- Email: [email protected]
Comparative Analysis of ABO-Incompatible Living Donor Kidney Transplantation With ABO-Compatible Grafts: A Single-Center Experience in Korea
Comparative Analysis of ABO-Incompatible Living Donor Kidney Transplantation With ABO-Compatible Grafts: A Single-Center Experience in Korea J.-K. Hwang, Y.-K. Kim, J.-M. Kim, B.-H. Chung, B.-S. Choi, C.-W. Yang, Y.-S. Kim, I.-S. Moon, and J.-I. Kim ABSTRACT Introduction. Serious organ shortages have necessitated the use of ABO-incompatible (ABOi) kidneys transplantation, which has been increasingly preformed in Korea. However there are few detailed comparative data regarding patient and graft survival, graft function, and complications in Korean patients receiving ABO-compatible (ABOc) and ABOi kidney transplants (KT). Methods. This retrospective study compared 35 consecutive ABOi living donor KTs with 138 ABOc living donor KTs using same immunosuppressive regimens. We examined preoperative demographic factors, immunologic risk factors, patient and graft survivals, postoperative renal function, acute rejection episodes, infections, medical and surgical complications, duration of hospital stay as well as cause for readmission, and their rates. Results. Patient survival, graft survival, and graft function over the 2 years after transplantation were similar between the 2 groups. There were no significant differences in terms of complications with exception of bleeding and BK virus infection. Acute antibodymediated rejection episodes, bleeding complications, BK virus infections, and preoperative hospital stay were significantly greater in the ABOi group (P ¼ .001, P ¼ .002, P ¼ .005, and P < .001 respectively). Conclusions. We concluded that, despite some disadvantages, ABOi KT is a viable, safe option for patients whose only available donor is blood group incompatible.
K
IDNEY TRANSPLANTATION (KT) is the best therapy to treat patients with end-stage renal disease. However, there is a worldwide shortage of donor kidneys, which has resulted in often unacceptably long wait times for an appropriate organ. In an effort to expand the pool of kidney donors, ABO-incompatible (ABOi) KT has been adopted many centers in Europe, Japan, and the United States since the pioneering work of Alexandre et al in the 1980s.1,2 Recent studies, using preconditioning regimens with anti-CD20 antibodies, intravenous immunoglobulin (IVIg), and removal of circulating blood group antibodies by plasmapheresis (PP) or selective immunoadsorption have revealed similar short- and long-term patient and graft survival as ABO-compatible (ABOc) KT.3e6 ABOi KT was first performed in Korea by Kong et al in 2007. The technique rapidly spread to many other Korean transplant centers. However, there are few data regarding this therapy in Korea. The aim of this study was to assess
patient survival, graft survival, graft function as well as medical, surgical and infectious complications between ABOc KT recipients and ABOi KT recipients in Korea. PATIENTS AND METHODS This observational single-center analysis included 35 consecutive patients who underwent ABOi KT between May 2009 and November 2011, using a protocol of anti-CD20 monoclonal antibody
From the Department of Surgery, Dajeon St Mary’s Hospital (J.-K.H.) and Department of Surgery, (Y.-K.K., J.-M.K., I.-S.M., J.-I.K.) and Internal Medicine (B.-H.C., B.-S.C., C.-W.Y., Y.-S.K.), Seoul St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea. Address reprint requests to Ji-Il Kim, MD, PhD, Seoul St Mary’s Hospital 505 Banpo-Dong, Secho-Gu, Seoul, Korea, 137040. E-mail: [email protected]
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.038
Transplantation Proceedings, 45, 2931e2936 (2013)
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2932 (Rituximab, Genentech Inc, San Francisco, Calif, USA), PP, IVIg, basiliximab induction, and immunosuppression with tacrolimus, mycophenolate mofetil, and corticosteroids. One hundred thirtyeight ABOc living donor KTs performed during this same period were selected as controls based on the same initial immunosuppressive maintenance therapy including basiliximab. The immunosuppressive protocol used in this study has been described in detail elsewhere.7 Briefly, the ABOi group was administered a single dose of Rituximab (100 or 375 mg/m2) 1 month before the anticipated transplantation. Oral immunosuppression was started 7 days before the operation. All patients undergoing ABOi KT were treated with every other day before transplantation with PP followed by IVIg (100 mg/kg). The last preoperative and all postoperative PP were performed with donor blood type, fresh frozen plasma. The number of pretransplant PP treatments was determined by the baseline A/B-antibody titers.8 The acceptance criterion for ABOi KT at the time of transplantations was 1:32 (except in 1 case). Postoperative PP was performed only if there was a rise in A/B-antibody titer with concomitant impairment of graft function except in the first case. A/B-antibody titers were determined using standard serologic techniques.7 To evaluate and compare outcomes, we collected the preoperative baseline characteristics of the 2 groups, incidences of biopsyproven acute rejection episodes, patient and graft survivals, renal function, infections, medical and surgical complications, duration of hospital stay, and readmission. This study was approved by the Seoul St Mary’s Hospital Institutional Review Board. All data are presented as mean values standard deviations. Comparisons between 2 groups were performed using Student t test or the chi-square test. Analysis of risk factors for bleeding complications and biopsy-proven acute rejection episodes were performed using Cox multivariate analysis. Survivals of groups was compared using the log-rank test. A P value of <.05 was considered to be statistically significant.
