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Expanding the living organ donor pool: Positive crossmatch and ABO incompatible renal transplantation.

There is no question that there is a severe shortage of available kidney donors. Currently, there I are over 54,000 people awaiting a kidney transplant. In 2001, 14,242 kidney transplants were performed including 910 simultaneous kidney and pancreas transplants. This number represents only about 25% of the candidates that were on the list at the time. The median waiting times, the time it takes for 50% of the candidates in a specific blood group to be transplanted, are long and getting longer. The median waiting times are longest for blood types B (1,426 days) and O (1,213 days). The median waiting time for blood type A is 862 days and for blood type AB only 479 days. In 2000, 3,066 patients died before they could receive a transplant, averaging about 8.6 deaths a day (United Network for Organ Sharing [UNOS], 2001).

Of those transplanted in 2001, 39% had a living donor, and the remainder had cadaveric donors (UNOS, 2001). Despite intensive attempts to educate the public about donation, the number of cadaveric donors has remained fairly static over the past decade. Expanding live donation has become the most promising strategy for closing the gap between patients waiting for transplantation and available organs. In response to this clear and ever-increasing need, the transplant community has devoted tremendous time, energy, and intelligence to the quest to find alternative strategies to allow more living donors to donate life-saving kidneys. Some of these strategies are new, and some have existed for decades but hold greater promise when combined with new immunosuppressant regimens and technology. This article will present an overview of two innovative strategies: positive crossmatch (+XM) and ABO incompatible (ABOI) transplantation.

Transplanting Across a Positive Crossmatch Barrier

Overview. Individuals become sensitized (form antibodies) in response to blood transfusions, pregnancy, and previous transplants (Ourahama et al., 1997). Those who are highly sensitized have decreased opportunities to find a compatible donor, extended waiting times, and a higher incidence of acute antibody-mediated rejection (Alarabi, Backman, Wikstrom, Sjoberg, & Tufveson, 1997; Opelz, 1996). This is a group of patients who have limited chances for transplantation unless alternate strategies are employed.

Prior to any transplant a crossmatch (XM) is done to determine if a recipient has pre-formed antibodies to the human leukocyte antigens (HLA) of the potential donor. If the XM is positive, this indicates the presence of preformed antibodies that would lead to hyperacute rejection if the organ were transplanted. Hyperacute rejection occurs minutes to hours after the transplanted kidney is reperfused and results in loss of the organ. In the past, a positive preoperative XM guaranteed cancellation of the transplant However, it was found that the transplanted kidneys of recipients who had a negative preoperative XM, but developed antibodies after the transplant due to a delayed response (acute antibody-mediated rejection), could be rescued (rescue therapy) by removing the offending antibodies from their blood using plasmapheresis. Intravenous immune globulin (IVIG) or CMV hyperimmune globulin (CMV-HG) in conjunction with high doses of immunosuppressants were used to prevent resynthesis of the anti-HLA antibody (Aichberger et al., 1997; Grandtnerova et al., 1995; Madan et al., 2000; Montgomery et al., 2000). With this knowledge, transplant physicians realized that this same therapy could be used to pre-emptively (pre-emptive therapy) remove antibodies to specific donor HLA antigens prior to transplant, thus preventing hyperacute rejection and allowing the transplant to proceed and be successful (Alarabi et al., 1997; Montgomery et al., 2000; Schweitzer et al., 2000). In this era of scarce resources, this therapy presents a tremendous opportunity for patients who would otherwise wait for prolonged periods of lime or may die on dialysis while awaiting a transplant

Literature Review

Plasmapheresis is a technological tool that has been used since the mid-1970s to remove antibodies present in a variety of diseases. In the field of transplantation, it has been used to globally reduce the overall level of antibodies in transplant candidates (Alarabi et al., 1997; Harano et al., 1999) and has been used precisely to remove donor specific antibodies that would cause hyperacute rejection or acute antibody-mediated rejection (Montgomery et al., 2000; Takeda et al., 2000; Zachary, Ratner,& Lefell, 2001).

