Calcineurin-Inhibitor Withdrawal May Improve Renal Allograft Outcomes

[xtrememoosetrax]

Calcineurin-Inhibitor Withdrawal May Improve Renal Allograft Outcomes
By Charles Bankhead, Staff Writer, MedPage Today
Published: June 19, 2008
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco 

RESEARCH TRIANGLE PARK, N.C., June 19 -- Following kidney transplantation, a planned phase out of a calcineurin inhibitor from sirolimus (Rapamune)-based immunosuppression improves outcomes and reduces costs, a statistical model suggested.

Calcineurin-inhibitor withdrawal and continuation of sirolimus plus steroids improved survival and reduced graft loss, compared with immunosuppression containing a calcineurin inhibitor, Stephanie R. Earnshaw, Ph.D., of RTI Health Solutions here, and colleagues reported online in the Journal of the American Society of Nephrology.

"The model suggests that treatment with sirolimus plus steroids is more efficacious and less costly than regimens consisting of a calcineurin inhibitor, mycophenolate mofetil (Cellcept), and steroids," the authors concluded.

"Calcineuri-inhibitor withdrawal not only shows potential for long-term clinical benefits but also is expected to be cost-saving over a patient's life compared with the most commonly prescribed calcineurin inhibitor-containing regimens."

Immunosuppression regimens associated with good short-term survival might not lead to high long-term survival after kidney transplantation. Consequently, immunosuppression should be modified over time to optimize short- and long-term outcomes, the authors said.

Calcineurin inhibitor-withdrawal regimens have been evaluated in adult renal allograft recipients as a means of mitigating long-term nephrotoxicity associated with the drug class. Sirolimus is the only immunosuppressive agent approved for calcineurin-inhibitor withdrawal.

The combination of sirolimus and steroids offers a mixed bag of potential advantages and disadvantages, the authors continued. The combination may increase the risk of acute rejection during the first year and cause dyslipidemia. On the other hand, the regimen is associated with lower blood pressure and better graft survival. The sirolimus-steroids regimen leads to a cumulative incidence of acute rejection similar to that of other regimens.

To examine the impact of calcineurin-inhibitor withdrawal on costs and life expectancy, Dr. Earnshaw and colleagues created a lifetime Markov model. The modeling allowed them to compare the cost-effectiveness of sirolimus-based calcineurin-inhibitor withdrawal with that of other commonly used calcineurin inhibitor-containing regimens.

Long-term graft survival was estimated by renal function, and the model incorporated published data on long- and short-term outcomes, utility weights, and health-state costs. Drug costs were based on average daily consumption and wholesale acquisition costs.

The researchers assumed calcineurin-inhibitor withdrawal would result in a one-year rate of acute rejection of 21.8% versus 19% with a cyclosporine-mycophenolate mofetil/steroids regimen and 17.1% for a regimen consisting of tacrolimus (Prograf), mycophenolate mofetil, and steroids.

The investigators found that the sirolimus-steroids regimen was associated with a lower rate of lifetime graft loss per patient, 0.90 versus 0.94 with the cyclosporine regimen and 0.92 with the tacrolimus regimen. The calculations suggested a slightly longer patient survival with calcineurin-inhibitor (CNI) withdrawal, 11.43 years versus 11.37 years with cyclosporine, and 11.13 years with tacrolimus.

Estimated total lifetime costs were $472,799 with the sirolimus-steroids regimen, $484,020 with cyclosporine, and $505,420 with tacrolimus. The sirolimus regimen was associated with lower drug costs and lower total medical costs.

"Despite the potential reduced benefit of preventing early acute rejection associated with the CNI withdrawal regimen, we observed overall improved long-term patient and graft survival," the authors wrote. "In addition, the model demonstrated that the CNI withdrawal regimen was cost saving . . . because of the long-term benefit through improved renal function."

The study was funded by Wyeth Pharmaceuticals.

Co-author Reiko Sato is a Wyeth employee. The remaining co-authors had no disclosures.

Primary source: Journal of the American Society of Nephrology
Source reference:
Earnshaw SR, et al "Lifetime cost-effectiveness of calcineurin inhibitor withdrawal after de novo renal transplantation"J Am Soc Nephrol 2008; DOI: 10.16181/ASN.2007040495.

