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What is chronic rejection? What is being done about it?

There are three general forms of rejection: hyperacute, acute, and chronic. "Hyperacute" rejection occurs within minutes of transplantation due to antibodies in the organ recipients blood stream that react with the new organ and result in organ failure within the first hours after transplantation. The kidney and heart are most susceptible to this problem, the liver is relatively resistant. Hyperacute rejection has not been sufficiently studied in pancreas or lung transplantation. Cross matches are done between a particular kidney and a potential recipient of that kidney to decrease the likelihood that hyperacute rejection will occur. "Acute" rejection generally occurs in the first 6 to 12 months after transplantation. Lymphocytes from the thymus (t-cells) are blamed for causing acute rejection. For most organs, the only way to show unequivocally that rejection is occurring is by biopsy of that organ. For practical reason, however, biopsies are not always done when acute rejection is suspected. In some circumances treatment for rejection is begun and a biopsy is performed at a later date if the organ doesn't seem to be improving. This strategy varies from organ to organ and transplant center to transplant center. The diagnosis and treatment of acute rejection can be extremely difficult at times.

Chronic rejection is less well defined than either hyperacute or acute rejection. It is probably caused by multiple factors: antibodies as well as lymphocytes. The definitive diagnosis of chronic rejection is again generally made by biopsy of the organ in question. The heart is an exception to this generalization: chronic rejection in heart grafts is felt to be manifest by accelerated graft atherosclerosis. In other words, the transplanted heart rapidly develops "hardening of the arteries". Kidneys with chronic rejection have fibrosis (scarring) and damage to the microscopic blood vessels in the substance of the kidney. Livers with chronic rejection have a decreased number of bile ducts on biopsy. This is referred to as the "vanishing bile duct syndrome". Transplanted lungs with chronic rejection are said to have "bronchiolitis obilterans" a scarring problem in the substance of the lung.

To date, most research has focused on graft survival for the first three years. It is not that we, the physicians involved with transplantation, don't care about long term results. The long term problem is simply tough to tackle. Animal models exist but they do not perfectly reflect what goes on in humans. Most studies on people that look at long term outcome are not well "controlled", so their conclusions are nebulous. To be "controlled" a study needs to have two groups of patients, one that received a particular treatment and one that didn't. The best kind of controlled study is prospective and randomized, meaning the decision as to which treatment the patient has is decided before the treatment begins in a random fashion. This eliminates many biases that otherwise appear. Theses studies take very long time periods, are extremely difficult and labor intensive and require large numbers of patients to look at long term results. More typically, studies use "historical controls" meaning that one group, say patnts transplanted from 1987 to 1990 is compared to another group of patients transplanted at a different time point, like 1984 to 1986. The problem with such studies is that so many things changed between the two groups. Techniques change: better perfusion solutions for the organs, quicker, more accurate methods of measuring blood levels of cyclosporine ("Sandimmune"). New agents, like FK506 (tacrolimus or "Prograf") are introduced and other agents are removed from the market. Understanding of common infections in transplant patients improves; this improves overall results even though the improvement wasn't exactly related to what immunosuppression they received. The studies therefore get muddled over the years. To look at ten year results today we have to look at transplants that were done in 1985 when techniques were significantly different in many ways from the way we do things now. So the bottom line is that much of what we do today is not firmly based on actual evidence that it is the one best treatment.his explains why different transplant centers do different things: their particular experience has been biased by the particular patient population.

Fortunately, much work is currently being done on chronic rejection, both in the lab and clinically. Some new agents not yet in use clinically look to be particularly effective at combating chronic rejection. As these new drugs appear long term graft survival will hopefully increase. In many situations, the current standard treatment for chronic rejection is retransplantation. This approach is not satisfactory, however, because it makes the existing organ shortage worse, and retransplantation is more difficult from a surgical perspective.

Jeff Punch
 Transplant Surgery
 University of Michigan
 jpunch@umich.edu

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