The initial studies on the use of plasmapheresis to reduce antibody levels focused on rescue therapy. Slapak, Naik, and Lee (1981) reported one of the earliest cases where plasmapheresis was used to remove donor specific antibodies. In this case report, antibodies to a foreign blood group were removed in a patient who had inadvertently received an ABOI transplant. At 20 months, the recipient still had good function. Grandtnerova et al. (1995), in a series of 50 renal transplants, had five develop anti-HLA antibodies that led to acute antibody-mediated rejection in the first week after transplant. This group of patients was treated with high dose immunosuppression, plasmapheresis, and IVIG. Four of the five patients recovered from the acute antibody-mediated rejection, and at 6-23 months of follow-up were stable with normal creatinines. Aichberger and colleagues (1997) had 28 transplant recipients with biopsy-proven acute antibody-mediated rejection. They received high dose immunosuppression in addition to plasmapheresis. Twenty-two of the 28 patients responded well to the therapy and left the hospital with a mean serum creatinine of 1.6 mg/dl. A 1-year graft survival rate of 71% was reported. Numerous infections including the cytomegalovirus were reported in the study group. Pascual, Crespo, and Tolkhoff-Rubin (2001) reported in a study of 232 kidney recipients, of which 10 developed refractory acute antibody-mediated rejection, treated with plasmapheresis, high dose immunosuppression, and IVIG, that 9 of the 10 responded with a reversal in acute antibody-mediated rejection. At mean follow-up of 42 months, patient survival was 100%, and graft survival was 80%. It was noted that IVIG was given to reduce the risk of infection.

Montgomery et al. (2000) successfully reversed acute antibody-mediated rejection in three transplant recipients using a combination of plasmapheresis, high dose immunosuppression, and IVIG. The mean creatinine with a mean follow-up of 58 +/- 40 weeks was 1.4 +/- 0.8 mg/dl. It was noted that IVIG was used for its immunomodulatory effects including suppression of new antibody formation and the presence of anti-idiotypic antibodies.

Montgomery et al. (2000) also reported on four cases where plasmapheresis was used pre-emptively to remove donor specific antibodies in living donor transplant candidates. In this case, the source of the IVIG was CMV-HG. In this study, candidates with known +XM and donor specific antibodies were plasmapheresed preoperatively until the XM became negative. The mean posttransplant creatinine was 1.4 +/- 0.8 mg/dl. Sonnenday et al. (2002) now has expanded this series to 21 patients that have received pre-emptive therapy for a positive preoperative XM. In this group, 20 of the 21 XMs converted to negative after therapy. One XM remained weakly positive. Twenty of the 21 candidates proceeded to transplant including the candidate with the weakly + XM. One candidate had to withdraw due to a change in the donor's medical condition. At a median follow-up of 23.5 months, the mean creatinine in the 19 surviving grafts is 1.3 +/- 0.8 mg/dl. One graft was lost due to noncompliance. Postoperatively, 10 of the 20 patients developed acute antibody-mediated rejection. In all cases, the acute antibody-mediated rejection was very responsive to additional plasmapheresis/CMV-HG therapy. Schweitzer et al. (2000) used plasmapheresis, high dose immunosuppression, and IVIG in a group of 15 patients with donor specific antibodies preoperatively. Eleven of the 15 patients became XM negative and proceeded to transplant The mean creatinine for this group was 1.6 +/- 2 mg/dl with a median follow-up of 13.3 +/- 2.4 months. Takeda et al. (2000) examined four patients with donor specific antibodies detected prior to transplant. Plasmapheresis and high dose immunosupression were instituted and the patients proceeded to transplant. Two of the four developed acute antibody-mediated rejection posttransplant, but recovered and no longer required dialysis.

The data support that both pre-emptive and rescue therapy for donor specific antibodies have great potential as treatment options. It is important to consider what factors have lead to improved results by certain transplant programs. To be successful, a complex treatment regimen must be implemented that depends on the expertise of many specialty groups including transplant surgeons and nurses, plasmapheresis physicians and nurses, tissue typing physicians and technicians, and nephrologists. A summation of the protocol follows.

Positive XM Protocol

The basis of this protocol is that the antibodies that would lead to hyperacute rejection or acute antibody-mediated rejection must be removed from the body, and the immune system must be modulated to reduce the production of the antibody in the future or dampen the immune response to the foreign antigen. When used as a pre-emptive therapy, this protocol includes pre- and postoperative plasmapheresis, administration of CMV-HG, and pretransplant immunosuppression. Additional immunsosuppression is given intraoperatively and higher doses are given postoperatively (see Table 1). When used as a rescue therapy, the protocol begins with postoperative plasmapheresis and administration of CMV-HG at the time acute antibody-mediated rejection occurs (see Table 2).

Pre-emptive protocol. Under this protocol, a potential transplant recipient has a healthy willing donor, but the recipient has antibodies to one or more of the donor's HLA antigens. Once the recipient and donor are cleared from medical and psychosocial standpoints, the protocol can be initiated. The goal of the protocol is to ensure a negative XM prior to transplant.