HWANG, KIM, KIM ET AL Table 1. Baseline Characteristics of the ABO-Compatible and ABO-Incompatible Groups
Recipient sex male (%) Recipient age (y) Recipient body mass index (kg/m2) Donor sex male (%) Donor age (y) Related donor (%) Cause of end-stage renal disease (%) Chronic glomerulonephritis Diabetes mellitus Hypertension Chronic pyelonephritis Othera HD vs PD vs none Duration of RRT (d) Diabetic mellitus before KT (%) Hypertension before KT (%) Hx of erythropoietin Tx (%) Number of KT >1 (%) Number of HLA mismatch PRA 20% (%) Nephron mass index (g/kg) Total ischemic time (min)
ABOc (n ¼ 138)
ABOi (n ¼ 35)
P value
86 (62.3) 42.8 11.2 22.9 3.6
21 (60.0) 44.1 9.2 22.9 3.6
.801 .544 .968
55 (39.8) 42.4 11.5 88 (63.8)
14 (40.0) 37.5 8.7 16 (45.7)
.988 .008 .051 .236
51 (37.0) 22 (15.9) 29 (21.0) 1 (0.7) 36 (26.1) 87 vs 16 vs 35 593 962 (n ¼ 103) 29 (21.0) 107 (77.5) 82 (59.4) 12 (8.7) 3.5 1.7 30 (21.7) 3.1 0.9 50.3 12.7
11 (31.4) 6 (17.1) 6 (17.1) 0 (0.0) 12 (34.3) 22 vs 3 vs 10 816 1058 (n ¼ 25) 6 (17.1) 28 (80.0) 28 (80.0) 8 (22.9) 3.8 1.3 16 (45.7) 3.1 0.7 54.3 15.3
.577 .311 .611 .753 .024 .034 .05 .004 .874 .113
All values represent means standard deviation. ABOc, ABO-compatible; ABOi, ABO-incompatible; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; KT, kidney transplantation; Hx, history; Tx, treatment; HLA, human leukocyte antigen; PRA, pane-reactive antibody. a Including polycystic kidney disease, lupus nephritis, chronic pyelonephritis and unknown.
RESULTS
As shown in Table 1, the preoperative baseline characteristics of both groups were similar except their immunologic characteristics and donor ages. Compared with the ABOc group more recipients of ABOi grafts had a history of previous KT, a panel-reactive antibody greater than 20%, and a higher incidence of human leukocyte antigen mismatches (P ¼ .034, .004, and .05, respectively). ABOi donors were younger than ABOc donors; 37.5 8.7 vs 42.4 11.5 years, respectively (P ¼ .008). Thirty-five adult living ABOi patients have been successfully transplanted at our institution since May 2009. The basic immunologic data, effect of PE, and serologic results of ABOi KT recipients are shown in Table 2. The baseline median A/B-antibody titer was 1:64; all patients except 1 reached the target titer after 7.4 3.4 preoperative PP sessions. There was no significant difference in patient and graft survivals between the 2 groups until 24 months after KT (Fig 1). There were 2 patient deaths in each group. All 4 subjects died with functioning grafts, due to pulmonary embolism and bone marrow failure in the ABOi group and sudden cardiac death and unknown cause in the ABOc group. Patient survivals at 1, 12, and 24 months were 100%,
98.2%, and 98.2% in the ABOc group and 97.1%, 94.3%, and 94.3% in the ABOi group, respectively (P ¼ .108; Fig 1A). Five graft losses occurred in the ABOc group: acute cellular rejection at 5 and 19 days and 2, 11, and 17 months postoperatively. One graft was lost in the ABOi group on postoperative day 22 because of biopsy site bleeding. Death-censored graft survivals at 1, 12, and 24 months were, 98.5%, 95.0%, and 92.3% in the ABOc group vs 94.3%, 91.4%, and 91.4% in the ABOi group, respectively (P ¼ .344; Fig 1B). Serum creatinine and estimated glomerular filtration rate by Modification of Diet in Renal Disease were obtained at 1 week as well as 1, 3, 6, 12, 18, and 24 months after transplantation. There were no significant differences between the 2 groups at any time (Fig 2). Rejection episodes, which were biopsy-proven, occurred among 14.5% and 34.3% in the ABOc and ABOi groups, respectively (P ¼ .007). Body mass index was the only risk factor for an acute rejection episode on multivariate analysis (Table 3). In the ABOc group, 18 patients experienced 20 acute rejection episodes: one acute antibody-mediated rejection (AAMR) and 19 acute cellular rejection episodes (ACR). In the ABOi group, 8 patients experienced acute
ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION
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Table 2. Immunohematologic Characteristics of the ABOincompatible patients (n [ 35) Blood group combinations (donor / recipient) A / O (%) 8 (22.9) B / O (%) 7 (20.0) B / A (%) 6 (17.1) AB / B (%) 4 (11.4) AB / O (%) 4 (11.4) AB / A (%) 3 (8.6) A / B (%) 3 (8.6) Isoaglutinin titers Initial titer before treatment (median) 1:64 [1:1e1:>1024] Just before operation (median) 1:8 [negativee1:64] Initial high-titer patients (>128), % 12 (34.3) Plasmapheresis Number of preoperative plasmapheresis 7.4 3.4 [2e17] to reach target titer Patients requiring postoperative 9 (25.7) plasmapheresis (%) Number of postoperative plasmapheresis 4.8 2.2 [1e8] if required Anti-CD-20 treatment Patients receiving low-dose Rituximab 16 (45.7) (100 mg/m2), % Patients receiving high-dose Rituximab 19 (54.3) (375 mg/m2), % All values represent means standard deviations [range], unless otherwise stated.
rejection episodes, 5 AAMR and 7 ACR. While there was a significant difference in the incidence of AAMR (P ¼ .001), the incidence of ACR was similar (P ¼ .357). All infectious, medical, and surgical complications listed in Table 4 showed no significant differences in overall incidences. However, the rate of BK virus infections and bleeding complications were greater among the ABOi group 17.1% vs 2.9% and 17.1% vs 2.2% (P ¼ .005 and P ¼ .002, respectively). Four patients in the ABOc group and 6 in the ABOi group displayed positive BK virus replication in the blood only without renal involvement. All 10 patients responded to a temporary decrease in immunosuppression. Two ABOc and 1 ABOi patient developed BK virus-associated nephropathy. Six ABOi patients including 1 with biopsy-related bleeding, experienced postoperative bleeding complications. Four subjects, were treated surgically and 2 were managed conservatively. There was 1 graft loss in the surgical treatment group. Three cases of postoperative bleeding occurred in the ABOc group, all of which were successfully managed with an operation. On multivariate analysis, ABO incompatibility was only significant risk factor for the bleeding complication (P ¼ .026, hazard ratio ¼ 23.695, confidence interval 1.468e 382.371; Table 5). The pretransplant hospital stay was significantly longer in the ABOi group compared with the ABOc cohort: l4.9 5.5, versus 5.6 2.1 days respectively (P < .001). The posttransplant hospital stay was similar between the 2 groups: 21.2 10.2 vs 18.0 4.7 days, respectively (P ¼ .077; Table 6). The readmission rate was also similar between 2
Fig 1. Patient and graft survival of ABO-compatible and ABOincompatible living donor kidney transplantation.
