ABO-incompatible Renal Transplantation Research Articles

AB0 Incompatible Renal Transplantation Shows Worse Graft Survival and Increased Rate of Antibody Mediated Rejection.

ABO incompatible (ABOi) renal transplantation (rTx) is increasingly used to overcome the organ shortage. Smaller studies evaluating the outcome of ABOi rTx showed no difference in outcome compared to controls, but may have been underpowered. Our aim was to provide a broader data pool by meta-analyzing the available studies. We used the terms “ABO OR AB0”, “incompatible” and “kidney OR renal” to search Medline. Additional studies were identified by review of cited literature and by using the Cochrane Library. Primary effectivity endpoint was probability of 1-year-graft survival. Random effects model was used. Subgroup analysis was performed for studies using rituximab or not, meta-regression analysis was used to evaluate the importance of continuous variables. From 536 articles identified 17 reports including 23 patient groups with ABOi rTx could be used for data retrieval. Analysis of all 23 patient groups revealed significantly worse 1-year-graft survival (OR 0.37, 95% CI 0.25-0.56, p<0.001) and 5-year-graft-survival (OR 0.66, 95% CI 0.59-0.75, p<0.001) in recipients of an ABOi graft The studies showed relevant heterogeneity (I2=62.3, Q test p<0.001). In those studies using rituximab as part of the preoperative preparation 1-year-graft survival was also worse in ABOi rTx (OR 0.34, 95% CI 0.16-0.77, p=0.01). Within these studies we detected no heterogeneity (I2=0, Q test p=.89). Rate of infections (OR 1.43, 95% CI 0.87-2.34, p=0.16) and of acute cellular rejection (OR 0.891, 95% CI 0.69-1.16, p=0.38) was identical, but rate of antibody mediated transplantation was higher (=R 7.11, 95% CI 3.42-14.77, p<0.001) in AB0 incompatible transplanted patients than in controls.Figure: No Caption available.Metaanalysis of the available evidence showed worse graft survival for recipients of an ABOi graft. This information should be acknowledged when informing patients about an ABOi rTx. However, we should also acknowledge that in real life the right comparator is not ABO compatible living related donorship (as used in most studies) but waiting for a deceased donation for several years.

Late-Onset Neutropenia and Acute Rejection in ABO-Incompatible Kidney Transplant Recipients Receiving Rituximab.

Recently, a new avenue in the management of ABO-incompatible kidney transplantation has been presented with the introduction of an anti-CD20 monoclonal antibody, rituximab. In May 2006, we started our program using this antibody for ABO-incompatible kidney transplantations. Using rituximab, we have experienced successful ABO-incompatible renal transplantations without splenectomy as well as in recipients with high pre-transplant anti-A/B antibody titers. At our institution, rituximab (150 mg/m2) was administered twice at 2 weeks priorto and on the day of transplantation except for elderly recipients. The recipients aged 65 years and older received only a single dose of 150 mg/m2 rituximab at 2 weeks prior to transplantation. An increasingly recognized toxicity of rituximab is late-onset neutropenia (LON), defined as unexplained grade III-IV neutropenia occurring at least 4 weeks after the last dose of rituximab in the absence of an alternative explanation. Patients and Methods Between May 2006 and December 2011, 25 patients who received rituximab underwent successful ABO-incompatible kidney transplantations. These 25 cases were enrolled as the subjects in this study. LON was defined as grade III to IV neutropenia after the last administration of rituximab, in the absence of any alternative reason to explain its occurrence. Results Twelve recipients (48%) experienced LON 1-11 months after transplantation. Five of the 12 patients (41.6%) who developed LON had an episode of biopsy-confirmed acute cellular rejection, as compared with one of the remaining 13 patients (7.7%) who did not develop LON. Moreover, 3 patients who experienced LON developed steroid and deoxyspergualin-resistant acute cellular rejection, and they required OKT-3 administration. Conclusion The frequency of acute cellular rejection tended to be higher in ABO-incompatible kidney transplant recipients with LON than in those without LON. Our findings suggest that recipients who develop LON after rituximab administration may be at an increased risk for acute cellular rejection.

