ABO-compatible Transplantation Research Articles

A new immunosuppressive therapy in ABO-incompatible kidney transplantation based on a new concept of accommodation

Since the advent of modern immunology, there have been two major principles in transplantation medicine: tolerance and accommodation. Owing to the shortage of cadaveric kidneys in Japan, since 1989, we have performed ABO-incompatible kidney transplantation to expand the indication for kidney transplantation. Through our experience, we have studied the basic and clinical characteristics of accommodation. During the past half-century, we were taught that ABO-incompatible kidney transplantation would result in hyperacute rejection and graft loss within 24 h after transplantation. However, rejection does not occur and the grafts survived in nearly all recipients of ABO-incompatible kidney transplants. We found that accommodation is the mysterious phenomenon responsible for graft survival despite the presence of ABO antigens on graft endothelial cells and of antibodies to these antigens in the recipient's blood. We initially thought that ABO antigens and HLA antigens could not be changed or modified. However, our experience with ABO-incompatible kidney transplantation shows that these two types of antigens differ. ABO antigens are governed by the ABO gene product ABO glycosyltransferase. ABO antigens cannot express antigenicity in the absence of this enzyme. During accommodation, the recipient's ABO genes suppress ABO genes in the graft, thereby inhibiting production of ABO glycosyltransferase. Antigenicity of graft ABO antigens is thus lost, leading to graft survival. Immunosuppressive therapy has been established on the basis of the theory of accommodation. In Japan, ABO-incompatible kidney transplantation has been performed in > 700 patients. Outcomes are similar to those of ABO-compatible kidney transplantation. Throughout the world including Europe and North America, ABO-incompatible kidney transplantation has been evaluated as safe and effective as ABO-compatible transplantation and is now applied for all types of organ transplantation. Since the discovery of human ABO blood type by Karl Landsteiner in 1901, 100 years were required to break through the wall of ABO blood type, a dream of transplantation medicine. We have delineated the mechanism of accommodation, leading to the establishment of new strategies for immunosuppressive therapy and enabling ABO-incompatible kidney transplantation to be performed throughout the world. We believe that this represents a major advance in transplantation medicine.

ABO-Incompatible Solid-Organ Transplantation

To increase transplantation access, particularly in living-donor renal transplantation, efforts have been made to overcome the barrier of ABO incompatibility. In adults, the most successful cases have involved renal transplantation. Although the overall goal of reducing antibodies against donor ABO before and after transplantation is a general principle, the protocols used to accomplish this goal vary. More well-designed, controlled clinical trials are needed to establish optimal peritransplantation management protocols. Incompatible liver transplantation still is viewed as a temporary measure until ABO-compatible transplantation can be performed. ABO-incompatible heart and lung transplantation in adults still is not performed intentionally. In children, particularly those with relatively immature immune systems, ABO-incompatible transplantation generally has more success. The immunologic mechanisms leading to successful transplantation are being elucidated. Accommodation is a process whereby the donor organ may participate in its own survival through a series of protective gene responses, possibly in response to low-level incompatible antibody (HLA and ABO). In infants, spontaneous, acquired B-cell tolerance seems to be a primary mechanism. Peritransplantation therapy might be tailored to invoke specific immune graft-sparing mechanisms. The stage is set to eliminate ABO as a barrier to solid-organ transplantation.

Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants

Recent data suggest that ABO blood group-incompatible donor hearts are immunologically well tolerated in infants undergoing transplantation. Competing-risks methodology was used to assess outcomes after listing and the impact of a strategy to accept heart grafts from any blood group donor for infants less than 18 months of age. From 1992 to 2002, there were 91 listing episodes in 84 patients (including 20 fetuses; 50% were male and 63% had congenital heart disease). Beginning in 1995, a strategy to accept ABO-incompatible organs was adopted. Competing-risks analysis showed that after 20 months 60% underwent transplantation, 18% died, and less than 1% were still listed; the remaining 21% were de-listed because of a change of surgical strategy (9%), improved clinical condition (8%), and deterioration to ineligibility (4%). Risk factors for transplantation included only a strategy to accept ABO-incompatible organs (P <.001). Risk factors for death included failure to accept ABO-incompatible organs (P =.002) and Canadian listing status 3 (P =.085) or 4 (P <.001). Multivariable parametric models were used to create competing risk predictions for outcomes specific to status and ABO-incompatible strategy. Higher status resulted in greater mortality regardless of strategy, although for any status, more patients underwent transplantation and fewer died using a strategy to accept ABO-incompatible organs. Parametric modeling of time-related freedom from death or retransplantation demonstrated no significant difference at 4 years posttransplantation (P =.78) for ABO-incompatible (74%) versus ABO-compatible transplants (72%). A strategy to accept ABO-incompatible donor hearts for infant transplantation significantly improves the likelihood of transplantation and reduces waiting list mortality while not adversely altering outcomes after transplantation.

ABO incompatible kidney transplantation – an analysis of UNOS Registry data

The ABO incompatible kidney transplants have been performed successfully from large numbers of living donors and some blood type A2 deceased donors. However, there are few reports to support the feasibility of ABO incompatible transplants from non-A2 deceased donors. This problem was examined in the United Network for Organ Sharing (UNOS) data file. The UNOS Registry data of kidney transplants performed between 1995 and 2003 from 256 centers was utilized for Kaplan-Meier curves and log-rank tests to compare graft and functional graft survival rates. Deceased donor transplants from all ABO incompatible donors had the same graft survival rates, as that from ABO compatible donors regardless of whether the blood group incompatibility was A (A1), A2 or B. Graft survival from 201 ABO incompatible donors was 66.9% at 5 yr, compared with 66.7% for ABO compatible donors (p = 0.83). Non-A2 incompatible donors also yielded comparable survival rates to ABO compatible donors. From living donors, ABO incompatible donors yielded significantly lower graft survival rates than the ABO compatible group, although long-term graft survival rates of those who survived >1 yr did not differ significantly. Except higher initial graft loss possibility because of insufficient removal of antibodies, non-A2 kidneys yielded equivalent graft survival rates to ABO compatible transplants. In addition to A2 incompatibilities, Blood group A1 and B incompatibilities can also be considered in ABO incompatible transplants.

Latent IgA deposition from donor kidney is the major risk factor for recurrent IgA nephropathy in renal transplantation

Previous studies have recognized risk factors for recurrent IgA nephropathy (r-IgAN) in renal transplantation. However the clinical significance of latent IgA deposition from the donor kidney remains to be determined. Between 1992 and 1999, 0-hour allograft biopsies were performed in 510 renal transplantation recipients at the Kidney Center of Tokyo Women's Medical University. Among these 510 patients, there were 49 whose primary disease was identified as IgAN. Among these 49 patients, 13 patients (26.5%) were diagnosed as having r-IgAN based on renal biopsy. We compared risk factors of r-IgAN, including IgA deposition, between the r-IgAN and non-r-IgAN groups. We assessed factors previously reported to be risk factors for r-IgAN, such as follow-up period after transplantation, sex, ages of donors and recipients, donor type, ABO compatible or incompatible transplantation, number of HLA-A, B, and DR mismatches, number of donors with HLA-A2, B35, B46, and/or DR4, duration to end stage renal disease, duration of dialysis, and latent IgA deposition from donor kidneys. Latent IgA deposition was the only risk factor that differed significantly in frequency between patients with and without recurrence (38.5% in r-IgAN group vs. 9.1% in non-r-IgAN group, p = 0.037). Other factors did not differ significantly between the two groups. Clinical factors, such as urinary protein excretion, urinary red blood cell sediment and serum creatinine, were significantly worse and the number of patients who required hemodialysis 5 yr after transplantation was significantly higher in the r-IgAN group than in the non-r-IgAN group (38.5 vs. 5.6%, p = 0.001). Four of the five patients who required hemodialysis in the r-IgAN group had latent IgA deposition from the donor kidney. Our data suggest that 26.5% out of patients with primary IgAN will develop recurrence within 5 yr after transplantation. Latent IgA deposition from the donor kidney was one of the risk factors of r-IgAN and it would lead to the development of r-IgAN. Moreover, r-IgAN will compromise graft survival, especially in cases with latent IgA deposition from the donor kidney.