groups: 0.96 1.00 vs 1.09 1.25 respective (P ¼ .572; Table 6). The most common cause of readmission in both groups was deterioration of renal function (Table 6). DISCUSSION
The persistent shortage of organ donors and the increasing number of patients a waiting KT necessitate new approaches to expand the pool of potential kidney donors. ABOi KT has been performed to alleviate the shortage since the first planned procedure in 1987.1 For ABOi donor kidneys to become widely used in KT, the success rate and potential risks must be equivalent to those of ABOc KT. The initial experience of Alexandre et al was disappointing due to high rates of infection and rejection.1 However, the development of new immunosuppressive agents and modern apheresis techniques have markedly improved the outcomes of ABOi KT.4e6 Although there have been many reports regarding patient survival, graft survival, and renal function in ABOi KT recipients, there have been few comprehensive comparative analyses of ABOi and ABOc KT recipients. In this study, we have reported the outcomes
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HWANG, KIM, KIM ET AL
Fig 2. Renal function estimated by serum creatinine (A) and estimated glomerular filtration rate by Modification of Diet in Renal Disease (B).
of 35 consecutive ABOi KT recipients comparing their clinical courses to a control group of 138 ABOc KT patients transplanted using the same maintenance immunosuppressive drugs over the same period. Theoretically, removing the ABO immunologic barrier could expand the living donor pool by more than 50%.8 Many other studies have reported an additional 10% to 20% of living donor procedures were performed by using ABOi KT.4,9,10 The number of living donor KTs at our hospital has increased by 19.9% (from 176 to 211), since the start of the ABOi KT program in May 2009. Our intermediate-term outcomes demonstrated that KTs from ABOi donors were equivalent to those from ABOc donors in terms of patient survival, graft survival, and kidney
function (Figs 1 and 2). The 2-year patient and graft survival rates for the ABOi group were 94.3% and 91.3%, respectively, which were comparable to other reports. Shimmura et al that initial maximum blood group antibody titers correlated with graft survival.11 The Johns Hopkins and Mayo Clinic groups have also identified initial blood group antibody titers as an important prognostic predictor.4,5 In contrast, we did not identify a similar correlation between initial blood group antibody titers and graft loss. Even patients with high initial blood group antibody titers (4 patients, 1024) were successfully transplanted in our series. Therefore, high initial blood group antibodies should not represent an exclusion criterion for ABOi KT as recommended by previous workers.12,13
ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION
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Table 3. Multivariate Analysis for the Risk Factors of BiopsyProven Acute Rejection Episode Characteristics
P value
Hazard ratio
95% confidence interval
Recipient age Gender of recipient Donor age Gender of donor BMI (kg/m2) Mismatch of HLA Number of KT (>1) ABO incompatibility PRA (>20%) Nephron mass index (g/kg) Total ischemic time
.156 .605 .124 .744 .023 .961 .797 .062 .758 .187 .158
0.966 0.732 1.037 0.837 1.212 1.008 0.740 2.897 0.806 0.543 0.970
0.922e1.013 0.225e2.383 0.990e1.085 0.287e2.438 1.027e1.429 0.725e1.401 0.074e7.385 0.950e8.840 0.204e3.177 0.219e1.345 0.929e1.012
BMI, body mass index; HLA, human leukocyte antigen; KT, kidney transplantation; PRA, panel-reactive antibody.
AAMR is a serious complication that is more frequently experienced after ABOi KT compared with ABOc KT. To prevent AAMR, many centers have adopted routine postoperative PP.6,9 However, this procedure increases costs, length of hospital stay, and complications. Therefore, some centers have elected to perform only preemptive or selective postoperative PP.14e16 We performed postoperative PP only if there was a rise in blood group antibodies with concomitant impairment of graft function, with the exception of the first case. As expected, AAMR was significantly more common among the ABOi group. The 5 Table 4. Complications of the Living Donor Kidney Transplantations Type of complications
Infectious complications (%) Viral (%) CMV infectiona (%) CMV diseaseb (%) BKV infectiona (%) BKV nephropathyb (%) HZV infection (%) Bacterial (%) Fungal (%) Surgical complications (%) Bleeding complications (%) Urologic complications (%) Deep vein thrombosis (%) Bowel perforation (%) Arterial complications (%) Lymphocele (%) Medical complications (%) NODAT (%) Steroid-induced complications (%) Hematologic complications (%) Cardiac complications (%)
ABOc (n ¼ 138)
89 65 46 2 4 2 11 23 2 20 3 7 6 2 1 1 26 17 4 2 3
(64.5) (47.1) (33.3) (1.4) (2.9) (1.4) (8.0) (16.7) (1.5) (14.5) (2.2) (5.1) (4.3) (1.5) (0.7) (0.7) (18.8) (15.6) (2.9) (1.4) (2.2)
ABOi (n ¼ 35)
23 18 9 0 6 1 2 3 2 9 6 0 0 0 2 1 10 6 0 3 1
(65.7) (51.4) (25.7) (0) (17.1) (2.9) (5.7) (8.6) (5.7) (25.7) (17.1) (0) (0) (0) (5.7) (2.9) (28.6) (20.7) (0) (8.6) (2.9)
P value
.893 .647 .387 >.999 .005 .459 >.999 .297 .183 .112 .002 .347 .350 >.999 .183 .365 .205 .513 .584 .057 .810
Values are presented as number (%). ABOc, ABO-compatible; ABOi, ABO-incompatible; BKV, BK virus; CMV, cytomegalovirus; HZV, herpes zoster; NODAT, new-onset diabetes after transplantation. a Diagnosed by more than 500 copies/mL by polymerase chain reaction. b Diagnosed by tissue pathology.
Table 5. Multivariate Analysis for the Bleeding Risk Factors Characteristics
P value
Hazard ratio
95% confidence interval
Recipient age Donor age BMI (kg/m2) Mismatch of HLA ABO incompatibility PRA (>20%) Duration of RRT Total ischemic time
.604 .750 .316 .342 .026 .316 .186 .462
1.033 0.979 1.217 0.596 23.695 0.207 1.001 0.948
0.915e1.166 0.857e1.118 0.829e1.789 0.205e1.733 1.468e382.371 0.010e4.483 1.000e1.002 0.823e1.093
BMI, body mass index; HLA, human leukocyte antigen; KT, kidney transplantation; PRA, panel-reactive antibody.
