but it is important to recognize it for what it is.