High Isoagglutinin Titers Research Articles

Outcomes of ABO-incompatible kidney transplants with very high isoagglutinin titers: a single-center experience and literature review

BackgroundABO-incompatible kidney transplantation (ABOi-KTx) represents a possible solution to address the shortage of kidney donors. However, these transplants present immunological challenges, particularly when isoagglutinin titers are elevated pretransplant.MethodsSingle-center retrospective study describing clinical and biological outcomes of 8 patients who underwent ABOi-KTx with initial isoagglutinin titers ≥ 1/512. All patients followed a desensitization protocol combining immunosuppression (rituximab, tacrolimus, mycophenolate mofetil, steroids), and specific or semi-specific apheresis sessions. Clinical and biological data were extracted from electronic medical records.ResultsThere were 5 males; median age of 62 years [34-82 years]; all achieved an isoagglutinin titer of ≤1/8 before transplantation after a median of 13 (range: 9-15) apheresis sessions. Three patients (37%) experienced acute humoral rejection, which required additional plasmapheresis sessions. Two patients developed chronic active rejection, successfully treated. On the infectious side, three patients developed BK-virus reactivation. Two patients developed cytomegalovirus viremia, and two others presented with bacterial infections. Surgically, two patients developed a lymphocele, and one had a perirenal hematoma. All patients survived the transplant with stable renal function: mean serum creatinine was 138 ± 15 µmol/L after four years of follow-up.ConclusionABO-incompatible kidney transplantation, even in patients with high isoagglutinin titers, is feasible and can achieve favorable long-term graft and patient survival outcomes. However, these procedures require substantial clinical expertise and close follow-up to monitor and manage the elevated risks of infection and rejection in this population.

Overcoming high pre-transplant isoagglutinin titers using high-dose intravenous immunoglobulin, salvage plasmapheresis, and booster rituximab without splenectomy in ABO-incompatible living donor liver transplantation: a case report

High pre-transplant isoagglutinin is a risk factor for antibody-mediated rejection in ABO-incompatible living donor liver transplantation. A 55-year-old man with alcoholic liver cirrhosis underwent ABO-incompatible living donor liver transplantation. The initial isoagglutinin immunoglobulin G titer was 1:1,024. Despite five sessions of plasmapheresis, the isoagglutinin titer was not significantly reduced (from 1:1,024 to 1:512). We decided to perform 11 plasmaphereses and proceed with liver transplantation regardless of the isoagglutinin titer (1:128 at transplantation day). Instead, we planned to administer 0.5 g/kg intravenous immunoglobulin and booster rituximab (200 mg) after transplant. On postoperative day 6, the isoagglutinin titer increased from 1:32 to 1:64, and the patient received plasmapheresis twice. The patient maintained stable liver function without evidence of further complications or rejection. The high-dose intravenous immunoglobulin, salvage plasmapheresis, and booster rituximab protocol might be able to overcome a pre-transplant high isoagglutinin titer in ABO-incompatible living donor liver transplantation without splenectomy.

Clinical Relevance of Isoagglutinin Rebound in Adult ABO-Incompatible Living Donor Liver Transplantation.

ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) can be performed successfully. However, anti-ABO isoagglutinin rebound may cause antibody-mediated rejection (AMR) and graft loss. The risk threshold of isoagglutinin rebound is still not defined. 76 ABO-I LDLT recipients were divided into group A (n = 56) with low isoagglutinin titers (<1:256), and group B (n = 20) with high isoagglutinin titers (≥1:256), at initial assessment for liver transplantation. The last 12 patients in group B received a modified desensitization regimen by adding bortezomib to deplete plasma cells. Six (10.7%) patients in group A and 10 (50.0%) patients in group B had postoperative isoagglutinin rebound (p < 0.001). Three patients (5.54%) in group A and two patients (10%) in group B developed clinical AMR (p = 0.602). The cutoff value of postoperative isoagglutinin rebound to cause clinical AMR was ≥1:1024. Among the 12 patients in group B with bortezomib administration, isoagglutinin rebounded up to 1:128 only, and no clinical AMR occurred. In conclusion, the patients with high isoagglutinin titers had a higher rate of postoperative isoagglutinin rebound. Isoagglutinin rebound ≥1:1024 is risky for developing clinical AMR. Adding bortezomib into the desensitization regimen may mitigate isoagglutinin rebound, and avoid clinical AMR.

Perioperative ABO Blood Group Isoagglutinin Titer and the Risk of Acute Kidney Injury after ABO-Incompatible Living Donor Liver Transplantation.