AAMR were observed in 5 recipients of ABOi KT (14.3%), compared with 1 (3.0%) in the ABOc group. The incidence of AAMR in this series (14.3%) was similar to that described by groups routine in the postoperative using PP period (14.3% vs 15%, respectively).9 All cases of AAMR were successfully treated with PP and steroid pulse therapy. The spectrum of adverse events in the present analysis was comparable to ABOc living donor KT with the exception of BK virus infections and postoperative bleeding complications (Table 4). There was a major concern that the vigorous preparation before ABOi KT (PP, rituximab, and longer preoperative immunosuppression) would increase the rate of infectious complications. However, there were no fatal or serious infectious complications among the ABOi group. The only significant difference between the two groups was BK virus infection, most of which resolved after rapidly lowering the maintenance immunosuppression. The incidence of cytomegalovirus (CMV) infection was same as the ABOc group (25.7% vs 33.3%, respectively). There were no CMV disease cases among the ABOi group. The incidence of CMV infection was relatively lower than in Table 6. Hospital Stay and Readmission of Living Donor Kidney Transplant Recipients ABOc (n ¼ 138)
Hospital stay (d) Total Preoperative Postoperative
ABOi (n ¼ 35)
P value
a
23.5 5.4 [18e47] 5.6 2.1 [1e14] 18.0 4.7 [14e39]
36.1 12.0 <.001 [14e73] 14.9 5.5 <0.001 [8-30] 21.2 10.2 .077 [4e59]
Cause of readmissionb Increased creatinine (%) 63 (45.7) 23 (65.7) Infectious complications (%) 29 (21.0) 5 (14.3) Urinary complications (%) 9 (6.5) 1 (2.9) Orthopedic complications (%) 3 (2.2) 2 (5.7) Vascular complications (%) 3 (2.2) 2 (5.7) Cardiac complications (%) 1 (0.7) 1 (2.9) Others (%) 25 (18.1) 4 (11.4) Readmission ratea,c 0.96 1.00 1.09 1.25
.034 .371 .689 .266 .266 .365 .325 .572
All values represent means standard deviations [range]. Values are presented as number (%). Total number of readmission during follow-up/total number of patient in each group. a
b c
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other studies.17 We administered valganciclovir prophylactically in the ABOi group, resulting in a relatively lower incidence and severity of CMV infection compared with other studies and with the ABOc group. These findings suggest that the current protocol does not carry an enhanced risk of over-immunosuppression. The overall incidence of surgical complications was similar between the 2 groups, except that bleeding complications were significantly more common in the ABOi group (P ¼ .002). Other studies have also reported a higher incidence of immediate postoperative bleeding complications with ABOi KT.18 A possible explanation relates to the method of removing blood group antibodies and the timing of IVIg administration. Theoretically, PP removes more coagulation factors than double filtration PP or immunoadsorption.19 Geyer et al reported a relationship between bleeding complications and timing of IVIg administration.20 The incidence of bleeding complications tended to be higher in patients receiving IVIg 1 compared with 5 days before the operation (50.0% vs 4.5%). The percentage of patients experiencing medical complications did not differ between the groups. As expected, the preoperative hospital stay was significantly longer in ABOi recipients, primarily because of preoperative PP (P < .001). However, the postoperative hospital stay was similar. The number of readmissions per patient was also similar between the ABOc and ABOi group: 0.96 1.00 vs 1.09 1.25, respectively. Impaired renal function was a more frequent cause of readmission in the ABOi group. One explanation was a perceived need for closer monitoring of changes in renal function due to the novelty of the ABOi program. This study demonstrated that ABOi living donor KT using a PP-based approach resulted in an increase in AAMR and bleeding complications as well as longer preoperative hospital stays compared with ABOc KT. However, patient survival, graft survival, transplant function, and other complications were comparable. In conclusion, ABOi living donor KT represents a viable option for patients whose only available donor is blood group incompatible. REFERENCES 1. Alexandre GP, Squifflet JP, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc. 1987;19:4538.
HWANG, KIM, KIM ET AL 2. Alexandre GP, De Bruyere M, Squifflet JP, et al. Human ABO-incompatible living donor renal homografts. Neth J Med. 1985;28:231. 3. Tanabe K, Takahashi K, Sonda K, et al. Long-term results of ABO-incompatible living kidney transplantation: a single-center experience. Transplantation. 1998;65:224. 4. Stegall MD, Dean PG, Gloor JM. ABO-incompatible kidney transplantation. Transplantation. 2004;78:635. 5. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers. Am J Transplant. 2004;4:561. 6. Genberg H, Kumlien G, Wennberg L, et al. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up. Transplantation. 2008;85:1745. 7. Chung BH, Lee JY, Kang SH, et al. Comparison of clinical outcome between high and low baseline anti-ABO antibody titers in ABO-incompatible kidney transplantation. Ren Fail. 2011;33:150. 8. Montgomery RA. ABO incompatible transplantation: to B or not to B. Am J Transplant. 2004;4:1011. 9. Montgomery RA, Locke JE, King KE, et al. ABO incompatible renal transplantation: a paradigm ready for broad implementation. Transplantation. 2009;87:1246. 10. Segev DL, Simpkins CE, Warren DS, et al. ABO incompatible high-titer renal transplantation without splenectomy or antiCD20 treatment. Am J Transplant. 2005;5:2570. 11. Shimmura H, Tanabe K, Ishikawa N, et al. Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation. Transplantation. 2000;70:1331. 12. Donauer J, Wilpert J, Geyer M, et al. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a single center experience. Xenotransplantation. 2006;13:108. 13. Shimmura H, Tanabe K, Ishida H, et al. Lack of correlation between results of ABO-incompatible living kidney transplantation and anti-ABO blood type antibody titers under our current immunosuppression. Transplantation. 2005;80:985. 14. Wilpert J, Geyer M, Pisarski P, et al. On-demand strategy as an alternative to conventionally scheduled post-transplant immunoadsorptions after ABO-incompatible kidney transplantation. Nephrol Dial Transplant. 2007;22:3048. 15. Schwartz J, Stegall MD, Kremers WK, Gloor J. Complications, resource utilization, and cost of ABO-incompatible living donor kidney transplantation. Transplantation. 2006;82:155. 16. Toki D, Ishida H, Horita S, et al. Impact of low-dose rituximab on splenic B cells in ABO-incompatible renal transplant recipients. Transpl Int. 2009;22:447. 17. Tanabe K. Japanese experience of ABO-incompatible living kidney transplantation. Transplantation. 2007;84:S4. 18. Wilpert J, Fischer KG, Pisarski P, et al. Long-term outcome of ABO-incompatible living donor kidney transplantation based on antigen-specific desensitization. An observational comparative analysis. Nephrol Dial Transplant. 2010;25:3778. 19. Tyden G, Kumlien G, Efvergren M. Present techniques for antibody removal. Transplantation. 2007;84:S27. 20. Geyer M, Fischer KG, Drognitz O, et al. ABO-incompatible kidney transplantation with antigen-specific immunoadsorption and rituximabdinsights and uncertainties. Contrib Nephrol. 2009;162:47.