Usefulness and Safety of High-dose Mizoribine on ABO-incompatible Living Related Kidney Transplantation Using Anti-cd20 and Anti-cd25 Antibodies Without Splenectomy: 3-year Results

BackgroundMizoribine (MZR) has been developed as an immunosuppressive agent in Japan, but has a less potent immunosuppressive effect up to 3 mg/kg/d. We previously reported that high-dose MZR, at 6 mg/kg/d, would be effective and safe for ABO-incompatible(ABO-i) living donor kidney transplantation (LDKT) patients when combined with cyclosporine (CsA) or tacrolimus(FK), anti-CD20 and anti-CD25 monoclonal antibodies, and corticosteroid without splenectomy in a 1-year study. Therefore, we observed these patients for 3 years. MethodsFrom 2007 to 2010, we encountered 24 cases of ABO-i LDKT using anti-CD20 and anti-CD25 monoclonal antibodies without splenectomy. The pretransplantation immunosuppressive regimen consisted of two doses of anti-CD20 antibody, mycophenolate mofetil (MMF, 25 mg/kg/d), prednisolone, calcineurin inhibitor (CNI; CsA 7 mg/kg or (FK 0.2 mg/kg) and two doses of anti-CD25 antibody. Antibody removal by plasmapheresis was performed before LDKT up to several times according to the antibody titer. The post-transplantation regimen consisted of high-dose MZR (6 mg/kg/d) instead of MMF (MZR group, N = 12) . ResultsThe 3-year graft survival rates for the MZR and MMF groups were 91.7% and 100%, respectively. Serum creatinine levels for the MZR and MMF groups were 1.44 mg/dL and 1.31 mg/dL at 1 year, 1.55 mg/dL and 1.41 mg/dL at 2 years, and 1.51 mg/dL and 1.48 mg/dL at 3 years, respectively (not significant [NS]). The MZR group did not show a higher rate of elevated serum uric acid values. The percentage of patients who were administered anti-uric medication was 42.5% (5/12) in the MZR group and 50% (6/12) in the MMF group (P = NS) at the third year. Severe infection, such as cytomegalovirus, herpes zoster, was not observed at the second and third years in both groups. ConclusionA high-dose MZR regimen including CNI (CsA or FK), steroid, and anti-CD20 and anti-CD25 antibodies without splenectomy was effective and safe in ABO-i renal transplantation.

Tailor-made medicine of ABO incompatible renal transplant recipients dsensitivity test at the beginning of desensitization therapy and just before operationesigned by lymphocyteimmunosuppressant

Tailor-made medicine of ABO incompatible renal transplant recipients dsensitivity test at the beginning of desensitization therapy and just before operationesigned by lymphocyteimmunosuppressant

A case of passenger lymphocyte syndrome following minor ABO incompatible renal transplantation

Immune hemolysis is one of the adverse effects that can occur following solid organ transplantation. Understanding the clinical settings and the various causes is necessary for prompt diagnosis and appropriate management. One such condition is passenger lymphocyte syndrome (PLS). This case report describes the case of a 27-year-old male renal allograft recipient of the B-positive blood group who received a kidney from an O-positive donor. Postoperatively, the patient showed declining hemoglobin (Hb) level and was transfused with B-group packed RBCs (PRBCs), following which there was steep fall in Hb level. A request for PRBCs was sent to the blood bank and this time cross-match with B-group PRBCs showed incompatibility. The patient's RBCs were found to be strongly DAT (direct anti-globulin test) positive and the eluate showed the presence of anti-B with a titer of 32. Thus, diagnosis of probable PLS was made. The patient was managed with methylprednisolone, plasmapheresis and O-group PRBCs. Gradually his condition improved and was discharged in stable condition.