For ABO-incompatible liver transplantation (ABO-i LT), therapeutic plasma exchange (TPE) is performed preoperatively to reduce the isoagglutinin titer of anti-ABO blood type antibodies. We evaluated whether perioperative high isoagglutinin titer is associated with postoperative risk of acute kidney injury (AKI). In 130 cases of ABO-i LT, we collected immunoglobulin (Ig) G and Ig M isoagglutinin titers of baseline, pre-LT, and postoperative peak values. These values were compared between the patients with and without postoperative AKI. Multivariable logistic regression analysis was used to evaluate the association between perioperative isoagglutinin titers and postoperative AKI. Clinical and graft-related outcomes were compared between high and low baseline and postoperative peak isoagglutinin groups. The incidence of AKI was 42.3%. Preoperative baseline and postoperative peak isoagglutinin titers of both Ig M and Ig G were significantly higher in the patients with AKI than those without AKI. Multivariable logistic regression analysis showed that preoperative baseline and postoperative peak Ig M isoagglutinin titers were significantly associated with the risk of AKI (baseline: odds ratio 1.06, 95% confidence interval 1.02 to 1.09; postoperative peak: odds ratio 1.08, 95% confidence interval 1.04 to 1.13). Cubic spline function curves show a positive relationship between the baseline and postoperative peak isoagglutinin titers and the risk of AKI. Clinical outcomes other than AKI were not significantly different according to the baseline and postoperative peak isoagglutinin titers. Preoperative high initial and postoperative peak Ig M isoagglutinin titers were significantly associated with the development of AKI. As the causal relationship between high isoagglutinin titers and risk of AKI is unclear, the high baseline and postoperative isoagglutinin titers could be used simply as a warning sign for the risk of AKI after liver transplantation.

Efficacy of selective plasma exchange as pre-transplant apheresis in ABO-incompatible kidney transplantation

BackgroundSelective plasma exchange (SePE) is a new simple plasma exchange (PE) modality that enables removal of small and medium-sized molecules without removing larger substances such as coagulation factors. In this study, we examined the efficacy of SePE for removal of isoagglutinins in pre-transplant desensitization for ABO-incompatible (ABOi) kidney transplantation.Materials and methodsA case series study was performed in 15 ABOi kidney transplant recipients (KTRs) who underwent SePE alone (7 cases) and SePE in combination with double-filtration plasmapheresis or simple plasma exchange (8 cases). The target processed plasma volume (PV) was set at 2 PV, and 5% albumin solution was used as the substitution fluid in all SePE sessions. Changes in isoagglutinin titers (IgG and IgM) and serum IgG, IgM, and fibrinogen levels were examined. We also compared the decrease in isoagglutinin titers between SePE and conventional methods (PE and double-filtration plasmapheresis).ResultsA total of 29 sessions of SePE were performed in the 15 KTRs. Isoagglutinin titers were controlled to ≤ 1:16 in all patients except for 2 with high isoagglutinin titers, and there were no cases of antibody-mediated rejection. SePE led to a median twofold decrease in isoagglutinin titers (IgG and IgM), with median IgG, IgM, and fibrinogen removal rates of 64.2, 11.7, and 25.5%, respectively. Side effects occurred in only 4 of the 29 sessions. Neither titer decreased after SePE in 30% of the sessions. However, the reductions in isoagglutinin titers in patients undergoing SePE were significantly less than those in patients treated with conventional methods.ConclusionBecause SePE is less efficient in removing isoagglutinins compared to conventional methods, the use of SePE alone should be limited to patients with low isoagglutinin titers, and SePE in combination with conventional methods should be used for patients with high isoagglutinin titers. SePE may be a useful treatment option, if applied in appropriate cases, due to its lower cost (about half the price of PE using fresh frozen plasma in Japan) and fewer side effects. However, care is required because about 25% of fibrinogen is removed during SePE.

Donor screening reduces the isoagglutinin titer in immunoglobulin products.

Hemolysis reaction is a rare class effect of therapy with intravenously administered human normal immunoglobulin (IVIG). Anti-A/B isoagglutinins (isohemagglutinins) originating from donor plasma are considered a probable risk factor for hemolysis. We hypothesized that screening and exclusion of plasma obtained from donors with high isoagglutinin titers from the manufacturing process would produce a meaningful reduction of anti-A/B isoagglutinin titers of the final IVIG product. A donor screening method for anti-A isoagglutinins using an automated indirect agglutination test (IAT) in gel cards was developed. Industry-scale donor plasma pools and final IVIG product were prepared according to the manufacturing process of Privigen (human 10% liquid IVIG). Anti-A/B isoagglutinin levels were measured by IAT, direct agglutination test, and a flow cytometry-based assay. Screening of plasma from 705 randomly selected donors identified 6.8% donors with high anti-A isoagglutinin titers in plasma. Exclusion of plasma from these donors resulted in a one-titer-step reduction of anti-A isoagglutinin in laboratory-scale pooled plasma. The same donor screening method applied to industry-scale production resulted in exclusion of 5.1% of donors and produced a one-titer-step reduction of both anti-A and anti-B isoagglutinin titers in the final IVIG product. Anti-A/B isoagglutinin titers in IVIG products can be reduced on an industrial scale through implementation of anti-A donor screening, which may lower the risk of hemolysis after IVIG therapy.