K
IDNEY TRANSPLANTATION (KT) is the best therapy to treat patients with end-stage renal disease. However, there is a worldwide shortage of donor kidneys, which has resulted in often unacceptably long wait times for an appropriate organ. In an effort to expand the pool of kidney donors, ABO-incompatible (ABOi) KT has been adopted many centers in Europe, Japan, and the United States since the pioneering work of Alexandre et al in the 1980s.1,2 Recent studies, using preconditioning regimens with anti-CD20 antibodies, intravenous immunoglobulin (IVIg), and removal of circulating blood group antibodies by plasmapheresis (PP) or selective immunoadsorption have revealed similar short- and long-term patient and graft survival as ABO-compatible (ABOc) KT.3e6 ABOi KT was first performed in Korea by Kong et al in 2007. The technique rapidly spread to many other Korean transplant centers. However, there are few data regarding this therapy in Korea. The aim of this study was to assess
patient survival, graft survival, graft function as well as medical, surgical and infectious complications between ABOc KT recipients and ABOi KT recipients in Korea. PATIENTS AND METHODS This observational single-center analysis included 35 consecutive patients who underwent ABOi KT between May 2009 and November 2011, using a protocol of anti-CD20 monoclonal antibody
From the Department of Surgery, Dajeon St Mary’s Hospital (J.-K.H.) and Department of Surgery, (Y.-K.K., J.-M.K., I.-S.M., J.-I.K.) and Internal Medicine (B.-H.C., B.-S.C., C.-W.Y., Y.-S.K.), Seoul St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea. Address reprint requests to Ji-Il Kim, MD, PhD, Seoul St Mary’s Hospital 505 Banpo-Dong, Secho-Gu, Seoul, Korea, 137040. E-mail: [email protected]
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.038
Transplantation Proceedings, 45, 2931e2936 (2013)
2931
2932 (Rituximab, Genentech Inc, San Francisco, Calif, USA), PP, IVIg, basiliximab induction, and immunosuppression with tacrolimus, mycophenolate mofetil, and corticosteroids. One hundred thirtyeight ABOc living donor KTs performed during this same period were selected as controls based on the same initial immunosuppressive maintenance therapy including basiliximab. The immunosuppressive protocol used in this study has been described in detail elsewhere.7 Briefly, the ABOi group was administered a single dose of Rituximab (100 or 375 mg/m2) 1 month before the anticipated transplantation. Oral immunosuppression was started 7 days before the operation. All patients undergoing ABOi KT were treated with every other day before transplantation with PP followed by IVIg (100 mg/kg). The last preoperative and all postoperative PP were performed with donor blood type, fresh frozen plasma. The number of pretransplant PP treatments was determined by the baseline A/B-antibody titers.8 The acceptance criterion for ABOi KT at the time of transplantations was 1:32 (except in 1 case). Postoperative PP was performed only if there was a rise in A/B-antibody titer with concomitant impairment of graft function except in the first case. A/B-antibody titers were determined using standard serologic techniques.7 To evaluate and compare outcomes, we collected the preoperative baseline characteristics of the 2 groups, incidences of biopsyproven acute rejection episodes, patient and graft survivals, renal function, infections, medical and surgical complications, duration of hospital stay, and readmission. This study was approved by the Seoul St Mary’s Hospital Institutional Review Board. All data are presented as mean values standard deviations. Comparisons between 2 groups were performed using Student t test or the chi-square test. Analysis of risk factors for bleeding complications and biopsy-proven acute rejection episodes were performed using Cox multivariate analysis. Survivals of groups was compared using the log-rank test. A P value of <.05 was considered to be statistically significant.
HWANG, KIM, KIM ET AL Table 1. Baseline Characteristics of the ABO-Compatible and ABO-Incompatible Groups
Recipient sex male (%) Recipient age (y) Recipient body mass index (kg/m2) Donor sex male (%) Donor age (y) Related donor (%) Cause of end-stage renal disease (%) Chronic glomerulonephritis Diabetes mellitus Hypertension Chronic pyelonephritis Othera HD vs PD vs none Duration of RRT (d) Diabetic mellitus before KT (%) Hypertension before KT (%) Hx of erythropoietin Tx (%) Number of KT >1 (%) Number of HLA mismatch PRA 20% (%) Nephron mass index (g/kg) Total ischemic time (min)
ABOc (n ¼ 138)
ABOi (n ¼ 35)
P value
86 (62.3) 42.8 11.2 22.9 3.6
21 (60.0) 44.1 9.2 22.9 3.6
.801 .544 .968
55 (39.8) 42.4 11.5 88 (63.8)
14 (40.0) 37.5 8.7 16 (45.7)
.988 .008 .051 .236
51 (37.0) 22 (15.9) 29 (21.0) 1 (0.7) 36 (26.1) 87 vs 16 vs 35 593 962 (n ¼ 103) 29 (21.0) 107 (77.5) 82 (59.4) 12 (8.7) 3.5 1.7 30 (21.7) 3.1 0.9 50.3 12.7
11 (31.4) 6 (17.1) 6 (17.1) 0 (0.0) 12 (34.3) 22 vs 3 vs 10 816 1058 (n ¼ 25) 6 (17.1) 28 (80.0) 28 (80.0) 8 (22.9) 3.8 1.3 16 (45.7) 3.1 0.7 54.3 15.3
.577 .311 .611 .753 .024 .034 .05 .004 .874 .113
All values represent means standard deviation. ABOc, ABO-compatible; ABOi, ABO-incompatible; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; KT, kidney transplantation; Hx, history; Tx, treatment; HLA, human leukocyte antigen; PRA, pane-reactive antibody. a Including polycystic kidney disease, lupus nephritis, chronic pyelonephritis and unknown.
