Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group-Incompatible Renal Transplantation

Antibody-mediated rejection (AMR) is one of the leading causes of allograft failure especially in patients undergoing ABO-incompatible (ABOi) renal transplantation. We hypothesized that complement inhibition with eculizumab, a C5 inhibitor, would protect against AMR and maintain graft function in ABOi renal transplant recipients. Four patients undergoing living donor kidney transplant from ABOi donors were treated with a 9-week eculizumab course without therapeutic plasma exchange, intravenous immunoglobulin, or splenectomy. All patients had successful transplants and have normal graft function at the time of last follow-up. There were no cases of AMR or acute cellular rejection. Of note, 2 patients were transplanted despite persistent ABO antibody titers of 1:32, conventionally considered a contraindication to proceed in standard protocols. Eculizumab is a promising option to prevent AMR with ABOi renal transplantation without the need for splenectomy, post-transplant therapeutic plasma exchange, and intravenous immunoglobulin. Future multicenter studies are needed to determine long-term efficacy and safety.     

Treatment of acute antibody-mediated rejection: a single-center experience

Introduction

Acute antibody-mediated rejection (AMR) leads to graft loss. The combination of plasmapheresis (PP), intravenous immunoglobulin (IVIG), and rituximab (RTX) has been reported to be effective therapy.

Patients and methods

Between October 2005 and September 2009, 8 (4.7%) kidney transplant recipients developed AMR, diagnosed by severe acute rejection and extensive C4d staining in peritubular capillaries.

Results

All patients were treated with two to six sessions of PP with IVIG added after the last PP. In two patients, RTX was prescribed after PP and IVIG. Baseline immunosuppression was based on steroids, mycophenolate mofetil or azathioprine, and tacrolimus or cyclosporine or everolimus. The presence of subsequent significant decrease in anti-HLA class I antibodies was demonstrated in a highly sensitized patient before and after transplantation with PP treatment. An increase was observed before the diagnosis of AMR. After a mean follow-up of 10 months (range = 1-23), patient and graft survivals were 100% and 50%, respectively. Three patients lost their transplants to AMR refractory to treatment and one patient, due to interstitial fibrosis and tubular atrophy at 23 months after AMR. Finally, four patients recovered renal function, showing a mean serum creatinine of 2.2 ± 0.45 mg/dL.

Conclusions

Early diagnosis and treatment with PP, IVIG, and RTX may resolve AMR. PP before and after transplantation in high-risk patients may result in anti-HLA class I and class II antibody removal from plasma and prevention of AMR.     

Antibody-mediated rejection after adult ABO-incompatible liver transplantation remedied by gamma-globulin bolus infusion combined with plasmapheresis

Adult ABO-incompatible liver transplantation has been known to be associated with markedly desperate outcomes. Antibody-mediated rejection (AMR) has been recognized as one of the primary causes of these desperate outcomes, but its clinical features and significance have not been well understood. Recently, some clinicians have succeeded in improving the outcome of adult ABO-incompatible liver transplantation. However, in some transplant patients undergoing these treatments, AMR has still led to graft losses. We recently encountered two patients suffering from AMR after adult ABO-incompatible liver transplantation and remedied their conditions with various therapeutic modalities including direct hepatic infusion therapy and gamma-globulin bolus infusion therapy combined with plasmapheresis. In this article, we describe the clinical features of these patients and the therapeutic strategies we applied. Furthermore, we show the histologic course of the recovery from AMR in the second patient, from whom we were able to extract serial liver biopsies.     

Clinical course and pathologic findings of successful second ABO-incompatible renal transplantation in a patient with donor-specific anti-HLA antibody