Plasmapheresis as preconditioning protocol in an extremely high titer ABO incompatible renal transplant (ABOiRTx) case: A new prospect for chronic kidney disease patients in India

The biggest hurdle in renal transplantation is the ABO blood group system. But recently ABO incompatible renal transplants have been performed using plasmapheresis (PP) as a part of the preconditioning protocol. In the present study, the objective of PP along with immunosuppression was to bring down the antibody titer of the patient to ⩽16 during the transplant and keep it low, around 32, until post-operative 4–14weeks. The patient (O Negative) had his mother (B Positive) as the ABO non-identical donor. The PP was performed with an apheresis equipment Com.Tec (Fresenius Kabi, Germany) to lower the anti-B antibody titer in the recipient. An Antihuman globulin (AHG) titer was performed for anti-B antibody following the departmental standard operating procedure. A total of 11 plasmapheresis procedures was performed preoperatively and four procedures were performed post-operatively to maintain the titer of the anti-B antibody at or below the desired level. The baseline anti-B antibody titer in the recipient was 512. The baseline titer came down to 8 after the end of the 11th procedure. Post-operatively we performed four plasmapheresis procedures to keep the titer at 32. During the post-operative follow up the titer has been maintained at 32 and the serum creatinine level has been maintained at approximately 1.0mg/dl and other parameters relevant to graft function were within normal limits. Our case could be the first reported case from India in which we used a plasmapheresis procedure as a part of preconditioning protocol instead of using an immunoadsorption column. Furthermore, it could be one of the few ABOiRTx cases, which has been performed at an isoagglutinin titer of 512 using plasma exchange as part of a preconditioning regime.

Clinical evaluation of the endothelial tie-2 crossmatch in ABO compatible and ABO incompatible renal transplants

The necessity of detection of other than the classical major histocompatibility complex (MHC) and MHC class I-related chain A (MICA) directed antibodies prior to organ transplantation has already been repeatedly reported. A commercial flow cytometric endothelial crossmatch (CM) using isolated peripheral blood tie-2 positive cells provides a tool to detect non-MHC antibodies in addition to antibodies directed to MHC class I and II. The vast majority of circulating tie-2 positive cells expresses HLA-DR but not the A, B blood group antigens. Tie-2 cells are circulating surrogate endothelial cells. In this retrospective study we evaluated the endothelial CM in 51 renal transplantations, 30 with ABO compatible grafts and 21 with ABO incompatible grafts. Fifteen of the ABO compatible recipients (group A) developed unexplained rejection episodes (RE) while the remaining 15 had no RE (group B). Five cases of group A and none of group B had a positive tie-2 CM before transplantation (p=0.042). A positive tie-2 CM was also correlated with graft failure in ABO compatible transplants (p=0.02). No significant correlation was found between a positive pre-transplant tie-2 CM and RE in the ABO incompatible group. This study strongly suggest that a positive tie-2 CM may predict post-transplantation complications in ABO compatible grafts while negative reactions are not predictive. The test is not significantly correlated with RE in ABO incompatible grafts possibly due to applied desensitization.

Successful Treatment of Severe ABO Antibody-Mediated Rejection Using Bortezomib: A Case Report

BackgroundOur program for ABO-incompatible renal transplantation includes antigen-specific immunoadsorption (extracorporeal columns with the A or B trisaccharides), rituximab, and standard maintenance immunosuppression. Anti-A or -B titers ≤8 in the indirect antiglobulin test (IAT) against panel A1 or B RBC are acceptable for transplantation. Case ReportA previously healthy, 15-month-old girl was diagnosed with Wilms' tumor and proteinuria. Denys–Drash syndrome was confirmed. Bilateral nephrectomy was performed. At 3.5 years of age she received an ABO-incompatible renal transplant from her father (A1 to O). The anti-A titers before transplantation were low. She was treated preoperatively with rituximab, immunoadsorption, immunoglobulin and mycophenolate mofetil (MMF). The maintenance immunosuppression protocol included basiliximab, tacrolimus, MMF, and prednisolone. The initial postoperative course was uncomplicated with rapid normalization of serum creatinine. The anti-A titers started to increase on postoperative day 5 (8 NaCl/16 IAT). Despite daily immunoadsorptions the titers rose to 1024 NaCl/1024 IAT on day 9. Renal function deteriorated and hemodialysis was started. A renal biopsy on day 9 showed acute severe antibody-mediated rejection. Additional treatment with bortezomib was given and after 2 doses the titers started to decline, renal allograft function improved and hemodialysis was stopped. On day 21 posttransplant the titers went down, creatinine was 28 μmol/L, and no more immunoadsorptions were performed. ConclusionBy using bortezomib, we were able to successfully reverse a severe ABO antibody-mediated rejection.