RESULTS
As shown in Table 1, the preoperative baseline characteristics of both groups were similar except their immunologic characteristics and donor ages. Compared with the ABOc group more recipients of ABOi grafts had a history of previous KT, a panel-reactive antibody greater than 20%, and a higher incidence of human leukocyte antigen mismatches (P ¼ .034, .004, and .05, respectively). ABOi donors were younger than ABOc donors; 37.5 8.7 vs 42.4 11.5 years, respectively (P ¼ .008). Thirty-five adult living ABOi patients have been successfully transplanted at our institution since May 2009. The basic immunologic data, effect of PE, and serologic results of ABOi KT recipients are shown in Table 2. The baseline median A/B-antibody titer was 1:64; all patients except 1 reached the target titer after 7.4 3.4 preoperative PP sessions. There was no significant difference in patient and graft survivals between the 2 groups until 24 months after KT (Fig 1). There were 2 patient deaths in each group. All 4 subjects died with functioning grafts, due to pulmonary embolism and bone marrow failure in the ABOi group and sudden cardiac death and unknown cause in the ABOc group. Patient survivals at 1, 12, and 24 months were 100%,
98.2%, and 98.2% in the ABOc group and 97.1%, 94.3%, and 94.3% in the ABOi group, respectively (P ¼ .108; Fig 1A). Five graft losses occurred in the ABOc group: acute cellular rejection at 5 and 19 days and 2, 11, and 17 months postoperatively. One graft was lost in the ABOi group on postoperative day 22 because of biopsy site bleeding. Death-censored graft survivals at 1, 12, and 24 months were, 98.5%, 95.0%, and 92.3% in the ABOc group vs 94.3%, 91.4%, and 91.4% in the ABOi group, respectively (P ¼ .344; Fig 1B). Serum creatinine and estimated glomerular filtration rate by Modification of Diet in Renal Disease were obtained at 1 week as well as 1, 3, 6, 12, 18, and 24 months after transplantation. There were no significant differences between the 2 groups at any time (Fig 2). Rejection episodes, which were biopsy-proven, occurred among 14.5% and 34.3% in the ABOc and ABOi groups, respectively (P ¼ .007). Body mass index was the only risk factor for an acute rejection episode on multivariate analysis (Table 3). In the ABOc group, 18 patients experienced 20 acute rejection episodes: one acute antibody-mediated rejection (AAMR) and 19 acute cellular rejection episodes (ACR). In the ABOi group, 8 patients experienced acute
ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION
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Table 2. Immunohematologic Characteristics of the ABOincompatible patients (n [ 35) Blood group combinations (donor / recipient) A / O (%) 8 (22.9) B / O (%) 7 (20.0) B / A (%) 6 (17.1) AB / B (%) 4 (11.4) AB / O (%) 4 (11.4) AB / A (%) 3 (8.6) A / B (%) 3 (8.6) Isoaglutinin titers Initial titer before treatment (median) 1:64 [1:1e1:>1024] Just before operation (median) 1:8 [negativee1:64] Initial high-titer patients (>128), % 12 (34.3) Plasmapheresis Number of preoperative plasmapheresis 7.4 3.4 [2e17] to reach target titer Patients requiring postoperative 9 (25.7) plasmapheresis (%) Number of postoperative plasmapheresis 4.8 2.2 [1e8] if required Anti-CD-20 treatment Patients receiving low-dose Rituximab 16 (45.7) (100 mg/m2), % Patients receiving high-dose Rituximab 19 (54.3) (375 mg/m2), % All values represent means standard deviations [range], unless otherwise stated.
rejection episodes, 5 AAMR and 7 ACR. While there was a significant difference in the incidence of AAMR (P ¼ .001), the incidence of ACR was similar (P ¼ .357). All infectious, medical, and surgical complications listed in Table 4 showed no significant differences in overall incidences. However, the rate of BK virus infections and bleeding complications were greater among the ABOi group 17.1% vs 2.9% and 17.1% vs 2.2% (P ¼ .005 and P ¼ .002, respectively). Four patients in the ABOc group and 6 in the ABOi group displayed positive BK virus replication in the blood only without renal involvement. All 10 patients responded to a temporary decrease in immunosuppression. Two ABOc and 1 ABOi patient developed BK virus-associated nephropathy. Six ABOi patients including 1 with biopsy-related bleeding, experienced postoperative bleeding complications. Four subjects, were treated surgically and 2 were managed conservatively. There was 1 graft loss in the surgical treatment group. Three cases of postoperative bleeding occurred in the ABOc group, all of which were successfully managed with an operation. On multivariate analysis, ABO incompatibility was only significant risk factor for the bleeding complication (P ¼ .026, hazard ratio ¼ 23.695, confidence interval 1.468e 382.371; Table 5). The pretransplant hospital stay was significantly longer in the ABOi group compared with the ABOc cohort: l4.9 5.5, versus 5.6 2.1 days respectively (P < .001). The posttransplant hospital stay was similar between the 2 groups: 21.2 10.2 vs 18.0 4.7 days, respectively (P ¼ .077; Table 6). The readmission rate was also similar between 2
Fig 1. Patient and graft survival of ABO-compatible and ABOincompatible living donor kidney transplantation.
groups: 0.96 1.00 vs 1.09 1.25 respective (P ¼ .572; Table 6). The most common cause of readmission in both groups was deterioration of renal function (Table 6). DISCUSSION
The persistent shortage of organ donors and the increasing number of patients a waiting KT necessitate new approaches to expand the pool of potential kidney donors. ABOi KT has been performed to alleviate the shortage since the first planned procedure in 1987.1 For ABOi donor kidneys to become widely used in KT, the success rate and potential risks must be equivalent to those of ABOc KT. The initial experience of Alexandre et al was disappointing due to high rates of infection and rejection.1 However, the development of new immunosuppressive agents and modern apheresis techniques have markedly improved the outcomes of ABOi KT.4e6 Although there have been many reports regarding patient survival, graft survival, and renal function in ABOi KT recipients, there have been few comprehensive comparative analyses of ABOi and ABOc KT recipients. In this study, we have reported the outcomes
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HWANG, KIM, KIM ET AL
Fig 2. Renal function estimated by serum creatinine (A) and estimated glomerular filtration rate by Modification of Diet in Renal Disease (B).