Abstract:  Donor-specific anti-HLA antibody and anti-blood group antibody could cause antibody-mediated rejection (AMR). Here, we report a successful second ABO-incompatible (ABO-I) renal transplantation in a patient with donor-specific anti-HLA antibody and its pathologic findings. A 50-yr-old woman underwent second ABO-I (A1 to O) renal transplantation. She had received the first renal graft from her mother following splenectomy in July 2003; however, graft function was lost 50 d after transplantation because of AMR. The patient received the second renal graft in November 2005, from her husband whose blood type was also A1. The recipient had donor-specific anti-HLA antibody because flow panel reactive antibody and flow cytometry crossmatch were strongly positive prior to the plasmapheresis (PP) therapy. Pre-transplant intensive immunosuppression, PP, and low dose (100 mg/m²) anti-CD20 antibody (rituximab) administration were performed as desensitization therapy. The recipient clinically developed acute rejection, and allograft biopsy specimen at day 6 post-transplant revealed AMR type II according to the Banff 2003 classification. However, the graft function was rescued by PP/low dose (100 mg/kg) intravenous immunoglobulin (IVIG) therapy, and the biopsy specimen at day 43 post-transplant showed border-line change without AMR. Rituximab and PP/low-dose IVIG therapy might improve the clinical course and pathologic findings in this AMR-related high-risk transplantation.     

High-Dose Intravenous Immunoglobulin and Rituximab Treatment for Antibody-Mediated Rejection After Kidney Transplantation: A Cost Analysis

Antibody-mediated rejection (AMR) generally occurs in highly sensitized patients. A pilot study was performed on 7 consecutive patients with AMR to assess the efficacy of high-dose intravenous immunoglobulin (IVIG; 2 g/kg) + rituximab (RTX; 375 mg/m²) without plasmapheresis. After a 24-month follow-up, 1- and 2-year allograft survivals were 86% and 58%, respectively. C4d became negative in 1 patient posttreatment. Donor-specific antibody (DSA) titers decreased to less than 1:4 in 2 cases. There were 4 infectious complications and 1 case of aseptic meningitis followed by cranial nerve VI palsy. The average hospital charge for 1 administration of IVIG + RTX, including hospital stay and renal biopsy expenses, was approximately $49,000. A combination of IVIG + RTX in late AMR may be beneficial but is an expensive treatment approach for selected renal transplant patients.     

The Stockholm experience with ABO-incompatible kidney transplantations without splenectomy

BACKGROUND: ABO-incompatible kidney transplantations have previously only been performed after several pre-operative sessions of plasmapheresis followed by splenectomy, and with the conventional triple-drug immunosuppressive protocol being reinforced with anti-lymphocyte globulin and B-cell-specific drugs. We have designed a protocol without splenectomy, based on antigen-specific immunoadsorption, rituximab and a conventional triple-drug immunosuppressive protocol. METHODS: The protocol called for a 1-month pre-transplantation conditioning period, starting with one dosage of rituximab and followed by full-dose tacrolimus, mycophenolate mofetil and prednisolone. Antigen-specific immunoadsorption was performed on pre-transplantation days -6, -5, -2 and -1. After the last session, 0.5 g/kg of intravenous immunoglobulin (IVIG) was administered. Postoperatively, three more apheresis sessions were given every third day. RESULTS: Twenty-one patients have received transplants with this protocol. The ABO-antibodies (Abs) were readily removed by the antigen-specific immunoadsorption and were kept at a low level post-transplantation by further adsorptions. There were no side effects, and all but one patient have normal renal transplant function. CONCLUSIONS: We conclude that after one infusion each of rituximab and IVIG, and antigen-specific immunoadsorption, blood-group incompatible renal transplantations can be performed with standard immunosuppression and without splenectomy, and with excellent short- and long-term results.     

Successful Renal Transplantation across Simultaneous ABO Incompatible and Positive Crossmatch Barriers

ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the two largest barriers to optimal utilization of kidneys from live donors. Here we describe the first successful transplantation of patients who were both ABO incompatible and crossmatch positive with their only available donor. A preconditioning regimen of plasmapheresis (PP) and low-dose CMV hyperimmune globulin (CMVIg) was delivered every other day until donor-specific antibody (DSA) titers were reduced to a safe level and isoagglutinin titers were < or =16. Each patient received quadruple sequential immunosuppression, splenectomy and three protocol post-transplant PP/CMVIg treatments. There was no hyperacute rejection. Two of the three patients had a persistent positive cytotoxic crossmatch on the day of transplant and eliminated their DSA subsequently. Antibody-mediated rejection (AMR) in one patient was reversed by reinitiating PP/CMVIg and anti-CD20. The patients are more than 9 months post-transplant with excellent graft function. Preconditioning with PP/CMVIg results in a durable suppression of DSA and permits accommodation of the allograft to a discordant blood type. The ability to cross these two barriers simultaneously is clinically important as sensitized patients have often exhausted their blood type compatible living donors during previous transplants.     

Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).     

Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients

Intravenous immunoglobulin products (IVIG) are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for nearly 30 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders, however the precise mechanism(s) of immune modulation are unknown. Recent data suggests that IVIG has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIG is also a recently recognized modifier of complement activation and injury. These attributes suggests IVIG would have clinical applications in solid organ transplantation. Analysis of clinical studies examining the use of IVIG in desensitization protocols and for treatment of antibody‐mediated rejection (AMR) are supportive for kidney transplant recipients, although no clinical trials using IVIG in sensitized patients were performed seeking an Federal Drug Administration indication. Data regarding the use of IVIG for desensitization and treatment of AMR in cardiac and lung allograft recipients is not conclusive. IVIG is useful in the treatment and prevention of posttransplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus. In addition, we address the risk of adverse events associated with IVIG use in sensitized end‐stage renal disease and transplant patients.     

Splenic Irradiation for the Treatment of Severe Antibody‐Mediated Rejection

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody‐mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long‐term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor‐specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short‐ or medium‐term adverse effects of the radiation therapy. One‐year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.     

Case Report: Eculizumab Rescue of Severe Accelerated Antibody-Mediated Rejection After ABO-Incompatible Kidney Transplant

ABO-incompatible (ABOI) living donor kidney transplantation has become a well-accepted practice with standard protocols using perioperative antibody-depleting therapies to lower blood group titers to an acceptable threshold for transplantation. However, a subset of patients will experience accelerated antibody-mediated rejection (AMR) after ABOI kidney transplantation and require aggressive intervention to prevent allograft loss. Here in we report the successful use of terminal complement inhibition with eculizumab to rescue an ABOI kidney allograft with accelerated AMR refractory to salvage splenectomy and daily plasmapheresis. This case emphasizes the fact that, despite close postoperative surveillance and aggressive intervention, graft loss from accelerated AMR after ABOI kidney transplantation remains a very real risk. Eculizumab may offer a graft-saving therapeutic option for isolated cases of severe AMR after ABOI kidney transplantation refractory to standard treatment.     

ABO Incompatible Kidney Transplantations Without Splenectomy, Using Antigen-Specific Immunoadsorption and Rituximab

ABO incompatible kidney transplantations have previously only been performed after several preoperative sessions of plasmapheresis and splenectomy, with the conventional triple-drug immunosuppressive protocol being reinforced with antilymphocyte globulin and B-cell-specific drugs, such as cyclophosphamide or deoxyspergualine. We have designed a protocol without splenectomy, based on antigen-specific immunoadsorption, rituximab and a conventional triple-drug immunosuppressive protocol. The protocol calls for a 10-day pretransplantation conditioning period, starting with one dosage of rituximab and followed by full dose tacrolimus, mycophenolate mofetil and prednisolone. Antigen-specific immunoadsorption was performed on pretransplantation days -6, -5, -2 and -1. After the last session, 0.5 g/kg of intravenous immunoglobulin (IVIG) was administered. Postoperatively, three more apheresis sessions were given every third day. Furthermore, if there was a significant increase in the antibody titers, extra sessions were considered. Eleven patients have received transplants with this protocol. The ABO antibodies were readily removed by the antigen-specific immunoadsorption and were kept at a low level post-transplantation by further adsorptions. There were no side effects and all patients have normal renal transplant function. We conclude that after an infusion each of rituximab and IVIG, and antigen-specific immunoadsorption; blood group-incompatible renal transplantations can be performed with excellent results using standard immunosuppression and no splenectomy.     