B cells and immunoglobulin in ABO-incompatible renal transplant patients receiving rituximab and double filtration plasmapheresis.

The effect of rituximab on B cell and immunoglobulin production after therapeutic apheresis has not been studied in ABO-incompatible renal transplant patients. Twenty consecutive ABO-incompatible renal transplant patients receiving rituximab induction and double filtration plasmapheresis were enrolled; one case was excluded because of repeated plasmapheresis and immunoglobulin therapy (Incompatible group). The B cell count of the Incompatible group was compared to another group of 18 ABO-compatible renal transplant patients who were operated on during the same period (Compatible group). In the Incompatible group, the total IgM, IgG, and IgG1-4 subclasses after transplantation were compared to those before desensitization. Tacrolimus, mycophenolate mofetil, and steroids were used for both groups. The B cell count of the Incompatible group was significantly lower than the Compatible group post-transplant from Month 1 to Month 11 only. The B cell count of the Compatible group also decreased for the first 6 months, suggesting that maintenance immunosuppressive agents suppress B cells. Total IgG and IgM levels after transplantation were significantly lower than before desensitization during the 24-month follow-up period. The post-transplant IgG3 level was significantly lower than before desensitization for only 3 months. With the aid of tacrolimus and mycophenolate mofetil, rituximab resulted in sustained suppression of B cell count and total IgG and IgM. Among the IgG subclasses, IgG3 was less sensitive to rituximab.

Does Incompatibility Matter? Comparative Outcomes Following Treatment of Early AMR in ABO-Incompatible (Aboi) Renal Transplants

Does Incompatibility Matter? Comparative Outcomes Following Treatment of Early AMR in ABO-Incompatible (Aboi) Renal Transplants

Bleeding complications in pediatric ABO-incompatible kidney transplantation

ABO-incompatible renal transplantation (ABOi-RTx) following preconditioning with immunoadsorption (IA) and rituximab is a promising approach to facilitate living-related RTx. However, clinical experience is limited in pediatric patients. Three patients underwent living-related ABOi-RTx in our center. Preoperative IA was performed six, ten and 11 times in patient one, two and three, respectively, to achieve isoagglutinin titers of ≤1:8 on the day of transplantation; rituximab was administered once. The immunosuppressive regimen further comprised tacrolimus, mycophenolate, methylprednisolone and basiliximab; immunoglobulin G (IgG) was infused on the day of ABOi-RTx. All three patients achieved normal renal function within 2-6 days post-RTx. Major postoperative bleeding occurred in two patients, with one requiring repeated blood transfusions and the other a surgical revision 4 h after RTx, despite local citrate anticoagulation use during the preoperative IA procedures in the latter patient. A pyelonephritis-associated increase of the isoagglutinin IgG/IgM titers to 1:64/1:128 led to a biopsy-proven acute humoral rejection in the third patient, which was treated successfully with plasma exchange and methylprednisolone pulses. The estimated glomerular filtration rate at 18, 8 and 23 months post-RTx was 96, 52 and 74 ml/min/1.73 m(2), respectively. ABOi-RTx can successfully be performed in pediatric patients after preconditioning with quadruple immunosuppression, rituximab and IA. Caution is required regarding bleeding complications, which are most likely due to the unspecific binding of coagulation factors during repeated IA.