of 35 consecutive ABOi KT recipients comparing their clinical courses to a control group of 138 ABOc KT patients transplanted using the same maintenance immunosuppressive drugs over the same period. Theoretically, removing the ABO immunologic barrier could expand the living donor pool by more than 50%.8 Many other studies have reported an additional 10% to 20% of living donor procedures were performed by using ABOi KT.4,9,10 The number of living donor KTs at our hospital has increased by 19.9% (from 176 to 211), since the start of the ABOi KT program in May 2009. Our intermediate-term outcomes demonstrated that KTs from ABOi donors were equivalent to those from ABOc donors in terms of patient survival, graft survival, and kidney
function (Figs 1 and 2). The 2-year patient and graft survival rates for the ABOi group were 94.3% and 91.3%, respectively, which were comparable to other reports. Shimmura et al that initial maximum blood group antibody titers correlated with graft survival.11 The Johns Hopkins and Mayo Clinic groups have also identified initial blood group antibody titers as an important prognostic predictor.4,5 In contrast, we did not identify a similar correlation between initial blood group antibody titers and graft loss. Even patients with high initial blood group antibody titers (4 patients, 1024) were successfully transplanted in our series. Therefore, high initial blood group antibodies should not represent an exclusion criterion for ABOi KT as recommended by previous workers.12,13
ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION
2935
Table 3. Multivariate Analysis for the Risk Factors of BiopsyProven Acute Rejection Episode Characteristics
P value
Hazard ratio
95% confidence interval
Recipient age Gender of recipient Donor age Gender of donor BMI (kg/m2) Mismatch of HLA Number of KT (>1) ABO incompatibility PRA (>20%) Nephron mass index (g/kg) Total ischemic time
.156 .605 .124 .744 .023 .961 .797 .062 .758 .187 .158
0.966 0.732 1.037 0.837 1.212 1.008 0.740 2.897 0.806 0.543 0.970
0.922e1.013 0.225e2.383 0.990e1.085 0.287e2.438 1.027e1.429 0.725e1.401 0.074e7.385 0.950e8.840 0.204e3.177 0.219e1.345 0.929e1.012
BMI, body mass index; HLA, human leukocyte antigen; KT, kidney transplantation; PRA, panel-reactive antibody.
AAMR is a serious complication that is more frequently experienced after ABOi KT compared with ABOc KT. To prevent AAMR, many centers have adopted routine postoperative PP.6,9 However, this procedure increases costs, length of hospital stay, and complications. Therefore, some centers have elected to perform only preemptive or selective postoperative PP.14e16 We performed postoperative PP only if there was a rise in blood group antibodies with concomitant impairment of graft function, with the exception of the first case. As expected, AAMR was significantly more common among the ABOi group. The 5 Table 4. Complications of the Living Donor Kidney Transplantations Type of complications
Infectious complications (%) Viral (%) CMV infectiona (%) CMV diseaseb (%) BKV infectiona (%) BKV nephropathyb (%) HZV infection (%) Bacterial (%) Fungal (%) Surgical complications (%) Bleeding complications (%) Urologic complications (%) Deep vein thrombosis (%) Bowel perforation (%) Arterial complications (%) Lymphocele (%) Medical complications (%) NODAT (%) Steroid-induced complications (%) Hematologic complications (%) Cardiac complications (%)
ABOc (n ¼ 138)
89 65 46 2 4 2 11 23 2 20 3 7 6 2 1 1 26 17 4 2 3
(64.5) (47.1) (33.3) (1.4) (2.9) (1.4) (8.0) (16.7) (1.5) (14.5) (2.2) (5.1) (4.3) (1.5) (0.7) (0.7) (18.8) (15.6) (2.9) (1.4) (2.2)
ABOi (n ¼ 35)
23 18 9 0 6 1 2 3 2 9 6 0 0 0 2 1 10 6 0 3 1
(65.7) (51.4) (25.7) (0) (17.1) (2.9) (5.7) (8.6) (5.7) (25.7) (17.1) (0) (0) (0) (5.7) (2.9) (28.6) (20.7) (0) (8.6) (2.9)
P value
.893 .647 .387 >.999 .005 .459 >.999 .297 .183 .112 .002 .347 .350 >.999 .183 .365 .205 .513 .584 .057 .810
Values are presented as number (%). ABOc, ABO-compatible; ABOi, ABO-incompatible; BKV, BK virus; CMV, cytomegalovirus; HZV, herpes zoster; NODAT, new-onset diabetes after transplantation. a Diagnosed by more than 500 copies/mL by polymerase chain reaction. b Diagnosed by tissue pathology.
Table 5. Multivariate Analysis for the Bleeding Risk Factors Characteristics
P value
Hazard ratio
95% confidence interval
Recipient age Donor age BMI (kg/m2) Mismatch of HLA ABO incompatibility PRA (>20%) Duration of RRT Total ischemic time
.604 .750 .316 .342 .026 .316 .186 .462
1.033 0.979 1.217 0.596 23.695 0.207 1.001 0.948
0.915e1.166 0.857e1.118 0.829e1.789 0.205e1.733 1.468e382.371 0.010e4.483 1.000e1.002 0.823e1.093
BMI, body mass index; HLA, human leukocyte antigen; KT, kidney transplantation; PRA, panel-reactive antibody.