Antibody‐mediated rejection of renal allograft in combined liver–kidney transplant

Barth RN, Campos L, Kukuruga DL, Drachenberg C, Philosophe B. Antibody‐mediated rejection of renal allograft in combined liver–kidney transplant.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01161.x
© 2009 John Wiley & Sons A/S. Abstract: Liver transplantation is performed based on ABO blood type compatibility without dependence on crossmatch results. Combined liver–kidney transplantation (CLKT) is similarly performed without dependence of crossmatch results as the liver is thought to confer protection to the renal allograft against alloantibody. We report a case of CLKT in a sensitized patient with antibody‐mediated rejection (AMR) of the renal allograft. AMR was confirmed with C4d staining and serial monitoring of donor‐specific antibody (DSA). Despite intensive therapy directed against AMR and the presence of the liver allograft, the patient demonstrated increasing titers of alloantibody, never demonstrated adequate renal function, and ultimately expired after two months. This result demonstrates the potential for AMR of the renal allograft in sensitized recipients of CLKT.     

Indication for splenectomy in the era of living-donor liver transplantation

Although end-stage liver disease (ESLD) is often associated with splenomegaly and thrombocytopenia, splenectomy is not necessary in liver transplantation (OLT) except in special situations. In this paper, we examined the indications for splenectomy in the era of living-donor living transplantation. Six of 46 patients underwent splenectomies. Among them, one received a cadaveric graft. Three splenectomies were performed at 6, 7, and 44 days after OLT because of a huge spleen, massive ascites, or impaired liver function. The other two patients received simultaneous splenectomy during OLT to prevent rejection of ABO-incompatible grafts with a positive anti-T-cell test; and one, for postoperative therapy of hepatitis C. All six patients had a good response to splenectomy. We concluded that splenectomy may be indicated for recipients with severe thrombocytopenia, small-for-size syndrome, ABO incompatibility with positive anti-T/B-cell tests and post-OLT therapy for hepatitis C.     

Upfront use of eculizumab to treat early acute antibody-mediated rejection after kidney allotransplantation and relevance for xenotransplantation

Acute antibody-mediated rejection (AMR) early after transplant remains a challenge, both in allotransplantation and in xenotransplantation. We report the case of an early and severe acute AMR episode in a kidney transplant recipient that was successfully treated with upfront eculizumab. A 58-year-old woman had been on dialysis since 2014. She underwent a first kidney transplant in 2018 with primary non-function and received several blood transfusions. Postoperatively, she developed anti-HLA antibodies. One year later, she received a second allograft from a deceased donor. At day 0, there was only one preformed low-level donor-specific antibody (DSA) anti-DQ7. After initial excellent allograft function, serum creatinine increased on days 7-9, and this was associated with oligo-anuria. On day 7, there was an increase in her DSA anti-DQ7 and 4 de novo DSA had developed at high MFI values. Allograft biopsy showed severe active AMR with diffuse C4d deposits in peritubular capillaries. The early acute AMR episode was treated with upfront eculizumab administration (2 doses) with efficient CH50 blockade (< 10% CH50). Rituximab was also administered on day 12, and intravenous immunoglobulin (IVIG) was given over the following days. There was an excellent clinical response to eculizumab administration. Eculizumab administration rapidly reversed the acute AMR episode without the need for plasmapheresis. Rituximab and IVIG were also used as B-cell immunomodulators to decrease DSA. Blocking efficiently the terminal complement pathway may become a useful strategy to treat acute AMR in sensitized recipients of allografts, and possibly in recipients of discordant xenografts.     

Plasmapheresis, CMV Hyperimmune Globulin, and Anti-CD20 Allow ABO-Incompatible Renal Transplantation Without Splenectomy

The majority of preconditioning protocols developed to allow ABO-incompatible (ABOi) renal transplantation include concurrent splenectomy as a prerequisite to successful engraftment. Our center has developed a preconditioning protocol that includes plasmapheresis (PP), low-dose CMV hyperimmune globulin (CMVIg), and anti-CD20 monoclonal antibody (rituximab) to allow ABOi renal transplantation without splenectomy. Our initial experience has included treatment of six recipients and successful transplantation from blood group A(1), A(2), and group B living donors. Mean (+/- SD) serum creatinine was 1.3 +/- 0.1 mg/dL among the six recipients and no episodes of antibody-mediated rejection (AMR) occurred at a median follow-up of 12 months. ABO antibody titers have remained below pretreatment levels. The absence of AMR and stable allograft function in this series show the potential of this preconditioning protocol to increase ABOi renal transplantation. The use of rituximab, allowing avoidance of splenectomy, may further remove one of the significant disincentives to ABOi transplantation, and eliminate the risk of post-splenectomy infections.     