Plasmapheresis is a process in which blood is removed from the potential recipient via a dual lumen catheter or a native fistula or graft and is centrifuged to separate the cells from the plasma. The plasma is discarded, as plasma is where antibodies reside and removing the plasma removes the antibodies to the donor HLA. The cellular components are then reinfused along with either 5% albumin or fresh frozen plasma to replace the volume loss. Necessary antibodies to bacteria, viruses, and fungi as well as clotting factors are also lost in the discarded plasma. The treatments are usually done every other day. If a patient is not scheduled for any invasive procedures in the next 24 hours, including surgery, the replacement fluid will be 5% albumin. If an invasive procedure is anticipated or plasmapheresis is being done daily, fresh frozen plasma will be used. As fresh frozen plasma contains clotting factors, it will prevent bleeding. Patients not replaced with plasma are at risk for bleeding for hours after plasmapheresis until they regenerate their clotting factors (Price, 1998). Depending on the amount of antibody present to the donor HLA, between one and seven plasmapheresis treatments may be required preoperatively.

To assess the success of the plasmapheresis in removing the antibody, antibody titers are measured and repeat XMs are done. The titers are reported as a ratio, and the higher the titer the higher the antibody level. A negative standard (cytotoxic) XM is necessary before proceeding to transplant. In some cases, low titer donor specific antibodies can not be detected by cytotoxic XM. In this situation a more sensitive XM test is utilized called the flow cytometry crossmatch (FCXM). If this test is positive, anti-HLA antibody is present (Takeda et al., 2000).

The infusion of an IVIG (100 mg/kg) product after every plasmapheresis is a key component of this protocol. We use CMV-HG as the source of MG. IVIG exerts a poorly understood immunomodulatory effect. After the transplant, the donor specific antibodies are eliminated (Montgomery et al., 2000; 2002; Sonnenday et al., 2002). It is this change in the immune system that allows this protocol to be successful even after the plasmapheresis and IVIG have been stopped. It has been postulated that MG contains anti-idiotypic antibodies and that these antibodies destroy the antibodies to the donor HLA, thus preventing rejection. Further, it is theorized that eventually the recipient's immune system may be able to produce these anti-idiotypic antibodies independently, explaining why the effect persists long after plasmapheresis and IVIG have been discontinued (Montgomery, 2001). The IVIG also replenishes good antibodies to bacteria, viruses, and fungi providing protection from infection that is essential due to the significant immunosuppression necessary for the success of this protocol.

To prevent cellular rejection and reduce T-cell dependent, B-cell responses and inhibit B-cells, immunosuppression is started preoperatively on the first day of plasmapheresis. Both tacrolimus and mycophenolate mofetil are initiated. Daclizumab, an interleukin 2 receptor blocker that prevents cellular proliferation and rejection, is given intraoperatively and then every other week for a total of five doses. The goal of these therapies is to prevent any incidental episodes of cellular (T-cell) rejection and suppress the B-cells or antibody producing cells.

Once the transplant is done, two or more additional plasmapheresis treatments are performed depending on the titers and XM data. The XM should remain negative. If the antibody titer begins to rise, rejection should be suspected. A kidney biopsy will be done to establish a definite diagnosis. The presence of C4d, a complement degradation product, usually confirms the diagnosis of acute antibody-mediated rejection (Pascual et al., 2001). Other indications of acute antibody-mediated rejection on biopsy include glomerulitis, vasculitis, fibrin thrombi, fibrinoid necrosis, and the margination of neutrophils into the peritubular capillaries (Crespo et al., 2001). Plasmapheresis coupled with CMV-HG will be initiated until the donor specific antibodies are eliminated.

Rescue therapy. The protocol is initiated at the time biopsy-proven acute antibody-mediated rejection is identified in the patient who prior to transplant had a negative XM. As with the pre-emptive therapy, the plasmapheresis and CMV-HG will continue until donor specific antibodies becomes undetectable. The number of treatments necessary to achieve this goal can vary widely (Montgomery et al., 2000). Some may require as few as two treatments, while others require 30 or more.

Case Study: + XM Pre-Emptive Therapy

F.W. was a 35-year-old, white female with a long history of Type 1 diabetes mellitus who had been on peritoneal dialysis for many years at the time of her transplant evaluation. She had numerous complications including a seizure disorder, hypothyroidism, and diabetic neuropathy, gastropathy, and retinopathy. Her retinopathy severely limited her vision. Further, she had been in a car accident at age 25 and was left with a permanent tracheostomy from a crash injury and multiple metal bars and screws in both lower extremities. To repair damage related to the accident and reconstruct her lower extremities, she had 42 surgeries. She also received 43 blood transfusions that caused her to become highly sensitized and nearly impossible to transplant by conventional means, as she had donor specific antibodies to every donor she was tested against.

