weaning off anti-rejection drugs?

Hi, I found these new studies interesting and have a question.

we know the reason studies are going on is because the average TP lasts only 5-10 years....much of that due to the SOC rejection drugs.

what I find fascinating is why they think now folks can be weaned off!!

Is it because of cell division being affected by bone marrow stem cells?
In other words, when a liver cell does normal cell division, doesn't it just replicate the donor cell..but as more of the patients stem cells filter to the liver, over time does the liver turn over, or revert to more tissue of the recipients type?

I don't know the answer here, whether the immune system itself becomes more settled with donor tissue, or whether the tissue is changing.

that's why I'm asking. Does anyone know anything about this?  It would be really good news if this was part of it...especially for younger TP people.
mb

[merryBe]

foo....too tired to be posting

http://www.clinicaltrials.gov/ct2/show/NCT00135694?term=hcv&state1=NA%3AUS%3AWA&rank=16

this study also has a european arm, in Spain, but it seems the antirejection drugs increase the rate of destruction HCV causes in the new liver, so this is one study we may all wish to keep an eye on.

[mikesimon]

You said: "we know the reason studies are going on is because the average TP lasts only 5-10 years....much of that due to the SOC rejection drugs."

Before I take time to read the rest of your post where did you get this number - 5 - 10 years? And are you referring to organs in general, the liver, kidney, pancreas, small intestine, heart or what?

Mike

[IAmTheWalrus]

Thanks for the post. The study looks interesting. My AR drugs are toxic to the kidneys.

I have the same question as Mike has though. I was hoping, with regular oil changes, to get a few more miles out of mine?  :)

Brent

[mikesimon]

Operational Tolerance after Liver Transplantation

Last updated: 07 April 2008
Category: No Domain > No Category Assigned
authors Dr George Mazariegos
Synopsis
-

Sporadic clinical transplant tolerance has been achieved following solid organ transplantation, most commonly after liver transplantation. Operational tolerance, defined as long term (>12 month) freedom from all immunosuppression in patients with normal graft function was first seen in both non-compliant patients and patients withdrawn for emergent infectious or malignant indications ( 1, 2). Individual centers have also reported the ability to slowly wean patients from immunosuppression over time or emergently for specific indications after liver ( 3-5)   and kidney   ( 6,7) transplant.

For reasons that are unclear, patients transplanted as children have been more likely to achieve this operational tolerance than those transplanted as adults ( 3). Estimates of ability to wean immunosuppression successfully following liver transplant vary from 3-5% of cases ( 1).  In very carefully selected patient populations, up to 20% of patients may be potentially weaned ( 4). In live donor transplant populations, up to 15% of all patients may be successfully withdrawn from immunosuppressive medications ( 8, 9).   Long term follow-up of patients successfully withdrawn, however, is limited to individual center reports. The true incidence and ability to withdraw drugs after liver or other organ transplants is unknown as is the natural history of these patients after drug withdrawal.   A registry of these patients would allow better characterization of the natural history of drug withdrawal and help develop predictive clinical factors that favor drug withdrawal. Furthermore, this would facilitate entry of these patients into ongoing or developing trials of assay development. The development of predictive, reproducible assays ( 10) that can identify patients who may safely be withdrawn from immunosuppression or conversely identify those who require maintenance immunosuppression will be critical to minimizing long term morbidity and mortality in organ transplantation ( 11). Assays performed in this unique patient population, such as cytokine gene polymorphisms and dendritic cell subsets, have yielded encouraging but preliminary results ( 10, 12-14). Other centers have reported the importance of T regulatory cells as a potential mechanism in their tolerant patients and are identifying gene profiles associated with tolerance ( 8, 15).   The two largest single center experiences in drug withdrawal after solid organ transplantation are from Pittsburgh ( 4) and Kyoto ( 8, 9). The Pittsburgh experience has primarily focused on deceased donor transplantation. We currently follow 47 patients who have been withdrawn from immunosuppression after liver transplant by planned physician intervention (protocol), emergently due to infectious disease indications (mostly EBV or PTLD indications), as well as those who self-weaned medication but are still under medical supervision with laboratory assessments. As noted in Table 1 ( 4 ), most of these patients were children at the time of transplantation. Return to immunosuppression has been rare (1/48), no graft loss has occurred, and no chronic rejection has been documented. Mean time off immunosuppression is over 10 years in the prospectively weaned cohort.  

