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Multi-center Study Finds Therapy Boosts Kidney Transplants In 'Highly Sensitized' Patients

ScienceDaily (Dec. 14, 2004) — LOS ANGELES (Dec. 8, 2004) – Although transplantation is by far the preferred treatment option for patients with end-stage renal disease (ESRD), those with high levels of "anti-donor" antibodies have had little hope of receiving a donated organ. Among the relatively few who have undergone transplantation, rejection rates have been very high.

Because the immune systems of "highly sensitized" individuals initiate a rejection response against the tissue of the majority of the population, these patients typically spend the rest of their lives undergoing kidney dialysis several times a week – a painful, costly process that extends life but usually results in a diminishing quality of life.

Now, a 12-center study, funded in part by the National Institutes of Health and reported in the December 2004 issue of the Journal of the American Society of Nephrology, found that an immune-modulating therapy pioneered for transplant patients at Cedars-Sinai Medical Center reduced high antibody levels and improved transplantation rates. The analysis was based on the experiences of 98 highly sensitized patients who were administered either the medication, called intravenous immunoglobulin (IVIG), or a placebo while awaiting transplantation.

"The study showed that there was a significant benefit of IVIG over placebo. In fact, the rates of transplantation for the IVIG group were more than double that for the placebo group. And for patients who had had a previous transplant – which is a very big risk factor for not being able to have another one – the IVIG group's transplant rate was triple that of patients on placebo," said Stanley C. Jordan, MD, director of Pediatric Nephrology & Transplant Immunology and medical director of the Renal Transplant Program at Cedars-Sinai.

"Most other anti-rejection drugs can make the patient more susceptible to infectious complications because they are globally immunosuppressive," said Dr. Jordan, the study's principal investigator, the article's senior author and a professor of pediatrics at the University of California, Los Angeles. "The good thing about IVIG is that it modulates the immune system, it doesn't suppress it. It appears to 'turn off' deleterious immune responses without damaging the immune system, and in fact, it strengthens the immune system because it provides antibodies to infectious agents as well."

Although tissue compatibility issues exist for all patients receiving transplanted organs, rejection risks are especially high for a patient who has the added barrier of an immune system that has been exposed to "non-self" human leukocyte antigens (HLAs). Exposure may occur through blood transfusions, earlier organ transplantation or even pregnancy, when the mother is exposed to antigens from the father expressed in the cells of the developing baby. The immune system is then "sensitized" to those antigens – primed with antibodies to attack, even if the antigens arrive in the form of a potentially life-saving donated organ.

The degree of sensitization is measured in terms of "panel reactive antibody" or PRA levels. For a non-sensitized patient with end-stage renal disease, the wait time for a cadaveric transplantation averages four to five years. For sensitized patients, the odds of being transplanted drop. According to the article, "the higher the PRA, the more difficult it becomes to find an immunologically compatible match. Transplant rates are lower for sensitized patients and the waiting times for a compatible crossmatch are longer. Furthermore, while many of these patients may have living donors, transplantation cannot proceed …."

In 2000, fewer than 3 percent of all kidney transplants were performed in patients with PRAs higher than 80 percent at the time of transplant, despite the fact that these patients represent about 20 percent of those on the waiting list. In fact, transplant rates for these patients have gone down over the past decade as antibody detection techniques improved and waiting lists for the limited number of donor organs grew.

Dr. Jordan began to develop the concept of using immunoglobulins in a transplant environment in the late 1980s as IVIG was becoming established as a therapy for immune system disorders. The proteins, naturally produced in the body, can act as antibodies – natural defenses against invading organisms called antigens. A processed form of immunoglobulin made from blood plasma can be administered to boost the body's natural levels.

Researchers led by Dr. Jordan have published several studies showing that IVIG therapy increases success rates for patients receiving cadaver organs as well as organs donated by relatives or friends. They also have developed a lab test that enables them to predict which patients will most likely benefit from IVIG. If IVIG changes a poor match into a more compatible one in the lab, it likely will help the patient's immune system accept a transplanted organ.