Because of her worsening medical conditions and poor clearances on dialysis, the patient was evaluated for the +XM program. Thirteen donors were screened before one was found (A.D.) with whom she had a 3/6 HLA antigen match (see Figure 1). A.D. was an altruistic donor. Unfortunately, F.W. had donor specific antibodies to one of the donor's HLA antigens (B60). F.W.'s titer to the B60 antigen was 1:128 (see Figure 2). She received six preoperative plasmapheresis treatments every other day and her titer fell to 1:1 the day before surgery. The surgical procedure, although difficult due to her numerous previous surgeries, went well. She had three postoperative plasmapheresis treatments. Her creatinine was very slow to fall and actually rose to 4.2 mg/dl at one point, but there was no evidence of acute antibody-mediated rejection, only tacrolimus toxicity. Eventually, over a 3-week period her creatinine fell to 1.8 mg/dl. She left the hospital off dialysis.

[FIGURE 1 OMITTED]

Since her initial discharge, F.W. has had one episode of acute antibody-mediated rejection that occurred about 5 weeks after transplant and was successfully treated with steroids and additional plasmapheresis/CMV-HG. She has also had several episodes of cellular rejection treated with steroids and muromonab CD3 (OKT3). She now has a creatinine of 1.8 mg/dl, remains off of dialysis, and is planning to return to college.

ABOI Transplantation

Overview. ABOI transplantation has a long history dating back to the 1950s. It is governed by many of the same principles as +XM transplantation. In +XM transplantation eliminating anti-HLA donor specific antibodies is crucial. In ABOI transplantation, removal or suppression of the antibody to the foreign blood group antigens (isoagglutinins) is the key to success. In the United States, Slapak et al. (1981); Starzl, Marchioro, Hermann, Brittain, and Waddell (1963); and Hume, Merrill, Miller, and Thom (1955) were some of the earliest pioneers in this area. Because of inconsistent and generally poor results, ABOI fell out of favor and languished for several decades in the United States. Conversely, in Japan, where very few cadaveric transplants are done due to the absence of uniform organ donor laws, ABOI transplantation continued and results gradually improved as immunosuppression and technology advanced.

ABOI transplantation takes place between a donor and recipient that are ABOI. In this protocol, plasmapheresis is used to remove isoagglutinins, and CMV-HG is used to prevent them from rebounding. The same cocktail of immunosuppressive agents given to the +XM patients is utilized. Additionally, the spleen is often removed to reduce antibody production, although the absolute necessity for this procedure remains controversial (Alexandre et al., 1987; Ishida et al., 2000; Tanabe et al., 2000).

Literature Review

The majority of the literature on ABOI transplantation is from Japan. There more than 300 ABOI transplants have been done at over 40 centers since 1989 (Takahashi et al., 1998). Tanabe et al. (1998) had a series of 67 patients who received live donor transplants between 1989 and 1995. The donors were blood types [A.sub.1], B, and AB. The recipients were blood type [A.sub.1], B, and O. Plasmapheresis or immunoadsorption, an alternate means of antibody removal, was used to remove antibody to the foreign blood group, and a five-drug immunosuppression regimen was employed. Splenectomy and graft irradiation were also done. Patient survival was 93% at 1 year and 91% at 8 years. Graft survival was 79% during years 1-4 and decreased to 73% by year 8. No significant difference in patient survival was found between ABOI and ABO compatible (ABOC) transplants, but the ABOI recipients had a significantly higher rate of early graft loss. After 4 years, however, the difference in graft survival between ABOI and ABOC transplant recipients was not statistically different. Takahashi and colleagues ,(1998) had a small series of patients where tacrolimus was added to the treatment regimen as a novel immunosuppressant. Seven ABOI transplants with living donors were done. Six of the seven cases survived and have a mean creatinine of 1.8 mg/dl. One patient died due to complications secondary to post-biopsy hemorrhage. Hadano, Ohara, Aikawa, & Hasegawa (2000) performed 48 ABOI transplants from 1989 to 1999. As of May 1999, 36 still had a functioning graft. One graft was lost to hyperacute rejection, four to chronic rejection, and the remaining patients died with functioning grafts.

