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Antibodies are certain kinds of proteins that circulate in our blood. They are part of our immune system. The immune system manufactures antibodies when the body is invaded by infectious agents such as viruses. These antibodies can bind to the infectious agents and destroy them. Each antibody molecule has a certain specificity. This means that it was created by the immune system to bind to a specific target molecule on the infectious agent. After someone is exposed to an infectious agent and creates these antibodies against it, the person is "immune" to the disease caused by the infectious agent. This means that these antibodies are ready and waiting in the person's blood to destroy the infectious agent if it tries to invade the person's body again.
The body can also create antibodies against the tissues of other human beings. Normally, we do not do this. However, it can happen when we are exposed to the tissues of other human beings, such as with a blood transfusion, a pregnancy, or an organ transplant. The antibodies that the body can create after these "sensitizing" events are called anti-human antibodies, or "alloantibodies".
If you have anti-human antibodies in your blood which react with the tissue type of a kidney donor, then you cannot receive a kidney transplant from that donor. The antibodies in your blood would attack and damage the kidney immediately after transplantation. In the past, when kidney transplants have been done into persons who have antibodies against the donor, the kidneys have often clotted off immediately. This is a tragic event called "hyperacute rejection" which usually results in loss of the transplanted kidney.
In order to prevent hyperacute rejection, a test called a "crossmatch" is done before every kidney transplant. The crossmatch is done by mixing the blood of the kidney donor with the blood of the kidney recipient. If the blood of the recipient kills the cells in the blood of the donor, it means that the recipient has antibodies to the tissue type of the donor. This is called a "positive" crossmatch, and means that the transplant should not be done because of the high risk for hyperacute rejection. If there is no bad reaction between the blood of the donor and the blood of the recipient (called a "negative" crossmatch), then it is OK to proceed with the kidney transplant.
PRA stands for Panel Reactive Antibody. It is a blood test that is routinely performed on patients waiting for kidney transplants. It is a way of measuring the anti-human antibodies in the blood. A person's PRA can be anywhere from 0% to 99%. Your PRA represents the percent of the U.S. population that the anti-human antibody in your blood reacts with. For example, if you had a PRA of 25%, then the antibodies in your blood would bind to the tissue types of 25% of the people in the population.
If a patient has a high PRA, then his blood contains antibodies that react with a large portion of the population. Therefore, a large portion of the population cannot be a kidney donor for him. As a consequence, patients with a high PRA usually wait much longer for a kidney transplant than patients with a low one. The following table shows data from the most recent UNOS annual report (which keeps track of national transplant waiting times, among other things):
|Peak PRA||Portion of Kidney Transplant Waiting List||Median Waiting Time before Transplant|
|0 -19||60%||490 days|
|20 - 79||21%||1042 days|
As you can see, for patients placed on the kidney transplant waiting list in 1992, those with a peak PRA over 20, which represented 40% of that years' kidney waiting list, median waiting times were 2 to 5 times longer than for patients with a low PRA. A substantial portion of the patients with the highest PRAs will never get transplanted without some treatment to reduce their antibody levels. The problem is especially frustrating for patients with a live kidney donor, since their waiting time could be very short were it not for the positive crossmatch.
Plasmapheresis and immunoadsorption are two methods of removing antibody from the blood. Plasmapheresis is a treatment similar to hemodialysis in that it involves circulating part of the patient's blood through a machine. The blood which is removed from the body is centrifuged so that the formed elements of the blood (red blood cells, white blood cells, platelets) are separated from the liquid part of the blood (the plasma which contains the antihuman antibodies and other plasma proteins). The plasma (with the anti-human antibodies) is then discarded, and replaced with another suitable fluid, such as fresh frozen plasma or albumin solution. The formed elements are then resuspended in the new fluid and returned to the patient. Immunoadsorption is another technique which can remove antibodies. This technique involves passing the patient's blood through a column of material which binds the antibody in the blood. After blood passes over the column it has lower levels of antibodies.