Flow Cytometric Detection of Anti-AB Antibody Titers in Blood Group O Recipients of Blood Group A2 Donor Kidneys

AimABO-incompatible kidney transplantation has been accepted for end-stage renal failure patients who have no ready opportunity for a deceased or living donor. Antibody titration for ABO-incompatible renal transplantation is not only difficult but also lacks conformity among laboratories. Herein we analyzed 20 living related renal transplant couples to detect recipient anti-A2 antibody using flow cytometric analysis. Materials and methodsPatients were admitted to our center for renal transplantation between January 1999 and December 2010. All but four of them had undergone a previous renal transplantation from an ABO-compatible donor but experienced graft failure. All donor blood groups were subtyped by our blood bank using a lectin-based dilution assay. To detect recipient anti-A2 antibody titers we used a tube hemagglutination method. A/B antibody titer analysis by flow cytometry incubated serially diluted serum samples with donor erythrocytes. Each analysis was repeated three times over a 2-week period using an older and the last sera simultaneously. ResultsThe 13 male and 7 female patients showed our overall mean age of 32 ± 12 years. All patients had panel-reactive antibody levels below 15%. The level of flow cytometric antibody titers did not vary upon repeated analysis (P = .01). When compared with the tube method there was a discrepancy of the level at which the antibody titer became negative. DiscussionFlow cytometric antibody titration is a practical and rapid technique to determine the amount of anti-A2 antibody in renal recipients.

Role of plasmapheresis in ABO-incompatible renal transplantation

BackgroundThousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO-incompatible (ABO-I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO-I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE. Study design and methodsThe TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti-human globulin (AHG) phase before surgery. Pretransplant therapy consists of every-other-day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti-A and anti-B titers until tolerance or accommodation occurs. The TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer. ResultsFifty-three ABO-I kidney transplants have been completed with no episodes of hyperacute antibody-mediated rejection (AMR), and only three episodes of AMR. One-year death-censored graft survival is 100% and patient survival is 97.6%. ConclusionWhile randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO-I renal transplantation.

Potent Immunosuppression for ABO-Incompatible Renal Transplantation May Not Be a Risk Factor for Malignancy

ABO-incompatible (ABOi) renal transplantation has been increasing, but malignant tumor is a troubling complication of kidney transplantation due to potent immunosuppression. Few previous studies, however, have demonstrated that potent immunosuppression for ABOi living-donor renal transplantation (LDRT) is a risk factor for malignancy. In the present research, data on 252 LDRT patients ftom 2003 to 2008 were retrospectively analyzed to clarify whether ABOi LDRT was associated with malignancy. A potent immunosuppressive regimen for ABOiLDRT consisted of splenectomy, cyclophosphamide, and double-filtration plasmapheresis to minimize the risk of antibody-mediated rejection, in addition to conventional immunosuppresssants including calcineurin inhibitor, prednisolone, and anti-CD25 monoclonal antibody. A total of 11 incidences of malignancy were observed during a median follow-up of 48 months. The incidence rates in ABO-compatible (ABOc; n = 189) and ABOi (n = 63) LDRT groups were 4.2 % (8/189) and 4.8 % (3/63), respectively. Kaplan-Meier survival analysis showed no statistical difference in event-free survival for malignancy between ABOc and ABOiLDRT groups (log-rank P = .73). Multivariable Cox regression analyses identified no associations of malignancy with ABOi LDRT or any immunosuppressant use. In conclusion, our investigation suggested that potent immunosuppression with splenectomy and cyclophosphamide for ABOi LDRT may not be a risk fietor for malignancy.

Antibody Removal Before ABO-Incompatible Renal Transplantation: How Much Plasma Exchange Is Therapeutic?