Six consecutive cases of successful adult ABO-incompatible living donor liver transplantation: a proposal for grading the severity of antibody-mediated rejection

BACKGROUND: The clinical symptoms, histological findings, and treatments for antibody-mediated rejection (AMR), which is the leading cause of graft loss in adult ABO-incompatible liver transplantation (ABO-I-LT), have rarely been discussed. METHODS: We performed adult living donor ABO-I-LT on six patients. We used anti-CD20 monoclonal antibody combined with plasma exchange preoperatively and intraportal or hepatic-arterial infusion, consisting of prostaglandin E1, corticosteroids, and protease inhibitor postoperatively to prevent AMR. Splenectomy was performed in patients 1, 4, 5 and 6 but not in patients 2 and 3. Weekly liver biopsies were performed after ABO-I-LT. When severe AMR was diagnosed, we performed plasma exchange combined with gamma-globulin bolus infusion (PE+IVIG). RESULTS: In patients 1-3, severe jaundice, rapid decreases in platelet counts, and severe coagulopathy were observed in the early postoperative period. Liver biopsies sampled after the onset of these clinical findings were characterized by severe periportal and lobular hemorrhagic and neutrophil infiltration, suggesting that severe AMR occurred. However, after the initiation of PE+IVIG, AMR was remedied in all three patients. In patients 4-6, severe AMR was not observed. Mild AMR characterized by mild portal hemorrhagic infiltration was observed in patient 4, and moderate AMR characterized by moderate periportal and lobular hemorrhagic infiltration was observed in patient 6. Patients 4-6 did not require PE+IVIG and their clinical course was uneventful. CONCLUSION: Given the experience of these six patients, we consider that AMR may be graded based on liver biopsy findings including hemorrhagic infiltration and neutrophil infiltration, as well as clinical findings. All six patients are currently doing well.     

Pathogenesis in ABO incompatible liver transplantation: a clinicohistological evaluation of four patients

Takeda K, Tanaka K, Morioka D, Kumamoto T, Endo I, Togo S, Shimada H. Pathogenesis in ABO incompatible liver transplantation: a clinicohistological evaluation of four patients.
Clin Transplant 2010: 24: 747–751. © 2009 John Wiley & Sons A/S. Abstract: The aim of this study was to clarify the pathogenesis of antibody‐mediated rejection (AMR) of ABO‐incompatible liver transplantation (ABO‐I‐LT). We investigated, within one month of surgery, the clinical courses of 10 patients who received ABO‐I‐LT. We encountered four cases of AMR, which were classified into two groups according to the stage of the AMR: early (within the first 14 postoperative days [PODs]) or late (after the 14th POD). There were three patients in the early stage, and one patient in the late stage. Three early‐stage AMR patients had both hyperbilirubinemia and thrombocytopenia within one month after LDLT, but the one late‐stage AMR patient had neither. On liver biopsy, hemorrhagic infiltration was seen more frequently in the early‐stage AMR patients than in the patient with late‐stage AMR. Plasma exchange combined with a large amount of gamma‐globulin bolus infusion therapy was effective in the three early‐stage patients, but the late‐stage AMR was controlled by antibiotic treatment. This study showed that the early‐stage AMR resulted from the antigen‐antibody reaction of ABO‐blood‐group antigens, while the late‐stage AMR may have been caused by an infection.     

Pinpoint targeted immunosuppression: anti-CD20/MMF desensitization with anti-CD25 in successful ABO-incompatible kidney transplantation without splenectomy