Find this article at:
http://www.medpagetoday.com/Nephrology/KidneyTransplantation/tb/9881 

[pelagia]

How do folks in this forum feel about this sort of study, one that is funded by the company that makes the drug?  Are the drug company results generally consistent with independent studies?  Just curious.   

[pelagia]

Here's another article about sirolimus.  It caught my attention for a few reasons.  First they are talking about a possible way to improve long-term graft survival.  Although the focus is on non-complaint patients, it would seem that the results are generally applicable.  They used the ImmuKnow assay (see links below).  And it is an independently funded study (not drug company).  On the down-side, the article is discussing a presentation at a conference and it doesn't appear that the study has made it to the publication stage yet. (I added bolding in text below for emphasis in a couple of places)

for this article: http://health.ucsd.edu/news/2008/5-30-kidney-transplantation.htm
for ImmuKnow:  http://www.cylex.net/
http://www.transplantbuddies.org/tbx/messages/3/8952.html?1175214871

Date:   May 30, 2008
Drug May Prolong Organ Life in Non-Compliant Kidney Transplant Patients
UC San Diego Researchers Present Findings at American Transplant Congress

New research from the University of California, San Diego Department of Medicine, Division of Nephrology, shows that the anti-rejection drug sirolimus (brand name Rapamune) may help prolong the clinical benefit of transplanted kidneys and delay rejection, especially in patients who do not regularly take their prescribed medications (are “non-compliant”).  While the transplant field has been highly successful at reducing rejection and graft loss in the first year, post-transplant, reducing risk for graft rejection in the long-term has proved more difficult.

The findings are being presented at the 2008 American Transplant Congress (ATC), in Toronto on Saturday, May 31, 2008, by Cheri Ye, M.D., who was mentored by Robert Steiner, M.D., professor of medicine, and Director of Transplant Nephrology.

“No one is perfect at taking medications,” explained Steiner.  “But missing doses of immunosuppression, or not taking full doses each day, will bring about gradual rejection of kidney transplants that is almost impossible to detect in its early stages.  Long acting drugs like sirolimus may help with this problem.”

A team of five UC San Diego investigators reported a careful assessment of immune function at “trough” levels (lowest daily levels) of the three most commonly used immunosuppressive drugs, using an assay (ImmuKnow®/ Cylex) designed specifically to measure the degree of immunosuppression at any given time.  Lower “mitogenic response” meant better immunosuppression and more protection from rejection.  On average, the participants, 160 kidney transplant patients, were 6.4 years out from their transplant.

At these trough levels of drug in the blood stream, the assay demonstrated that sirolimus caused a significantly lower level of mitogenic response, and results appeared to be stable in individual patients over time.  “At least half of transplanted kidneys are lost through chronic graft rejection, usually within 10 years.  When patients do not have those rejection problems, they can go for 20 to 30 years before kidney rejection or other serious problems.  This is an especially important issue now because of our nationwide donor-organ shortage,” said coauthor, David Perkins, M.D., Ph.D., professor of medicine & surgery, and Director of Research for Transplantation.

“This study was not commercially funded,” added Steiner.  “We just wanted to confirm what we suspected from experience in our transplant clinic, where we focus on compliance in many ways to help our patients keep their kidneys functioning well. We showed that when the daily dose is wearing off and another dose is due to be taken, patients taking sirolimus could be more protected against rejection than other commonly used agents.”

The assay used is the only commercially available of its kind, and potentially valuable, but researchers emphasized that experience and understanding of it is limited.

“Our ATC abstract is a report of clinical experience, but real progress is often made at the level of basic science.  My laboratory is studying this intensively at a basic level in several ways, including looking at the genetics associated with various responses to the assay,” said Perkins.
The researchers believe that this new study may help develop tools to monitor patients in the long-term, and also contribute to a protocol for using sirolimus in less compliant patients.  Steiner pointed out that, “The best results will occur if we prevent rejection, because once rejection is established the threat to graft survival is much greater, no matter what we do.”

Co-authors of the study, “Sirolimus (SRL) Blunts Mitogen Response at Trough (C0) Levels More Than Cyclosporin (CSA) or Tacrolimus (TAC): A Safeguard for Our Many Long Term Noncompliant Kidney Transplant Patients (KTPs)” include UC San Diego School of Medicine physicians Nitin Khosla M.D., and Rodolfo Batarse, M.D., assistant professor of medicine.   
       