The new study results showing that IVIG can make transplantation available to many patients who previously would have lingered on dialysis comes just months after some Medicare and other insurance providers began offering coverage for IVIG therapy in certain situations. Using IVIG to get even half of the sensitized patients transplanted and off of long-term dialysis would bring huge savings, according to cost analyses.
"From a financial standpoint and from a quality of life standpoint, there is no question that IVIG therapy and transplantation have more to offer than years of dialysis," Dr. Jordan said.

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The study was supported by grants 1UO1-AI40129 and 1UO1-AI37313 from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and a grant from the Rebecca Sakai Memorial Fund. Bayer Corp. co-sponsored the study by providing medication and placebo.

A Magnet Nursing facility, Cedars-Sinai Medical Center is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, it has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthroughs in biomedical research and superlative medical education. It ranks among the top 10 non-university hospitals in the nation for its research activities and was recently fully accredited by the Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP). Additional information is available at http://www.cedars-sinai.org.

Adapted from materials provided by Cedars-Sinai Medical Center.

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Therapy Modulates Highly Sensitized Immune System to Let Mother Give Kidney to Daughter

Source: Cedars-Sinai Medical Center Released: Thu 21-Dec-2006

Newswise — As the holidays approached last year, Soraya Kohanzadeh, 30, Muir Beach, CA, was living day to day, extremely ill, with no hope and expecting to live a shortened life dependent on kidney dialysis. She needed a kidney transplant but because her “anti-donor” antibody levels were so high, her doctors believed that a transplant was not possible – perhaps ever. However, thanks to a specialized type of anti-rejection therapy pioneered at Cedars-Sinai Medical Center, Soraya successfully underwent a transplant in May of this year and has a “new lease on life” as she looks forward to 2007.

Soraya, was among the estimated 33 percent of kidney failure patients who have high “anti-donor” antibody levels and who are often told that a transplant is not possible even if a potential donor’s tissue and blood types otherwise match perfectly.

But on May 16, 2006, she received a kidney donated by her mother, Joan Lando, at Cedars-Sinai . The transplanted kidney started working immediately, both patients recovered well, and Soraya has had no episodes of rejection – the result of a therapy that makes the incompatible compatible and the impossible a reality in many cases.

Soraya had expected to live a shortened life, dependent on kidney dialysis -- a painful, expensive, time-consuming procedure that cleans blood well enough to maintain existence but not well enough to contribute to quality of life.

Physicians in the San Francisco area said transplantation was not an option because a donor organ would be rejected by her hyper-vigilant immune system – a prospect faced by about one-third of the more than 70,000 patients on the nation’s kidney transplant waiting lists. But Soraya conducted an Internet search and found that Cedars-Sinai is one of the very few centers in the nation addressing this problem.

Tissue compatibility issues exist for all patients receiving transplanted organs, but rejection risks are dramatically increased for those with high exposure to “non-self” human leukocyte antigens (HLAs). Exposure may come through blood transfusions, previous transplantation or even pregnancy, when the mother is exposed to the father’s antigens, which are expressed in the cells of the developing baby. The immune system is then “sensitized” to those antigens – primed with antibodies to attack, even if the antigens arrive in the form of a potentially life-saving donated organ.

Stanley C. Jordan, M.D., medical director of Renal Transplantation and Transplant Immunology at Cedars-Sinai’s Center for Liver and Kidney Diseases and Transplantation, pioneered in the late 1980s the use of intravenous immunoglobulin (IVIG) as a way to reduce organ rejection among highly sensitized individuals. After undergoing years of experiments and clinical trials, IVIG became a fully accepted, Medicare-approved therapy in 2004 when it was found effective in a multi-center study partly funded by the National Institutes of Health.

IVIG modulates the immune system without suppressing it. In fact, says Jordan, the therapy actually boosts the immune system because the antibodies found in IVIG help fend off infections. For most of their highly sensitized patients today, IVIG therapy is combined with a new drug, Rituxan®, which brings treatment time down from about four months to one before transplantation, and the therapy can be used in both living-donor or cadaver-donor transplants.

Soraya says it may have been three or four months from the time she learned about IVIG and called Cedars-Sinai to the day of the operation. During that time her mother underwent many tests to make sure that she was as able a donor as she was willing.

“It seemed like it all happened very quickly,” Soraya says. “My mother and I went to Cedars-Sinai fairly soon after I talked to them and they tested both of us and said, ‘We can do something for you.’ I just remember thinking, you’ve got to be kidding me. They can solve everything? And they’ve done it for other people?”