In Japan, there are numerous ABOI protocols, but most utilize plasmapheresis or immunoadsorption, three- to five-drug immunosuppressive regimens, and splenectomy. Tacrolimus and mycophenolate mofetil were usually absent from the Japanese protocols. Local graft irradiation was also employed at some centers (Ishida et al., 2000; Tanabe et al., 2000). IVIG was not reported as an adjunct in the Japanese protocols.

Alexandre et al. (1991) have one of the largest series outside Japan. They performed 38 ABOI transplants in 37 patients beginning in 1982. All but one were living donors. Plasmapheresis, splenectomy, and an immunosuppressant regimen including anti-lymphocyte serum and steroids plus azathioprine or cyclosporine were employed. Later patients received all four drugs. Of the 37 original transplants, eight lost their grafts within a month. One patient who lost his kidney to chronic rejection in less than 2 years received a second ABOI transplant that is still functioning. Four others lost their grafts at 0.5, 4, 5, and 7 years. There were two deaths. The remainder still had graft function with creatinines of 2.2 mg/dl at their last follow-up in 1991.

More recently in the United States, Alkhunaizi, DeMatteos, Barry, Bennett, and Norman (1999) did 15 ABOI transplants using [A.sub.2] donors from 1991-1998 with a patient survival rate of 100% and graft survival rate of 93% at 1 year. Nelson et al. (1998), in a 10-year review of 50 ABOI transplants with A2 donors at their center from 1986 to 1996, found that results were equivalent to ABOC transplants. Plasmapheresis was not used, and their results improved when they instituted a policy of only transplanting recipients with a titer < 1:4. One-year graft survival was 88%. They also noted that their success was likely influenced by using [A.sub.2] donors. The blood group A has two subtypes, Al and [A.sub.2]. Subgroup [A.sub.2] expresses very low levels of the A antigen on the surface of the kidney. Montgomery et al. (2002) had a group of four patients transplanted between 1999 and 2002 with a patient and graft survival rate of 100% and a mean creatinine of 1.3 +/- 0.7 mg/dl with a follow-up range of 127 months. [A.sub.1] [A.sub.2] and AB donors were used in this series. Plasmapheresis, CMV-HG, daclizumab, and steroids were utilized for all of the recipients. This series includes patients with very high starting isoagglutinin titers. Although all of the patients have had some rebound in isoagglutinin titers after surgery, it does not seem to adversely affect the allograft. There has only been one episode of rejection that was successfully treated with additional plasmapheresis, CMV-HG, and pulse steroids. This unresponsiveness to the foreign blood group may be the result of changes in the expression of proteins on the surface of cells in the allograft, a process called accommodation (Platt & Bach, 1991).

Despite the formidable concerns that stem from the historical avoidance of crossing ABO barriers due to expected catastrophic results, ABOI transplantation appears to be gaining acceptance in the United States again. This has been due, in part, to the recent success of the Johns Hopkins protocol in transplanting patients across both +XM and ABOI barriers (Montgomery et al., 2000; 2002; Sonnenday et al., 2002). In the United States, several centers have substantial experience with [A.sub.2] donors into O and B recipients. These centers do not routinely use plasmapheresis and tend to transplant only patients with low starting anti-A antibody. The use of IVIG and splenectomy are inconsistent. Additional experience will likely clarify some of these gray areas.

The results in many studies have been comparable to ABOC transplant, but not in others. Tanabe et al. (1998) notes that donor age (> 53 years) and the occurrence of acute antibody-mediated rejection are important predictors of poor, long-term function. The results overall appear good enough to continue to offer ABOI transplantation as a treatment option in appropriate patients, but careful screening is essential, and potential recipients must understand the greater risk involved. As with +XM transplants, the process is complicated and requires a team of specialists including transplant surgeons and nurses, plasmapheresis physicians and nurses, blood bank physicians and technicians, and nephrologists.

ABOI Protocol

Under this protocol the transplant candidate has a healthy, willing donor, but the recipient and donor have incompatible blood types. After both the donor and recipient are medically cleared for transplant, the protocol can be implemented (see Table 3). As the spleen will be removed to decrease antibody production, there is one step that must be taken at least 4 weeks prior to transplant. The spleen, in addition to other functions, filters bacteria from the blood. Once the spleen is removed, bacteria such as pneumococcus, meningococcus, and tetanus will not be filtered effectively. As a result, the recipient will need to be vaccinated against these diseases to reduce the risk of infectious complications. These immunizations need to be administered at least a month pre-transplant to allow time for the immune system to mount a normal response conferring protection.