AAMR were observed in 5 recipients of ABOi KT (14.3%), compared with 1 (3.0%) in the ABOc group. The incidence of AAMR in this series (14.3%) was similar to that described by groups routine in the postoperative using PP period (14.3% vs 15%, respectively).9 All cases of AAMR were successfully treated with PP and steroid pulse therapy. The spectrum of adverse events in the present analysis was comparable to ABOc living donor KT with the exception of BK virus infections and postoperative bleeding complications (Table 4). There was a major concern that the vigorous preparation before ABOi KT (PP, rituximab, and longer preoperative immunosuppression) would increase the rate of infectious complications. However, there were no fatal or serious infectious complications among the ABOi group. The only significant difference between the two groups was BK virus infection, most of which resolved after rapidly lowering the maintenance immunosuppression. The incidence of cytomegalovirus (CMV) infection was same as the ABOc group (25.7% vs 33.3%, respectively). There were no CMV disease cases among the ABOi group. The incidence of CMV infection was relatively lower than in Table 6. Hospital Stay and Readmission of Living Donor Kidney Transplant Recipients ABOc (n ¼ 138)
Hospital stay (d) Total Preoperative Postoperative
ABOi (n ¼ 35)
P value
a
23.5 5.4 [18e47] 5.6 2.1 [1e14] 18.0 4.7 [14e39]
36.1 12.0 <.001 [14e73] 14.9 5.5 <0.001 [8-30] 21.2 10.2 .077 [4e59]
Cause of readmissionb Increased creatinine (%) 63 (45.7) 23 (65.7) Infectious complications (%) 29 (21.0) 5 (14.3) Urinary complications (%) 9 (6.5) 1 (2.9) Orthopedic complications (%) 3 (2.2) 2 (5.7) Vascular complications (%) 3 (2.2) 2 (5.7) Cardiac complications (%) 1 (0.7) 1 (2.9) Others (%) 25 (18.1) 4 (11.4) Readmission ratea,c 0.96 1.00 1.09 1.25
.034 .371 .689 .266 .266 .365 .325 .572
All values represent means standard deviations [range]. Values are presented as number (%). Total number of readmission during follow-up/total number of patient in each group. a
b c
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other studies.17 We administered valganciclovir prophylactically in the ABOi group, resulting in a relatively lower incidence and severity of CMV infection compared with other studies and with the ABOc group. These findings suggest that the current protocol does not carry an enhanced risk of over-immunosuppression. The overall incidence of surgical complications was similar between the 2 groups, except that bleeding complications were significantly more common in the ABOi group (P ¼ .002). Other studies have also reported a higher incidence of immediate postoperative bleeding complications with ABOi KT.18 A possible explanation relates to the method of removing blood group antibodies and the timing of IVIg administration. Theoretically, PP removes more coagulation factors than double filtration PP or immunoadsorption.19 Geyer et al reported a relationship between bleeding complications and timing of IVIg administration.20 The incidence of bleeding complications tended to be higher in patients receiving IVIg 1 compared with 5 days before the operation (50.0% vs 4.5%). The percentage of patients experiencing medical complications did not differ between the groups. As expected, the preoperative hospital stay was significantly longer in ABOi recipients, primarily because of preoperative PP (P < .001). However, the postoperative hospital stay was similar. The number of readmissions per patient was also similar between the ABOc and ABOi group: 0.96 1.00 vs 1.09 1.25, respectively. Impaired renal function was a more frequent cause of readmission in the ABOi group. One explanation was a perceived need for closer monitoring of changes in renal function due to the novelty of the ABOi program. This study demonstrated that ABOi living donor KT using a PP-based approach resulted in an increase in AAMR and bleeding complications as well as longer preoperative hospital stays compared with ABOc KT. However, patient survival, graft survival, transplant function, and other complications were comparable. In conclusion, ABOi living donor KT represents a viable option for patients whose only available donor is blood group incompatible. REFERENCES 1. Alexandre GP, Squifflet JP, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc. 1987;19:4538.
HWANG, KIM, KIM ET AL 2. Alexandre GP, De Bruyere M, Squifflet JP, et al. Human ABO-incompatible living donor renal homografts. Neth J Med. 1985;28:231. 3. Tanabe K, Takahashi K, Sonda K, et al. Long-term results of ABO-incompatible living kidney transplantation: a single-center experience. Transplantation. 1998;65:224. 4. Stegall MD, Dean PG, Gloor JM. ABO-incompatible kidney transplantation. Transplantation. 2004;78:635. 5. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers. Am J Transplant. 2004;4:561. 6. Genberg H, Kumlien G, Wennberg L, et al. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up. Transplantation. 2008;85:1745. 7. Chung BH, Lee JY, Kang SH, et al. Comparison of clinical outcome between high and low baseline anti-ABO antibody titers in ABO-incompatible kidney transplantation. Ren Fail. 2011;33:150. 8. Montgomery RA. ABO incompatible transplantation: to B or not to B. Am J Transplant. 2004;4:1011. 9. Montgomery RA, Locke JE, King KE, et al. ABO incompatible renal transplantation: a paradigm ready for broad implementation. Transplantation. 2009;87:1246. 10. Segev DL, Simpkins CE, Warren DS, et al. ABO incompatible high-titer renal transplantation without splenectomy or antiCD20 treatment. Am J Transplant. 2005;5:2570. 11. Shimmura H, Tanabe K, Ishikawa N, et al. Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation. Transplantation. 2000;70:1331. 12. Donauer J, Wilpert J, Geyer M, et al. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a single center experience. Xenotransplantation. 2006;13:108. 13. Shimmura H, Tanabe K, Ishida H, et al. Lack of correlation between results of ABO-incompatible living kidney transplantation and anti-ABO blood type antibody titers under our current immunosuppression. Transplantation. 2005;80:985. 14. Wilpert J, Geyer M, Pisarski P, et al. On-demand strategy as an alternative to conventionally scheduled post-transplant immunoadsorptions after ABO-incompatible kidney transplantation. Nephrol Dial Transplant. 2007;22:3048. 15. Schwartz J, Stegall MD, Kremers WK, Gloor J. Complications, resource utilization, and cost of ABO-incompatible living donor kidney transplantation. Transplantation. 2006;82:155. 16. Toki D, Ishida H, Horita S, et al. Impact of low-dose rituximab on splenic B cells in ABO-incompatible renal transplant recipients. Transpl Int. 2009;22:447. 17. Tanabe K. Japanese experience of ABO-incompatible living kidney transplantation. Transplantation. 2007;84:S4. 18. Wilpert J, Fischer KG, Pisarski P, et al. Long-term outcome of ABO-incompatible living donor kidney transplantation based on antigen-specific desensitization. An observational comparative analysis. Nephrol Dial Transplant. 2010;25:3778. 19. Tyden G, Kumlien G, Efvergren M. Present techniques for antibody removal. Transplantation. 2007;84:S27. 20. Geyer M, Fischer KG, Drognitz O, et al. ABO-incompatible kidney transplantation with antigen-specific immunoadsorption and rituximabdinsights and uncertainties. Contrib Nephrol. 2009;162:47.