About ATC

The ATC is the premier educational event in the field of basic and clinical transplantation, with the widest range of educational opportunities.  Topics range from toll-like receptors and composite limb grafts to recent immuno-suppression trials and issues in the globalization of transplantation.

The American Society of Transplant Surgeons (ASTS) was founded in 1974 in an effort to unite surgeons involved in the fledgling field of transplantation.  Since then, the Society has established a strong presence in transplantation research, education and training, and advocacy. 

The American Society of Transplantation (AST) was founded in 1982 and is an organization of more than 2,600 transplant professionals dedicated to research, education, advocacy and patient care in transplantation. AST’s goal is to offer a forum for the exchange of knowledge, scientific information and expertise in the field of transplantation. 

About UCSD Center for Transplantation

The UCSD Center for Transplantation at UCSD Medical Center performed San Diego County’s first kidney transplant in 1968 and has since performed more than 2,000 kidney transplants on patients of all ages.  In 1999, the kidney transplant program began using a new, less invasive technique for living kidney donation, using endoscopic instruments through very small incisions.  In addition, UC San Diego Medical Center’s clinical research programs are at the forefront of discovering new information on the biology of organ rejection, organ preservation and long-term medical management for transplant recipients.

# # #

Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

[stauffenberg]

The term 'chronic graft rejection' is misleading, since the loss of graft function over the long term has little to do with immunological rejection, and much more to do with other, poorly understood factors, such as the destruction of the graft through hypertension, hyperfiltration because of the patient having only one kidney, manifestation of the long-term effects of the traumatic injury to the organ in its harvesting and transplantion, elevated lipid levels, and the nephrotoxicity of the immunosuppressive drugs themselves.  Sutble immunological rejection over the long term is thought to be part of the process of decline in function of the graft over time, but it is not the major factor.

Sirolimus has its own negative side-effects, which are not highlighted in these studies.  What good does it do the patient if switching to sirolimus reduces the progression of chronic graft loss but increses dyslipidemia to the point that the patient is dead of coronary artery disease long before the transplanted kidney fails?

Also, changing the immunosuppressive regimin is always profoundly disruptive and risky, greatly increasing the chance of acute rejection.  Once an episode of acute rejection occurs, the graft is permanently damaged, even if the rejection is beaten back by a temporary increase in immunosuppression.  This permanent damage from the acute rejection sets the transplanted kidney on a faster downward trajectory, reducing its life expectancy.

So, as is always the case in transplant medicine, the best you can do is pick your poison; there is no escaping the fact that you are always dealing with toxic treatments when you are dealing with immunosuppressives.

As for these studies being self-serving because they are funded by the company which stands to profit greatly by increased sales of sirolimus, this is true of almost all medical studies, since they are so expensive that their main source of funds is usually from companies motivated by a profit interest.  As a result, many therapies which were demonstrated to have great curative potential in the 19th century, but which involve the use of medications which cannot be patented and thus cannot generate huge profits for Big Pharma, have been grossly neglected in modern scientific research.  If anyone tries now to argue for their reintroduction in medicine, the chorus of objection is raised that there is no recent research supporting their use, so they continue to be neglected.  Examples of such forgotten therapies include alkalinizing therapy for cancer by giving the patient large doses of sodium bicarbonate and Cooley serum for tumor destruction.  Modern medicine exists to support private profit, not to cure disease.

[pelagia]

Thanks for the insights.  I am still very much in the learning phase. 

The other thing here that caught my eye is that they seem to imply that there are two "populations" of transplant recipients - those who will lose a graft within 10 years and those who will go 20-30 years.  Have you read that before?

[Zach]

 

The other thing here that caught my eye is that they seem to imply that there are two "populations" of transplant recipients - those who will lose a graft within 10 years and those who will go 20-30 years.  Have you read that before?

The 20-30 year figures are not actual but estimates.

From Emory Transplant Center:
http://www.transplant.emory.edu/kidney/patient/evaluation.cfm

There's something called half life, which is the estimated time for 50% of transplants to develop failure, or conversely 50% to survive.

Type of kidney transplant      Kidney graft half-life in years
Living Donor

HLA Identical                          26.5 years

Offspring                                18.7 years

Spouse Unrelated                    15.8 years

Distant Relative                       18.4 years