ABOi transplantation is an accepted method of expanding the kidney donor pool but there is little analysis of the protocols used. We established an ABOi programme utilising leukocyte depletion, tacrolimus, TPE and IvIg. There are few reports in the literature on the success rates of antibody removal protocols or relating to patients in whom antibody removal fails. The purpose of this study was to define the likelihood of achieving transplantation depending on ABO antibody titers. 56 patients entered our ABOi program. Data were analysed to determine the likelihood of achieving transplantation, ABO antibody titre prior to antibody removal and amount of TPE required to achieve transplantation. The median antibody titer was 1:64 (Range 0-1:1024). Transplantation proceeded when the ABO titer reached ≤1:4. 51/56 (91%) patients achieved transplantation after 8.3±5 TPE. Five patients with high ABO titers were not transplanted despite extensive TPE. The number of TPE required to reach an ABO titer of ≤1:4 correlates best with pre-treatment IgG titers. This is the first study to demonstrate a cut off titer for entry in to the ABO incompatible program using the relationship between ABO titer and amount of TPE required to reach transplantation. We now tailor the antibody removal protocol prior to transplantation and have introduced a cut-off entry titer to the program (≤1:256), because of the unacceptable risk of exposing patients with higher titers to long-lasting immunosuppression and costly, prolonged, courses of TPE without the guarantee of successful transplantation. Patients whose ABO titer exceeds the cut-off are counselled and offered alternative routes to transplantation.

A case of progressive thrombotic microangiopathy after ABO‐incompatible renal transplantation

A 21-yr-old man of blood type O receiving hemodialysis for IgA nephropathy underwent living-related ABO-incompatible (ABOI) renal transplantation from his mother, whose blood type is A. He was negative for flow cross-match, anti-human leukocyte antigen (HLA) antibody, and anti-MICA antibody. Pre-treatment anti-A IgG titer was 1:256. Desensitization consisted of tacrolimus, mycophenolate mofetil, methylprednisolone, rituximab, and plasmapheresis. He developed acute antibody rejection at day 2 post-transplant, which was successfully treated. After renal artery reconstruction surgery at day 91 for renovascular hypertension caused by renal artery stricture, the patient suffered from acute prostatitis, which subsequently induced type III acute antibody-mediated rejection. Even after recovery from the rejection after temporary hemodialysis, graft function progressively deteriorated and consecutive allograft biopsy showed progressive thrombotic microangiopathy (TMA) without any evidence of donor-specific antibody other than anti-A antibody. The tacrolimus dose was kept low for fear of tacrolimus-induced TMA. Despite these efforts, the patient resumed hemodialysis six months' post-transplant.

Increase of infectious complications in ABO-incompatible kidney transplant recipients--a single centre experience

Due to the shortage of deceased donors ABO-incompatible (ABOi) living kidney transplantation has become a popular alternative to deceased kidney transplantation. In recent years, recipient desensitization with a combination of anti-CD20 treatment (rituximab), antigen-specific immunoadsorptions (IA) and intravenous immunoglobulin (IVIG), led to promising short-term and intermediate-term results. However, little is known about the impact of this intensified desensitization protocol on the risk of surgical and infectious complications. We retrospectively analysed 21 consecutive recipients who underwent ABOi renal transplantation. Pre-transplant desensitization included administration of rituximab (375 mg/m(2)), mycophenolate mofetil (MMF), tacrolimus and prednisolone 4 weeks prior of scheduled transplantation as well as IA and IVIG. Forty-seven patients who underwent ABO-compatible (ABOc) renal transplantation served as the control group. Medical records and electronic databases were reviewed for patient and graft survival, renal function, rate of rejections, viral and bacterial infections as well as for surgical complications (SCs) post-transplantation. All patients showed an immediate graft function. During a mean follow-up of 15.7 ± 8.3 months (interquartile range 11.9) patient survival was 95 and 98% in the ABOi and ABOc group, respectively. Allograft survival and function, as assessed by serum creatinine levels and calculated glomerular filtration rate at 1 year, did not differ between ABOi and ABOc recipients. Furthermore, the rate of biopsy-proven acute rejections was comparable between the two groups. However, there was a trend towards more SCs within the ABOi group (29 versus 11%, non-significant). In addition, the rate of viral infections including cytomegalovirus, Herpes simplex virus, Varicella zoster virus and polyoma virus was significantly increased among the ABOi recipients (50 versus 21%; P = 0.038) despite comparable tacrolimus trough levels and MMF and steroid doses. Our results, in line with the extended experience of other groups, demonstrate favourable short-term allograft survival and function after ABOi renal transplantation after desensitization with antigen-specific IA, IVIG and rituximab. However, the intensified desensitization was associated with an increased risk of infectious complications. This observation prompted us to briefly escalate the desensitization protocol in ABOi kidney recipients in our centre.