Pediatric Heart Transplantation across ABO Blood Type Barriers: A Case Study

Heart transplantation with ABO blood type-incompatible donors has historically been contraindicated because of the high risk of an immediate hyperacute humoral graft rejection. The immature neonatal immune system presents an immunologic window that allows for breaching the ABO barrier before the natural development of anti-ABO antibodies. Information from a small series of neonates has demonstrated similar survival rates and posttransplant outcomes compared to ABO-compatible transplantations. In the posttransplant period, particular attention is placed on the surveillance of graft-specific antibody production and monitoring for immunologic signs and symptoms of early graft vasculopathy. This article presents a case study of a neonate with congenital heart disease who underwent one of the first successful ABO-incompatible heart transplantations in the United States.

Pediatric heart transplantation across ABO blood type barriers: a case study

Heart transplantation with ABO blood type-incompatible donors has historically been contraindicated because of the high risk of an immediate hyperacute humoral graft rejection. The immature neonatal immune system presents an immunologic window that allows for breaching the ABO barrier before the natural development of anti-ABO antibodies. Information from a small series of neonates has demonstrated similar survival rates and posttransplant outcomes compared to ABO-compatible transplantations. In the posttransplant period, particular attention is placed on the surveillance of graft-specific antibody production and monitoring for immunologic signs and symptoms of early graft vasculopathy. This article presents a case study of a neonate with congenital heart disease who underwent one of the first successful ABO-incompatible heart transplantations in the United States.

ABO-incompatible organ and bone marrow transplantation: current status.

Despite the presence of preformed antibodies against AB oligosaccharide epitopes on the donor vascular endothelium, approximately one-third of ABO-incompatible organ allografts are not rejected by a humoral mechanism. With the growing immune-manipulation of the recipient, survival rates can be raised considerably, although they remain significantly inferior to those of ABO-compatible transplantation. Data from the Collaborative Transplant Study indicate a 1-year graft survival rate of approximately 50-60% following cadaveric ABO-incompatible kidney, liver or heart transplantation, compared with 70-80% for an ABO-compatible organ. The results for infants and young children, however, are very much better than those of adults, particularly for liver and heart transplantations, and the data suggest that B-cell tolerance can develop in the infant age group. We here review clinical and experimental experience with ABO-incompatible organ and bone marrow allotransplantation and address the mechanisms by which organs or cells survive in the presence of natural anti-carbohydrate antibodies.

Ten-year experience in transplantation of A2 kidneys into B and O recipients.

This article summarizes our 10-year multicenter experience with transplantation of 50 blood group A2 and A2B kidneys into B and O patients. Since 1986, we have transplanted kidneys from 46 cadaver donors and 4 living donors who were blood group A2 (47 donors) or A2B (3 donors) into 19 B and 31 O patients. In 1991, we began allocating these kidneys preferentially to B and O recipients who were selected based on a history of low (< or =4) anti-A IgG isoagglutinin titers. Immunosuppression was no different from that used in ABO-compatible grafts. The 1-month function rate before thus selecting the patients was 68% (19/28), but is now 94% (17/18). Two-year cadaver-donor graft survival with this selection method is 94%, compared with 88% for 640 concurrent and consecutive ABO-compatible transplants (log-rank, 0.15). All four living-related transplants are still functioning, with a mean follow-up of 71 months. Since we began allocating A2 kidneys preferentially to B and O recipients, the percentage of the B patients who received A2 or A2B kidneys has increased from 29% (8/28) to 55% (10/18). Transplantation of A2 or A2B kidneys into B and O patients is clinically equivalent to that of ABO-compatible transplantation when recipients are selected by low pretransplant anti-A titer histories. This approach increases access of blood group B recipients to kidneys.