The next step in the process is to start plasmapheresis. To ensure the complete removal of the antibody to the foreign blood group, at least 3-10 treatments may be required pre-operatively depending upon the level of the starting isoagglutinin titer. The last three treatments of the series may need to be done on consecutive days to avoid rebound of the antibody that could result in cancellation of the transplant surgery. Each plasmapheresis is followed by CMV-HG (100 mg/kg) that serves the same purpose as it does for the +XM transplants. Immunosuppression is initiated on the first day of plasmapheresis to facilitate suppression of antibody production and prevent cellular rejection. Throughout the course of plasmapheresis the isoagglutinin titers are monitored. The goal is to reduce the titer to < 1:16. Rydberg (2001), in a large scale review of all published data on ABOI, noted that donor specific antibodies titer reduction to < 1:16 is essential for the success of ABOI transplantation. A study by Toma, Tanabe, and Tokumoto (2001) supports this finding.

During the transplant surgery, daclizumab is administered for the same reasons it is given for +XM transplants. Four additional doses are given every other week. The splenectomy is usually done laparoscopically at the time of transplant. Both the white blood cell (WBC) and platelet (PLT) counts can rise significantly postoperatively as WBCs and PLTs that have previously been sequestered in the spleen are now in the central circulation. Penicillin VK (250 mg twice a day) is administered after surgery to prevent pneumococcal pneumonia. Annual flu vaccine and pneumonia vaccinations every 5 to 10 years are also indicated.

Two or more additional plasmapheresis treatments with IVIG are provided postoperatively depending on the antibody titer activity. It is important to note that in ABOI transplantation, antibody titers can rise after the surgery, but this does not necessarily correlate with rejection or effect renal function (Alexandre et al., 1991; Montgomery et al., 2002; Sonnenday et al., 2002). There seems to be some mechanism of accommodation that likely involves one or more of the following: endothelial changes that may allow for resistance against the antibodies to develop, changes in the antigens that result in less antibody binding, expression of protective molecules, decreased antibody production, and/or production of anti-idiotypic antibodies by the host (Montgomery, 2001; Platt & Bach, 1991).

These patients are followed by obtaining routine blood work; isoagglutinin titers; and routine biopsies done at 1 month, 3 months, 6 months, and 1 year. It can be difficult to detect rejection initially, as the titer does not necessarily correlate with rejection episodes. However, a sudden rise in titers should elicit a high index of suspicion for rejection. A rapid decline in the PLT count due to hemolysis may be an early indicator of rejection.

Case Study: ABOI Transplant

P.A. was a 20-year-old male college student at the time of his transplant. His blood type was O. He had two previous transplants that had made him highly sensitized (HS), and it difficult to find a donor to whom he did not have donor specific antibodies. He could expect to wait a long time on the cadaveric waiting list because of his HS status and blood type. His mother wanted to be his donor, but she was blood type [A.sub.2]. He and his mother decided to proceed with an ABOI transplant. Their XM was negative.

Per protocol, he received his vaccinations over 1 month prior to surgery. He received five plasmapheresis treatments followed by CMV-HG preoperatively. He started on tacrolimus (3 mg twice a day) and mycophenolate mofetil (1 g twice a day) on the first day of plasmapheresis. As his blood type was O and his mother's was A, the goal of plasmapheresis was to remove as much antibody to blood type A (anti-A) as possible. His titer prior to the first plasmapheresis was 1:64 (see Figure 3). The last three plasmapheresis treatments were done on three consecutive days, the last being on the morning of surgery to ensure that the titer did not rebound. His anti-A titer was 1:4 after the final treatment well below the established cutoff of < 1:16. The transplant surgery proceeded along with the laparoscopic splenectomy without incident. Daclizumab was initiated intraoperatively and then continued every other week for a total of 5 doses. He continued on the tacrolimus and mycophenolate and prednisone was added. The target for his tacrolimus level was 15 ng/dl. He had two additional plasmapheresis treatments postoperatively, and his anti-A titers were 1:4-1:8. His creatinine declined steadily from 13.6 mg/dl to 1.7 mg/dl at discharge. He left the hospital on postoperative day 5. Anti-A titers done at 6 and 9 months after transplant were both 1:32. Despite the increased titer, he has normal renal function and no evidence of rejection indicating that he has likely accommodated to his ABOI renal transplant. He developed a CMV infection 3 months posttransplant that was successfully treated with ganciclovir. He continues to go to college at this time.