Soraya’s kidneys were healthy until March 2003 when she underwent surgery for a congenital heart defect and a major vein was accidentally severed. The 24 units of blood she was given over the next few hours saved her life, but her kidneys suffered irreparable damage, and along with all those transfusions of other people’s blood came high exposure to non-self HLAs.

Jordan estimates that about 40 percent of Cedars-Sinai’s kidney transplant patients are in the highly sensitized category, referred to the program – or self-referred – because they could not be considered for transplantation elsewhere. “We’re able to transplant probably about 95 to 97 percent of the patients we see,” he adds.

Joan’s donor operation was performed by Gerhard Fuchs, M.D., director of Cedars-Sinai’s Minimally Invasive Urology Institute. He is one of the few surgeons who specialize in laparoscopic donor nephrectomy, which requires only a few small incisions to remove a kidney for transplantation. Minutes after Joan’s kidney was removed, a team headed by J. Louis Cohen, M.D., began the process of placing it into Soraya’s abdominal cavity and connecting it to her urinary system. Cohen is surgical director of Kidney Transplantation and medical director of Operating Room Services.

“This time last year, Soraya was living day to day, extremely ill and with no hope. Now she is back to herself – healthy, cheerful and energetic,” says Joan, 58. “And this is someone who was told that she was so highly sensitized that she could never get a kidney. We should have been totally hopeless, but somehow – I don’t know how – we kept thinking there has to be somebody doing something somewhere. And as it turned out, it was just in L.A. It’s over for us, but to think that there are other people, just like us, sitting in clinics, who don’t even have a clue.”

Soraya, who used to teach high school algebra, has been able to go back to work as a volunteer teacher at Marin County’s Juvenile Hall in San Rafael.

“Somewhere between 25 to 30 percent of patients on the kidney transplant list could benefit from this therapy to help them get transplanted,” says Jordan. “Patients who are on dialysis and those who are progressing toward renal failure need to know that they have a right to be considered for a kidney transplant. Their doctor should refer them to a transplant center even before they start dialysis so that they can be evaluated and the best treatment options can be determined for them. Patients who have a living donor do not need to be on dialysis before being transplanted, and the data show that if patients get transplanted before they start dialysis, they actually do better.”

One of seven hospitals in California whose nurses have been honored with the prestigious Magnet designation, Cedars-Sinai Medical Center is one of the largest nonprofit academic medical centers in the Western United States. For 18 consecutive years, it has been named Los Angeles’ most preferred hospital for all health needs in an independent survey of area residents. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthroughs in biomedical research and superlative medical education. It ranks among the top 10 non-university hospitals in the nation for its research activities and is fully accredited by the Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP). Additional information is available at http://www.cedars-sinai.edu.
© 2008 Newswise.  All Rights Reserved.

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Desensitization of highly human leukocyte antigen-sensitized patients: immunomodulation with high-dose intravenous immunoglobulin (the Cedars-Sinai protocol)

IVIg products are derived from the plasma of thousands of donors thus ensuring a wide diversity of antibody repertoire. There are numerous proposed mechanisms of action that may be relevant to the modification of allosensitization. These include modulation of autoantibody and alloantibody levels through induction of antiidiotypic circuits, inhibition of cytokine gene activation and anticytokine activity, anti-T-cell receptor activity, Fc receptor-mediated interactions with antigen presenting cells to block T-cell activation, anti-CD4 activity, stimulation of cytokine receptor antagonists and inhibition of complement activity.

Using the mixed lymphocyte culture (MLC) system, the group at Cedars-Sinai has shown that IVIg can significantly inhibit T-cell activation and reduce the expression of CD40, CD19, ICAM-1, CD86, and MHC class II on antigen presenting cells (APCs) in the MLC. The primary effect is on B-cells and indeed; it appears that IVIg induces significant B-cell apoptosis in vitro through Fc receptor-dependent mechanisms. Samuelsson et al. demonstrated that IVIg induces the expression of FcgRIIB, an inhibitory receptor on B-cells. Recently, Kaneko, et al. showed that IVIg prevented anti-glomerular basement membrane nephritis in a mouse model by inducing inhibitory FcγIIb and downregulating the activating receptor FcγRIV. These exciting data suggest that the inhibition of antibody-mediated injury is regulated by FcR interactions and is effective across species. In addition, Li et al. demonstrated that IVIg ameliorates antibody-mediated injury by inducing FcRn on endothelium.