Successful ABO Incompatible Kidney Transplant After an Isolated Intestinal Transplant

To our knowledge, we herein report the first case in the literature of a living unrelated ABO incompatible (ABOi) renal transplantation after successful isolated small bowel and colon transplantation. This case illustrates several interesting immunologic findings. The patient is a 50-year-old woman with a history of hypertension and cholecystectomy who suffered with complicated endometriosis, which lead to multiple intestinal resections for recurrent obstruction and enterocutaneous fistulae. These ultimately led to short gut syndrome and total parenteral nutrition dependence for 5 years. The patient underwent an ABO identical isolated intestinal transplant (small bowel and right colon) with systemic venous drainage and basiliximab and steroid induction. Posttransplant maintenance included tacrolimus, sirolimus, and prednisone. No rejection was encountered, parenteral nutrition was discontinued, and her ileostomy was reversed 18 months later. Because of poor wound healing and wound infection, sirolimus was discontinued thereafter. One year after small bowel transplantation, the patient experienced progressive renal insufficiency presumed because of tacrolimus toxicity. Despite diuretic therapy, volume management ultimately led to hemodialysis 16 months after transplant. Her only potential live kidney donor was ABOi; the patient was blood group O; and her donor was blood group A. She subsequently underwent an ABOi renal transplant 24 months after her intestinal transplant. The desensitization protocol consisted of pretransplant and posttransplant tacrolimus and mycophenolate mofetil with four preoperative and two postoperative rounds of plasmapheresis and intravenous cytomegalovirus immune globulin. Induction therapy also included 1.5 mg/kg rabbit antithymocyte globulin intraoperatively and on the first 4 postoperative days along with methylprednisolone. Her baseline anti-A antibody titer was 1:64. After plasmapheresis, it decreased to 1:8 below the threshold of 1:32, necessary for successful ABOi renal transplantation (1). It is now 46 months after intestinal transplant and 26 months after her kidney transplant. She continues on a low fat diet with no nutritional support. In addition, she has a good kidney function and a serum creatinine level of 1.8. She is maintained on tacrolimus, mycophenolate mofetil, and prednisone for immunosuppression. The patient has had no evidence of rejection of graft or opportunistic infection. DISCUSSION Intestinal transplantation has improved in the past decade, achieving 1-year patient and graft survival rates in excess of 90% at several centers (2). It has been associated with a 30% to 40% risk of rejection in the first 3 months (3). Ojo et al. (4) report rates of renal failure as high as 21.3% in recipients of intestinal transplants, likely related to aggressive immunosuppression protocols. In this case, we successfully performed an isolated intestinal transplant with an excellent functional outcome using an aggressive immunosuppressive protocol including rabbit antithymocyte globulin induction and maintenance tacrolimus, sirolimus, and prednisone. Eventually the patient developed chronic renal failure, and we followed up this with an ABOi living donor kidney transplant. Despite the exposure to a second set of non-self-human leukocyte antigens and crossing the ABO barrier, there was no episode of rejection of either allograft. We hypothesize that her previous immunosuppression and our desensitization protocol would decrease the likelihood of such an occurrence. At our center, we use sirolimus as a part of our strategy for maintenance immunosuppression for intestinal transplantation, because this has been shown to be of benefit in combating acute rejection (5). She did not have evidence of rejection but did develop a wound infection and poor wound healing necessitating discontinuation of sirolimus. After 1 year, the patient ultimately developed progressive chronic renal failure and required hemodialysis. We believed that this occurred because of tacrolimus toxicity and recurrent dehydration because of high ileostomy output. At her kidney transplantation evaluation, we considered both deceased donor and living donor; ABOi or entering her into a paired kidney donor exchange. Because of a long expected wait time for a deceased donor organ, we opted for a living donor. Her only living donor was ABOi. The patient had no donor-specific antibody and a low ABOi titer to her donor. Such a donor recipient phenotype (O recipient and A donor) have less than 20% chance of a match in a paired kidney donation pool with long projected waiting times (6). Thus, we believed that an ABOi transplant was achievable in a short period of time with less morbidity on hemodialysis. The current shortage of deceased donor kidneys necessitate the use of all strategies to increase the donor pool for patients with end-stage renal disease. This case demonstrates the effective use of ABOi kidney transplantation for end-stage renal disease after intestinal transplantation with the absence of both rejection and opportunistic infection. Lee S. Cummings1 Jason S. Hawksworth1 Juan-Francisco Guerra1 Chirag S. Desai2 Raffaele Girlanda1 Cal S. Matsumoto1 Thomas M. Fishbein1 Lynt B. Johnson3 Joseph K. Melancon1 1Division of Transplantation and Hepatobiliary Surgery Georgetown University Hospital WA 2University of Arizona College of Medicine Tucson, AZ 3Department of Surgery Georgetown University Hospital WA