Summary

In the case of +XM and ABOI transplantation, the scarcity of donor kidneys has been the mother of invention. Both +XM and ABOI transplantation are providing opportunities for kidney transplants to individuals who likely would never have received a transplant or would have waited for a protracted period. These modalities are complex and require intensive involvement of the health care providers, the patient, and prospective donors. To achieve the desired goal of a successful transplant takes significant time and effort on the part of all involved. In the face of the ever-growing cadaveric waiting list, these strategies are essential and have great potential to become simpler and more successful as technology improves and experience increases. These special types of transplants are not indicated for all patients, but should be offered as an option to all reasonable candidates.
Table 1

Positive Crossmatch Pre-emptive Therapy Protocol

                Steps                               Purpose

Establish positive crossmatch/           Establishes diagnosis
elevated DSA titer.                      indicating the need for
                                         implementation of the special
                                         protocol.

Preoperative PP (1-6 treatments) with    Removes anti-HLA antibodies
replacement with albumin or FFP.         (DSA) that would cause
                                         hyperacute rejection or AMR.

Preoperative CMV-HG (100 mg/kg)          Exerts immunomodulatory effect
after every PP.                          decreasing production of DSA
                                         or the immune system response
                                         to DSA. Replenishes good
                                         antibodies to bacteria,
                                         viruses, and fungi.

Initiation of immunosuppressants         Prevents incidental episodes
(tacrolimus and mycophenolate            of cellular rejection and
mofetil) on first day of PP.             suppresses antibody production.

DSA titer monitoring.                    Assesses success of PP and
                                         CMV-HG therapy.

Repeat crossmatch.                       To determine if XM is
                                         positive. A + XM would
                                         indicate the presence of
                                         significant DSA that would
                                         lead to hyperacute rejection.
                                         Additional PP/CMV-HG would
                                         be required before proceeding
                                         to transplant.

Transplant surgery with intraoperative   Prevents incidental episodes
daclizumab followed by four additional   of cellular rejection and
doses every other week.                  suppresses antibody
                                         production.

Postoperative PP (2 treatments or        Same as for preoperative.
more).

Postoperative CMV-HG (100 mg/kg)         Same as for preoperative.
after every PR

DSA titer monitoring.                    Assesses ongoing antibody
                                         activity.

Repeat crossmatch.                       Elevated antibody titers
                                         and/or a + XM may be
                                         indicative of AMR and requires
                                         further PP/CMV-HG.

Assessment of creatinine and urine       Assesses renal function.
output.

Biopsy, if indicated.                    If elevated may indicate the
                                         need for a biopsy. A positive
                                         C4d would indicate AMR and the
                                         need for additional PP
                                         and CMV-HG.

Note: AMR = antibody-mediated rejection; CMV-HG = CMV hyperimmune
globulin; DSA = donor specific antibody; HAR = hyperacute rejection;
HLA = human leukocyte antigen; PP = plasmapheresis; XM = crossmatch

Table 2

Rescue Therapy Protocol for Acute Antibody-Mediated Rejection

             Steps                               Purpose

Establish +XM/elevated DSA titer.    To establish diagnosis of AMR
(This would be done in response to   indicating need for implementation
increased creatinine and decreased   of protocol.
urine output.) Biopsy, if
indicated.

PP (Treat until DSA is               Removes anti-HLA DSA that are
undectectable).                      causing AMR.

CMV-HG (100 mg/kg) after every PP.   Same as for pre-emptive therapy.

Increased imunosuppression.          To prevent cellular rejection and
                                     suppress antibody production.

DSA titer monitoring.                To assess success of
Monitoring of creatinine and urine   anti-rejection therapy and
output.                              determine how long therapy should
Repeat XM.                           continue.
Repeat biopsy, if indicated.

Note: AMR = antibody-mediated rejection; CMV-HG = CMV hyperimmune
globulin; DSA = donor specific antibody; HLA = human leukocyte antigen;
PP = plasmapheresis; XM = crossmatch

Table 3

ABO Incompatible Protocol

              Steps                               Purpose

Confirm ABO incompatibility and      To establish need for initiation
measure antibody titer to foreign    of protocol and determine number
blood group.                         of PP treatments needed.

Administer vaccinations for          Helps prevent development of these
meningococcus, pneumococcus, and     infections post-operatively.
tetanus at least 1 month before      Recipient will be more susceptible
surgery.                             to these infections due to the
                                     splenectomy.

Preoperative PP (at least 5-10       Removes isoagglutinins to foreign
treatments; the last 3 may be done   blood group.
on consecutive days including the
day of surgery).

Preoperative CMV-HG (100 mg/kg)      Exerts immunomodulatory effects
after every PP.                      that decrease antibody production
                                     and promote accommodation.
                                     Replenishes good antibodies to
                                     bacteria, viruses, and fungi.