Abstract: Background: In Japan, ABO‐incompatible (ABO‐I) kidney transplantation began in 1989; these transplantations have flourished because of the lack of cadaveric donors, and more than 600 cases were performed up to 2004. Splenectomy has been considered to be necessary for successful ABO‐I kidney transplantation, and the majority of pre‐conditioning protocols include splenectomy in Japan. However, we have lost some grafts due to antibody‐mediated rejection (AMR) accompanying explosive elevation of anti‐A/B antibody (Ab) titer even though the patients had a low pre‐operative Ab titer. Patients and methods: We utilized two doses of anti‐CD20, rituximab, simply combined with mycophenolate mofetil (MMF)/low‐dose steroid desensitization started 1 month before surgery in ABO‐I kidney transplantation. Two sessions of pre‐operative Ab removal by double filtration plasmapheresis or plasma exchange were carried out. We performed six ABO‐I kidney transplantations without splenectomy. Anti‐A/B Ab titers were more than 16 to 32 times before treatment. We did not plan any post‐operative repeated Ab removal or intravenous immunoglobulin G (IVIG). Results: Pre‐operative anti‐A/B Ab titers were successfully reduced to less than eight times in all cases. Except for one case in which we had to remove the graft due to aspiration pneumonia and methicillin‐resistant staphylococcus epidermidis (MRSE) sepsis, the other five cases did not experience antibody‐mediated rejection (AMR). An additional session of post‐operative Ab removal and/or IVIG was not necessary. In all patients, B cells (CD19⁺, CD20⁺, CD21⁺) and activated T cells (CD25⁺) were selectively suppressed, although CD3⁺, CD4⁺and CD8⁺ cell populations remained stable, thus we call our protocol “pinpoint targeted immunosuppression.” Plasma immunoglobulin level was also successfully suppressed, especially after 6 weeks of surgery. Conclusion: Anti‐CD20/MMF desensitization is safe and allows successful ABO‐I kidney transplantation without splenectomy.     

Anti-AB titer changes in patients with ABO incompatibility after living related kidney transplantations: survey of 101 cases to determine whether splenectomies are necessary for successful transplantation

BACKGROUND: A shortage of organ donors for transplantation has become a serious problem throughout the world. To overcome this problem, transplantations across ABO blood barriers have been performed with some success. In general, however, the graft survival rate for transplantation with ABO incompatibility is lower than that of transplantation with ABO compatibility. Unfortunately, the mechanism by which isohemagglutinins might injure an ABO-incompatible graft remains uncertain. Here, the pre- and posttransplantation anti-AB titers in patients who received transplants from ABO-incompatible living donors are reviewed and the pathological findings are compared. METHODS: One hundred and one patients underwent ABO-incompatible living related kidney transplantation (i-LKT) between January 1989 and October 1999 at our hospital. Plasmapheresis and immunoadsorption were performed in all of the i-LKT patients before the transplantation to remove anti-AB antibodies. A splenectomy was also performed during the operation, followed by the local irradiation of the graft with a dose of 150 rad. The anti-AB titers and pathological findings for 93 i-LKT patients, excluding 8 patients who died, were then examined. RESULTS: Immediately after the i-LKT, the anti-AB titer dropped rapidly to below 1:4 in all 93 cases. Seventy of patients (70/93, 75%) showed no elevation in their anti-AB titer during their follow-up. However, the remaining 23 patients (23/93, 25%) showed a significant elevation of their anti-AB titer to over 1:16. Sixteen of these patients (16/93, 17%) exhibited an anti-AB titer of over 1:32. Out of these 16 patients, 11 patients (11/16, 69%) lost their grafts. The anti-AB titer in the remaining five patients (5/16, 31%) spontaneously decreased without any special treatment. Seven patients (7/93, 8%) exhibited an elevated titer of 1:16. Out of these patients, only one patient (1/7, 14%) lost his graft. The elevated titers in the remaining six patients (6/7, 86%) eventually decreased. The graft function improved in patients whose elevated anti-AB titers eventually decreased. Control patients (ABO-compatible kidney transplant patients) showed a normal elevation of their titer values compared with preoperative titers. Pathological findings showed severe humoral rejections in all cases with high anti-AB titers that lost grafts. Humoral rejection was also detected in most of the patients whose anti-AB titer was elevated to over 1:16 after the transplantation, but excellent renal function was resumed once the titers decreased to below 1:4. CONCLUSIONS: In 23 out of 93 i-LKT patients (25%), the anti-AB titers were significantly elevated after the splenectomy. In view of other reports of i-LKT without splenectomy, we feel that a splenectomy in i-LKT patients might be unnecessary. Pathological evidence suggests that the decrease in the anti-AB titer after transplantation might be the net result of plasmapheresis before the operation and the adsorption of antibodies to the endothelium of the transplanted organ after the operation, neither of which is influenced by a splenectomy.