TABLE 1 Operationally tolerant liver transplant recipients University of Pittsburgh- long term follow-up (1992-2006)

Method of drug withdrawal
                                                    Protocol Emergent Non-Adherance
# Patients                                               28      13                6
Median Age at Tx (years)                       3.8      1.6                      11.4
Years from Tx to Wean                               5.7      3.13                     7.3
Years from Wean to drug cessation         2.2         N/A                 N/A
Mean Years off drugs currently                    10.8    11.7           17.1



The Kyoto group has documented 87 of 659 children (15%) who underwent live donor liver transplant between 1990 and May 2005 and have achieved complete withdrawal of immunosuppression ( 8).Taken in aggregate, predictive factors for successful drug withdrawal have included pediatric age at transplant, lack of autoimmune disease, and live donor transplant. A smaller cohort of 18 patients who underwent drug withdrawal at King’s College London England also demonstrated the positive predictive effect of non-auto-immune disease, as well as fewer donor-recipient HLA mismatches and low incidence of pre-weaning rejection history ( 16).

http://topics.scirus.com/Operational_Tolerance_after_Liver_Transplantation.html#

Mike

[mikesimon]

Sorry about the chart - I really wasn't trying to test your eye-mind coordination. I think you can handle it. Mike

[mikesimon]

Women Given Liver Transplants Outlive Male Recipients By Around 4 Years

ScienceDaily (Sep. 29, 2006) — Female liver transplant recipients outlive men given the same procedure by an average of 4.5 years, suggests research published ahead of print in Gut.


And while younger people tend to live longest of all, they also stand to lose more years of their life compared with those who have not had liver transplants, the research shows.

The research team assessed the life expectancy and years of life lost of 2702 people who had received a liver transplant between 1985 and 2003, and who had survived more than six months afterwards..

The information was taken from the National Transplant Database, held by UK Transplant, and compared with that from healthy people matched for age and sex.

The analysis showed that, on average, after reaching the critical six month period, survival time for liver transplant recipients was 22 years compared with 29 years for the general population.

The life expectancy of male liver transplant recipients was 18 years compared with 26 years for women.

This compares with 27 years for men and 31 years for women in the general population, equating to twice as many years of life lost for male transplant recipients compared with their female counterparts.

Those aged between 17 and 34 had the highest life expectancy of 28 years after a liver transplant. But this compares with a life expectancy of 51 years for their peers in the general population.

Transplant recipients with primary liver disease fared significantly better than those undergoing the procedure because of hepatitis C infection, cirrhosis, or cancer.

The authors note that while one year survival rates have increased over time, death rates beyond this period have remained more or less the same.

They attribute this to the types of patients undergoing the procedure, who now include older, sicker patients, as well as the use of more "marginal" livers.

[mikesimon]

Table I-4. Unadjusted
Organ Transplanted               1-Year Survival   5-Year Survival
Kidney
  Deceased donor                  94.8%                  80.6%
  Living donor                               98.0%                 90.3%
Pancreas alone                               96.7%                88.1%
Pancreas after kidney                 96.6%                  83.9%
Kidney-pancreas                  95.0%                   86.1%
Liver
  Deceased donor                  86.9%                73.6%
  Living donor                               90.6%               76.1%
Intestine                              81.0%                 53.6%
Heart                                         87.8%                  74.4%
Lung                                         84.0%                  52.6%
Heart-lung                            75.0%                49.7%

Source: 2007 OPTN/SRTR Annual Report, Table 1.13.

[Bill1954]

Thanks for the clarification, Mike; I’d previously heard short survival rates (i.e. 5 years) quoted for TP patients, but attributed that to age and existing co-morbidities. This gives a brighter, more accurate picture.

Now, according to the UK stats, when do you recommend I request the sex change operation… can I have that done concurrent with the TP :o)?