These treatments have been used sporadically over the years to eliminate alloantibodies before kidney transplantation, with variable results. A recent study from Norway reported 17 patients on dialysis who had a positive crossmatch with a living person who wanted to donate a kidney to them (Reisaeter, Transplantation, 1995). After the treatment caused the crossmatch to become negative, the patients received the live donor kidney transplant. After surgery they were given cyclosporine, cyclophosphamide or azathioprine, and prednisone, which are standard drugs that have been given to prevent kidney rejection over the years. 77% of the patients were still off dialysis one-year later. 65% experienced acute rejection within 3 months. 24% had a very early acute rejection episode. 18% of the kidneys were lost to early rejection.
While results from prior clinical trials of plasmapheresis to prepare patients for kidney transplantation were encouraging, the high rates of rejection have generally discouraged its routine use in most transplant centers. The fear has been that, while plasmapheresis could reduce the antibody levels before transplant, if the body resynthesized new antibodies after transplant, then the kidney would be destroyed from rejection prematurely.
Over the past few years, physicians at the Maryland Institue for Transplantation have been gaining a large experience with the newer oral immunosuppressants now available to prevent kidney transplant rejection. These include tacrolimus (Prograf) and mycophenolate mofetil (CellCept). With the introduction of these agents into routine clinical practice between 1995 and 1997, rejection rates have fallen substantially. These agents have biologic activities which could prevent the resynthesis of anti-human antibodies after their removal with plasmapheresis.
A High PRA Rescue Protocol was designed to assist patients who have a suitable live kidney donor, but who are prevented from receiving the transplant because of a positive crossmatch. The protocol involves removal of antibody by plasmapheresis, and prevention of resynthesis of antibody through use of modern immunosuppressants.
In order to be eligible for the protocol, patients with kidney failure must have:
Before transplant. The following timetable shows the details of the protocol before transplantation. It was designed to include oral immunosuppressants before the first plasmapheresis treatment, followed by a maximum of six plasmapheresis treatments on alternate days (Monday, Wednesday, Friday, Monday, Wednesday, Friday). The recipient also receives seven days of intravenous hyperimmune globulin (IVIG, total dose of 500 mg/kg, divided over 7 days), which is an intravenous protein solution that can reduce anti-human antibody levels, and prevent the antibody from coming back. The donor-recipient crossmatch is repeated on the morning following each plasmapheresis treatment (Tuesday, Thursday, Saturday, Tuesday, Thursday, Saturday). While the crossmatch is running in the lab, the patient receives dialysis. If the crossmatch is negative, then the transplant is performed in the early afternoon, and the protocol shifts over to the after transplant section. The donor and recipient remain out-patient until the day of the transplant.
In addition, the follow prophylactic medications are given concomitantly:
After transplant. After transplantation, patients receive 10 days of OKT3, which is a powerful intravenous antirejection drug. They keep taking the oral immunosuppressants that were started at the beginning of the protocol. The remainder of the postop management is the same as that of other kidney transplant recipients at the University of Maryland.
Eight patients have been enrolled in the protocol since March, 1998. Their ages ranged from 27 to 64. Three were females, five males. Four were primary transplants, four retransplants. Donor relations were children in three cases, two were siblings, two unrelated and one was a parent. Two of the patients were type 1 diabetics and wanted a simultaneous cadaver pancreas with their LD kidney. Average PRAs for the recipients were 60% at the time of transplant, and 73% peak.
The plasmapheresis treatments were well tolerated. Weakness and fatigue was reported in half the patients (4/8). Two developed coagulopathies and had to be reexplored shortly after the transplants for hematoma evacuation. To prevent this problem we are now using fresh frozen plama instead of albumin solution to prevent plasmapheresis-induced depletion of coagulation factors. The other complaints were more likely caused by the oral immunosuppressants rather than the plasmaphersis itself (diarrhea in 5/8 or 63% of patients; high blood sugar in 2/8 or 25% or patients; headache or tremulousness in 2/8 or 25% of patients).
Two of the eight patients did not attain a negative crossmatch after the six planned plasmapheresis treatments. They did not receive the live donor kidney transplant, but returned to dialysis to wait for a cadaver kidney. The remaining six patients were successfully transplanted. The crossmatches turned negative after 2 or 3 plasmapheresis treatments. There have been two mild rejection episodes in two patients. Both were easily reversed with either steroids or plasmapheresis. All six patients are dialysis-free after 2-18 months followup.