Initiation of immunosuppressants     Prevents incidental episodes of
(tacrolimus and mycophenolate        cellular rejection and suppresses
mofetil) on first day of PP.         antibody production.

Isoagglutinin titer monitoring.      Measures the success of PP and
                                     CMV-HG at reducing antibody titer.
                                     Titer should be < 1:16.

Transplant surgery and               Prevents incidental episodes of
intraoperative daclizumab followed   cellular rejection and suppresses
by four additional doses every       antibody production.
other week.

Laparoscopic splenectomy.            Reduces antibody production.

Postoperative PP                     Same as for preoperative.
(2 or more treatments).

Postoperative CMV-HG (100 mg/kg)     Same as for preoperative.
after every PP.

Isoagglutinin titer monitoring.      Assesses ongoing antibody
                                     activity. An elevation in
                                     antibody level to the foreign
                                     blood group does not necessarily
                                     indicate rejection.

Assessment of creatinine and urine   Assesses renal function and
output.                              potential need for biopsy.

Renal biopsy at 1 month,             Assesses for AMR. A positive C4d
3 months, 6 months, and 1 year.      on biopsy suggests AMR.

Note: AMR = antibody-mediated rejection; CMV-HG = CMV hyperimmune
globulin; PP = plasmapheresis

Figure 1

Recipient (FW) and Donor (AD) HLA Tissue Typing Results

FW and AD match on A3, B8, and DR4 (in italics), but mismatch on three
antigens. In addition FW has donor specific antibody to AD's B60.

Recipient (FW) HLA:    A3   A25   B8   B62   DR4   DR17

Donor (AD) HLA:        A3    A1   B8   B60   DR4   DR13

Figure 2

Antibody Titers Pre- and Post-Plasmapheresis: Patient F.W.

Antibody titers are checked pre- and post-plasmapheresis. F.W.'s
antibody titer declined to 1:4 by the morning of surgery allowing the
transplant to proceed as scheduled. PP was not done the day of surgery.

              Pre PP     Post PP      Titer on
Date         Antibody    Antibody    non-PP day
              Titer       Titer

2/7            128         32
2/9             64         64
2/12            64         16
2/14            16          8
2/16             8          2
2/19             4          1
2/20 (OR)                                4
2/21                        1

Note: Table made from bar graph.

Figure 3

Antibody Titers to Foreign Blood Group: Patient P.A.

P.A. received five preoperative PP treatments. Titer decreased to 1:4
the morning of surgery the transplant to proceed as scheduled. Although
titers rose post-operatively, no decrement in renal function was see.

                Pre PP     Post PP      Titer on
Date           Antibody    Antibody    non-PP day
                Titer       Titer

6/8/01           64
6/11/01          32          32
6/13/01          32          16
6/14/01          16          16
6/15/01(OR)      32           4
6/18/01           8           4
10/11/01                                   32
1/23/02                                    32

Note: Table made from bar graph.


Acknowledgments: The authors would like to acknowledge Lloyd Rather, MD; Christopher Sonnenday, MD; and the Johns Hopkins Tissue Typing Lab and Blood Bank for their contributions to the Positive Crossmatch and ABO Incompatible Transplant Programs.

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Mary Jo Holechek, MS, CRNP, CNN, is Nurse Practitioner in the adult abdominal organ transplant service, Johns Hopkins Hospital, Baltimore, MD. She is a member of ANNA's Baltimore Chapter.

Janet M. Hiller, MSN, RN, is Transplant Nurse Coordinator for special programs including positive crossmatch, ABO incompatible, altruistic donor, and paired kidney exchange transplants, Johns Hopkins Hospital, Baltimore, MD. She is a member of ANNA's Baltimore Chapter.

Melinda M. Paredes, MSN, RN, is Clinical Nurse Specialist in the adult abdominal organ transplant service, Johns Hopkins Hospital, Baltimore, MD.

Jennifer C. Rickard, BSN, RN, is Transplant Nurse Coordinator for the kidney and special programs, Johns Hopkins Hospital, Baltimore, MD.

Robert A. Montgomery, MD, DPhil, is Transplant Surgeon and Associate Professor of Surgery, Johns Hopkins University, Baltimore, MD. He is the Director of the transplant special programs including positive crossmatch, ABO incompatible, altruistic donor, and paired kidney exchange transplants.
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Author:Holechek, Mary Jo; Hiller, Janet M.; Paredes, Melinda; Rickard, Jennifer C.; Montgomery, Robert A.
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Apr 1, 2003
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