Williamina  

[mikesimon]

I like you just the way you are Bill.
I am 8 years out and I don't think I am unusual. I know several others from my class and they are alive and kicking. I know a guy who was on methadone for heroin addiction who was transplanted 1 week before I was and he cleared HCV and was alive in 2005 or maybe 2006. I haven't heard from him in a while but I believe he is still with us. I know a woman who was transplanted for Primary Sclerosing Cholangitis very close to the time I was and I know she's well - I spoke with her 2 weeks ago. I know of only one death and there were around 20 in my class. There is probably more deaths but I don't know for sure.
When you look at those numbers from my post you have to remember that HCC accounts for some of the transplants and the attendant mortality is not as good in that group. And from Elaine's perspective, very few of the recipients were in her Son's age group and, of course, generally all things being equal, the younger do better. While HCV does have its own set of problems and they are significant, I believe that treatment, even with the current SOC, is considered earlier than it has formerly been and it is pursued more aggressively which should improve the numbers in that subset. And, the PIs could dramatically improve things in terms of success and tolerability. My surgeon told me he was excited about Vertex for HCV patients as well as transplant recipients years ago - really excited. So overall I think the future is bright. I would guess you know where I am coming from and why I thought that blanket statement about mortality was not helpful in the least.
Mike

[Bill1954]

Hi Mike,

Ah, but will you still like me when I transgender.

Anytime I see a blanket statement I become suspicious; this applies to any subject, not just medical interests. Given a chance, this forum does an excellent job of dispelling false info and innuendo, as I’ve discovered the hard way myself many times over the last few years :o).

With the advances in TP medicine as well as viral management, Nick should be around to cause his mom problems for many, many years to come :o).

Thanks again for the data, and take good care, my friend—

Bill

[merryBe]

whew, well I stand happily corrected. I know it was some liver transplant site that had that info, but visiting 100 plus pages a day makes it hard to recall where I read that.
It may have been Janis site....some of the info there hasn't been updated in years I noticed....and I really have to watch that in pubmed also, sometimes thing 2 years old are already refuted.
Anyway, sorry if I alarmed anyone....that wasn't my goal. Very happy if that's misinformation for all our sakes!!

Now that you mention it, I don't recall them giving any clarification as to whether it was always directly due to liver failure either or the kidneys etc.

In any case it was months ago I read it...otherwise I'd try to retrace my steps for you.

The main question that would be intersting to discuss is whether the liver rebuilds our liver cells, or only donor type cells, and whether this is what makes weaning possible
AND is the weaning a good idea
because obviously whether the liver or kidneys fail as a result of the AR drugs, the end result is the same, and not the desired effect.

I would imagine the whole concept of weaning would be of interest to all liver TP patients and that a lot of thought would go into whether to participate in it BEFORE any damge is done to say the heart or kidneys.
Weighing how one might treat ahead of an event could prove productive.

anyway, I was mainly
just wondering if anyone knows how the cell division really stacks up...
like how much does the liver tissue change over time, if at all...or does it forever remain entirely the donors tissue type in spite of our own stem cells migrating there to repair tissue.
I guess what I'm wondering is, if our stem cells contain our own RNA/DNA then why wouldn't the liver eventually become our own and have no, or less rejection issues?
If this is not the case, then weaning would be feasible because of what other premises?
mb

[merryBe]

also, I think your article kind of backs up my ruminations since children have more stemcell production, perhaps this is why they have the higher rate of operation tolerance?

>>>>>>>>For reasons that are unclear, patients transplanted as children have been more likely to achieve this operational tolerance than those transplanted as adults

and of course, then you see where I'm going to go with it (being it's me) is that in the absence of liver stem cell grafting (which is being researched as we speak) then wouldn't marrow stem cell stimulation via the hormone HGH be a logical progression for an interim treatment strategy until stem cell/test tube liver tissue can be achieved?
mb

[merryBe]

this article shows why I have the concern. Note the rate of increase of 528% expected in the not too distance future for livers.

http://www.wikio.com/article/51674747

this is part of why the whole stem cell/regeneration and weaning concept has me going....it's knowing that with each year the demand will far exceed the supply.
In the US I read the odds are already plummeting, so those numbers mean another way
to regenerate and keep those already transplanted going need to be of top priority.