ABO-incompatible renal transplantation: From saline flushes to antigen-specific immunoadsorption-Tools to overcome the barrier

On April 23, 1951, a 30-year-old woman received the first intentional ABOi (ABO incompatible) renal transplantation in Boston. At that time, it was commonly believed that intensely rinsing the graft to remove blood would be sufficient to overcome any immunological problems associated with blood type incompatibility. However, when the abovementioned patient and another ABOi transplant recipient died within a month, Humes and colleagues arrived at the same conclusion: "We do not feel that renal transplantation in the presence of blood incompatibility is wise." In the decades that followed, we learned that the oligosaccharide surface antigens representing the ABO-blood group antigens are expressed not only on erythrocytes but also on cells from various tissues, including the vascular endothelium. The growing gap between organ demand and availability has sparked efforts to overcome the ABO barrier. After its disappointing results in the early 1970s, Japan became the leader of this endeavor in the 1980s. All protocols are based on 2 strategies: removal of preformed antibodies with extracorporeal techniques and inhibition of ongoing antibody production. Successful ABOi renal transplantation became possible with the advent of splenectomy, new immunosuppressive drugs (e.g., rituximab, a monoclonal antibody against CD20), and extracorporeal methods such as antigen-specific immunoadsorption. This review summarizes the underlying pathophysiology of ABOi transplantation and the different protocols available. Further, we briefly touch potential short- and long-term problems, particularly the incidence of infectious complications and malignancies, that can arise with high-intensity immunosuppressive therapy.

Effect of Apheresis for ABO and HLA Desensitization on Anti-Measles Antibody Titers in Renal Transplantation

Desensitization strategies for ABO-incompatible renal transplants with plasma exchange (PE) or specific immunoadsorption (IA) decrease immunoglobulin levels. After recent measles outbreak and decreasing vaccination rates, we studied the impact of apheresis on anti-measles antibodies. Anti-measles antibodies were measured before desensitization, before transplantation and during followup in 12 patients with ABO incompatibility (2x PE only, 8x IA only, and 2x IA and PE) and 3 patients with donor-specific HLA antibodies (all PE). Patients received rituximab, IVIG, and standard immunosuppressive therapy. All patients had detectable anti-measles antibodies before desensitization (mean 3238 mU/l, range 560–8100). After 3–6 PE sessions, titers decreased significantly to 1710 mU/l (P < 0.05), in one patient to nondetectable values, while IA only maintained protective titers. After a median followup of 64 days, anti-measles antibodies returned to baseline in all patients. Immunity against measles was temporarily reduced by apheresis but remained detectable in most patients at time of transplantation. Desensitization maintains long-term protective immunity against measles.