Magee et al. showed that IVIg treatment significantly prolonged the survival of pig-to-baboon xenotransplants. This beneficial effect was through inhibition of complement-mediated endothelial cell injury. IVIg inhibits the generation of C5b-C9 MAC, thus preventing antibody-medicated injury. IVIg also inactivates C3b and accelerates C3b catabolism. IVIg can inhibit the activation of endothelial cells in in-vitro models of inflammation. Data by Bayry et al. suggest that IVIg inhibits the maturation and function of dendritic cells, impairing their APC activity and inducing IL-10 production. These data are in concert with data demonstrating similar effects on B-cells. Recently, Abe et al. examined gene expression in patients with Kawasaki disease before and after high-dose IVIg infusion. Here, the immunomodulatory effects of IVIg were probably mediated by suppression of an array of immune activation genes in monocytes and macrophages. Gill et al. showed that IVIg has direct inhibitory effects on leukocyte recruitment in vitro and in vivo through inhibition of selectin and integrin functions. Others have also demonstrated a potent effect of IVIg on suppression of vaso-occlusion by inhibition of leukocyte adhesion in a mouse model of sickle cell disease. More recently, Park-Min et al. showed that IVIg interacts with FcγIII on immune cells to downregulate IFNγ receptors thus preventing IFNγ signaling.

While the precise mechanisms that support desensitization of patients harboring anti-HLA antibody have been incompletely elucidated, the clinical results of empiric protocols using these preparations have been impressive. Data from the Cedars-Sinai group and others suggest that IVIg therapy given to highly sensitized patients results in reduced allosensitization, reduced ischemia-reperfusion injuries, fewer acute rejection episodes, and higher successful long-term allograft outcomes for cardiac and renal allograft recipients. We and others have confirmed that pretreatment with IVIg results in reductions of anti-HLA antibodies, and is effective in treatment of allograft rejection episodes. We have also shown that IVIg is effective in reducing anti-HLA antibody levels and significantly improving transplant rates in highly HLA sensitized patients in a controlled clinical trial.

The high-dose IVIg protocol developed at Cedars-Sinai evolved from our experience in treating a highly sensitized child in 1991. For IVIg alone, we usually give four doses of IVIg monthly (2 g/kg, maximum dose 140 g) until a negative or acceptable (<250 CS by flow-cytometry crossmatching) crossmatch is obtained. We have also adapted this protocol to use for highly sensitized deceased-donor transplant candidates who have been on the US United Network for Organ Sharing waitlist for over 5 years, have a panel reactive antibody (PRA) of over 50% and who receive frequent offers for kidneys from donors with whom they have a positive crossmatch. These patients have an in-vitro IVIg PRA, and if suppression or inhibition of the PRA is seen with IVIg, the patients are offered IVIg 2 g/kg monthly four times in the hope of achieving desensitization and receiving a crossmatch compatible kidney or other organ.

From July 2002 to October 2005, we evaluated 89 patients who were highly HLA sensitized and had a positive crossmatch with potential donors in the in-vitro IVIg-PRA test system. Eighty-five percent showed inhibition to some degree in the in-vitro PRA or crossmatch system. Seventy-nine of 89 (89%) were transplanted after IVIg desensitization therapy (46 living donor, 33 deceased donor). Of the 10 patients who were not transplanted, six were awaiting a cadaver transplant offer and two did not respond to IVIg. Two others were successfully desensitized for living donors, but medical conditions prevented transplantation. Thus, only two of 89 (2.2%) failed to respond to IVIg sufficiently to allow transplantation to be considered. The mean PRAs for the cadaver recipients were 83% and most patients had antibodies specific to their donors that were eliminated or reduced by IVIg therapy. The incidence of allograft rejection is 28% with a 3-year patient and graft survival of 97.5% and 87.1%, respectively. Five grafts were lost to rejection. The mean serum creatinines at 3 years were 1.4 mg/dl.

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