[IAmTheWalrus]

MerryB - A very astute observation about the greater need to maximize the benefit (longevity) of the scarce donor organs. I wish I knew the answer to your question about why weaning is possible, It is of interest to me. I have been on an extremely low dose of just one AR drug (UND in serum at one point). A sort of "unplanned weaning", if you will. I did have some issues that seemed to be solved by increasing the dosage, but it makes me wonder if the weaning was done per protocol (more gradually), it would be successful in me.  Something I will be thinking about, but not sure I would want to risk.

Mike/Bill - Great reports. I don't know as many post TP patients as you do, but the one I know personally was transplanted over 22 years ago in Omaha. He is in his 70's now and still plays and teaches competetive tennis. I guess I'll keep changing the oil!

[mikesimon]

I didn't really explain that adequately.
My surgeon believed that my enzymes started to soar as a result of my immune system attacking the little bit of HCV in my liver. His opinion was that when my  my anti-rejection drugs were reduced (I was taking a small dose every other day instead of every day) my immune system became stimulated and whereas before it ignored the little HCV in my liver when it became stimulated - awakened, if you will - it attacked the HCV. As we know, when there is an immune response like this there can be, and often is, collateral damage - bystander cells get destroyed along with the infected cells - and that accounted for my escalating enzymes. He said to me regarding HCV in transplant SVRs - "maybe a little HCV is good for you" speculating that when there is no detectable trace of HCV for the immune system to keep an eye on it looks around and sees the liver and says "does that belong here - I don't think so and then we get rejection". That is a silly way to try and conceptualize it but I don't understand  the science so, that is how I visualize this phenomenon. I think of it as a truce or a balance between the HCV and the immune system. I don't know whether this is even close to the true story of what is going on here. I do know what happened to me and this is the only way I can even pretend to understand it.
Mike

[merryBe]

well I can see it is highly complex...and I worried about the risk also, maybe you can ask your doc about the stem cell part?

As to Elaine,
I really hadn't known or conversed, not having been in here much for the last 3 months, since the surgury, so didn't even know about what elaine was going through. I know now.
Never would I try to upset her or anyone......actually I myself got very upset when I read that figure, and only posted here hoping those numbers weren't accurate...praying there was more hope on the horizon for us all. Hence the research into it.
In any case, sorry Elaine if it gave you any consternation.

One thought occurred to me is that the averages, whichever numbers we believe, are based on the overall populace. they may take into account every fatality, and the fact that most are given to older folk plays a role in eventual outcome. The avagaes are probably going up every year with new meds and improved surgical procedures etc.
I also think since protocol is now not to give them to alcoholics, that this will also improve the munbers if they aren't already reflected therein.
mb

[merryBe]

The numbers made me think everyone would want to know what was being done about it to prolong positive outcomes.
I truly did not know that anyone in here was awaiting transplant.
In fact I only discovered the transplant forum was even here 2 wks ago,

Plus Elaine, I just lost a dear friend of 30 years, who because of rejections had to have not one but 3 transplants. She was a real fighter but her troubles with AR drugs were very real.
So I'm just trying to figure out how to help us all, and those like Valerie, whose loss was great to many in our town and neighborhood..

Here's what I was asking in a nut shell. Each of us has stem cells in our bone marrow.
These cells come out, migrate to the liver, and help make new liver cells as they are needed. In other words the liver does not rely on cell division alone, but on stem cell migration regeneration. It replaces all it's tissue in 1 1/2 years, unlike any other body part....so I was trying to get my mind around how does the new liver look on the genetic level.

My question therefore is, do the new cells take on the nature of the host (you,me, or Nick) or do they become identical to the donor tissue alaways, or both.
Secondly the question is how does this effect the weaning process. In other words, is the liver changing over time to our DNA profile what makes weaning possible, or is it purely the adjustment of the immune system alone that makes it possible.
If more of the cells become like our own, then in theory, over time there would be no immune response because there would be no long term foreign tissue.