RESISTANT HEPATIC ALLOGRAFT REJECTION SUCCESSFULLY TREATED WITH CYCLOPHOSPHAMIDE AND PLASMAPHERESIS

We report 2 patients who underwent ABO compatible orthotopic liver transplantation with acute rejection that appears to be cellular ― as well as antibody-mediated

Regeneration of peripheral blood cells following ABO incompatible allogeneic bone marrow transplantation for severe aplastic anaemia.

The regeneration of peripheral blood cells in six patients receiving ABO incompatible bone marrow transplants for severe aplastic anaemia has been studied. The results are compared with those of 18 similar aplastic patients treated with ABO compatible transplants. Reticulocyte recovery in the ABO incompatible cases was significantly delayed (P less than 0.01) and associated with greatly prolonged red cell transfusion requirements (P less than 0.001). Peripheral blood regeneration of neutrophils, lymphocytes and platelets was also significantly delayed (P less than 0.01). Platelet support was required for longer in the ABO incompatible cases (P less than 0.001) but there was no increase in the incidence or severity of infections in the post transplant period.

Regeneration of peripheral blood cells following allogeneic bone marrow transplantation for severe aplastic anaemia.

We have studied the pattern of regeneration of peripheral blood cells following ABO compatible bone marrow transplantation for severe aplastic anaemia. 18 patients were treated with cyclosporin A and six with methotrexate for post graft immunosuppression. The number of days taken for the neutrophil count to reach 0.5 x 10(9)/l, the lymphocyte count to reach 1.0 x 10(9)/l, the platelet count to reach 100 x 10(9)/l and the reticulocytes to reach 1% was shorter in the CyA treated patients. This finding reached statistical significance for all types of cells except the platelets (neutrophils, P less than 0.001; lymphocytes, P less than 0.02; platelets, P greater than 0.05; reticulocytes, P less than 0.001). The more rapid regeneration of peripheral blood cells in patients treated with cyclosporin A has contributed to reducing the length of time patients are dependent on blood product support in the post transplant period.

ABO-incompatible marrow transplants.

We analyzed data from 81 ABO-incompatible marrow transplants performed between 1972 and 1980. Patients with high anti-red blood cell antibody levels pretransplant had a significantly increased probability of antibody return post-transplant. This was true for IgG and for IgM as independent variables. However, the return of antibody post-transplant had no effect on engraftment, survival, or blood product requirements posttransplant. Patients who received ABO-incompatible marrow had a similar time to engraftment, survival, and incidence of rejection and graft-versus-host disease as patients receiving ABo-compatible transplants. Neither pretransplant treatment regimen nor the development of graft-versus-host disease had an effect on post-transplant antibody levels. ABO-incompatible marrow transplants can be performed with no greater morbidity or mortality than ABO-compatible grafts. The procedures for antibody removal may be useful in other organ transplant settings.

Conjunctival lymphocytosis after corneal transplantation.

Conjunctival lymphocytosis was followed after penetrating corneal transplantations. Examinations were made of scrapings taken with the spatula and stained according to May‐Griinwald‐Giemsa. In a series of 22 ABO compatible transplantations a semi‐quantitative correlation was found between the HL‐A compatibility and the degree of lymphocytosis in the second to fifth postoperative month. It is suggested that conjunctival lymphocytosis reflects immune processes in the cornea. Clinical use of the method could probably be made in the second or third month when strong lymphocytosis would contraindicate a reduction or indicate an initiation of immunosuppressive therapy.