However, after reading Mikes response, it seems more complex than that. Since years afterwards one might still have an immune response.  (like who would have thought a doctor would say "a little HCV may be good for you" ...but indeed he was saying maybe if the immune system is focusing on one problem it ignors others.
This makes a kind of real oddball sense though, and may also explain part of why people get backlash autoimmune disease when tx is successful and over. The immune system is used to having something to fight, and  can turn on its own tissue with no immediate enemy in sight.

In any event, I would not worry yourself about any of this, There are lots of good tests to monitor even slight rejection setting in, and I'm sure Nick will be well looked after.
take  care
mb

[MsJonesInCO]

Hello - I am an 8-year kidney transplant recipient and very thankful to my cadaver kidney!  Has anyone lowered their dosage of anti-rejection drugs, or gone completely without?  Dr. Thomas Starzel (one of the inventors of the anti-rej drugs) started taking his patients off the drugs and they lived long, prosperous lives; Dr. Starzel has passed on.  Now there is that "doctor - pharmaceutical relationship" which motivates doctors with incentives - ahem.  With the cost of the drugs zooming ... I'm currently unemployed and looking ... I wondered if I might try minimizing dosages to prolong the drugs I get (btw - have to get them thru Canada now - since the last president changed the law from "Medicare helps cover the cost of anti-rej drugs "for the life of the transplanted organ" to .. "we've got ya covered, under Medicare, for only 3 years now.")  The U.S. gov't thinks they are saving money?  I know people who are completely off the meds - so they can get back on dialysis - which medicare covers; it's a lot more than anti-rejection drugs!  Go figure.  After one month of no drugs - my labs were still within normal range.  I just don't have an extra few grand laying around to get the drugs!  I have been retaining fluids - and have gained 5 lbs since I "haven't" been taking Cellcept ... (I am taking the prograf and prednisone).  Does the creatinine continue to climb?  (1.5 now) ... I am waiting to get Cellcept from Canada .. just takes a lot longer than I thought - first time around.  Thank you for your forum - I look forward to all replies - is Mr. Simon a doctor?  A transplant recipient?  Just curious.  Thank you all in advance.  Ms. Jones

[grendslori]

I wish you guys all well if this works for the kidney and liver; it sure doesn't work for the heart this way. The 5 year survival was what given to heart transplant patients several years ago and is still the marker point for the development of a type of coronary artery disease and vascolopathay which affects ALL heart transplant patients at a much faster rate than the general public. Many of the drugs given also destroy the kidneys over time. If one dose of the AR drugs is missed, they should be given IV because the blood levels drop that quickly so it would be impossible to wean people off of the AR drugs.  

[mikesimon]

Doctor Thomas Starzl did not pass on. He is alive and appears healthy.

"Retired from clinical and surgical service since 1991, Dr. Starzl now devotes his time to research endeavors and remains active as professor of surgery at the University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center’s (UPMC) program named in his honor: the Thomas E. Starzl Transplantation Institute. Since his “retirement,” he has earned the additional distinctions of being one of the most prolific scientists in the world as well as the most cited scientist in the field of clinical medicine.[9]..."
http://en.wikipedia.org/wiki/Thomas_E._Starzl

I am not in the medical field in any capacity.
I received a liver transplant in June 2000 at the Thomas E Starzl Transplantation Institute

I wish you luck but I do think you are putting yourself at risk if you are not being closely monitored by a transplant physician.

Mike

[mikesimon]

I stated back in June, 2008:

"....My surgeon believed that my enzymes started to soar as a result of my immune system attacking the little bit of HCV in my liver. His opinion was that when my  my anti-rejection drugs were reduced (I was taking a small dose every other day instead of every day) my immune system became stimulated and whereas before it ignored the little HCV in my liver when it became stimulated - awakened, if you will - it attacked the HCV....."

About a year ago I got additional information regarding my biopsy and, regarding what my surgeon believed, I think he was wrong. I believe that I was experiencing a minor component of acute organ rejection brought on by the decrease in my anti-rejection meds - the weening off attempt. I won't bore you with the details but if I had to bet my life I would bet that what I experienced was organ rejection and not an immune response to a little bit of hepatitis c.

Mike