FP817IMPACT OF BASELINE AND POSTOPERATIVE ISOAGGLUTININ TITER ON CLINICAL OUTCOMES IN ABO-INCOMPATIBLE LIVING DONOR KIDNEY TRANSPLANTATION

Introduction and Aims: ABO-incompatible (ABO-i) kidney transplantation (KT) has expanded in consequence of the development of desensitization protocol. However, the impact of baseline and postoperative isoagglutinin titer on clinical outcomes remains undetermined. Methods: Between February 2009 and December 2013, 214 patients with end-stage renal disease underwent ABO-i KT. After excluding patients with positive cross-matching results by T-cell flow cytometry, data from 180 patients were retrospectively reviewed. These patients were divided into the 2 sets of groups according to the baseline isoagglutinin titer and the appearance of titer-rebound (≥1:16) within 2 weeks after KT; initial high titer (≥1:256) group (n=29) vs. low titer (<1:256) group (n=151) and rebound group (n=41) vs. non-rebound group (n=139). Results: The mean age was 46.3±11.5 and the median follow-up period was 25 (range 2-63) months. Initial high titer group was related to more frequent preoperative and postoperative plasmapheresis sessions, lower titer reduction rate, higher titer just before KT, and more frequent titer-rebound within 2 weeks after KT than low titer group. Rebound group showed shorter interval between rituximab administration and the first plasmapheresis session, higher baseline isoagglutinin titer, more frequent preoperative plasmapheresis sessions, and lower titer reduction rate than non-rebound group. However, there were no significant differences in clinical outcomes including patient and graft survival, graft function, acute rejection episodes, infections, and postoperative medical and surgical complications regardless of the isoagglutinin titer. Additionally, male recipient (OR, 3.9; 95% CI, 1.4-10.8; p=0.008), previous KT history (OR, 5.8; 95% CI, 1.4-23.3; p=0.014), lower titer reduction rate (OR, 0.1; 95% CI, 0.02-0.6; p=0.008), and initial high isoagglutinin titer (OR, 3.5; 95% CI, 1.3-9.5; p=0.011) were associated with the development of titer-rebound within 2 weeks after KT in multivariate analysis. Conclusions: With the development of desensitization protocol, ABO-i KT could be performed and managed safely regardless of initial isoagglutinin titer and titer-rebound within 2 weeks after KT.

Selective Exclusion of High Titer Donor Plasma and Immunoadsorption Chromatography As Steps to Reduce Isoagglutinin Titers in IVIG

Hemolysis is a rare but potentially serious complication of high-dose IVIG therapy. Isoagglutinins originating in donor plasma are believed to play a major role in these reactions, but host factors are also important. We determined the effects of excluding plasma from donors with high isoagglutinin titers from the pools used to prepare IVIG, and of specific anti-A/B immunoaffinity chromatography (IAC), on the anti-A and anti-B titers of IVIG products prepared using the process for Privigen/Hizentra.

Isoagglutinin Reduction in Human Immunoglobulin Products by Donor Screening.

IntroductionHemolysis is considered a class effect and a rare adverse event that can occur following therapy with human normal immunoglobulin for intravenous administration [i.e., intravenous immunoglobulin (IVIG)]. Anti-A/B isoagglutinins (also referred to as isohemagglutinins) originating from donor plasma are present in polyvalent immunoglobulin G (IgG) products and are considered a probable risk factor for hemolysis. We hypothesized that, by excluding plasma from donors with high isoagglutinin titers, the final IVIG product would have a meaningful reduction in anti-A/B isoagglutinin titers.MethodsA method for screening donor plasma for anti-A isoagglutinins using an automated indirect agglutination test (IAT) was developed. A cut-off for donor plasma exclusion was defined. Industry-scale donor plasma pools and final IVIG product were prepared according to the manufacturing process of Privigen® (CSL Behring, Berne, Switzerland; human 10% liquid IVIG). Anti-A/B isoagglutinin content in pooled plasma and final IVIG product was measured by IAT, direct agglutination test, and a flow cytometry-based assay [fluorescence-activated cell sorting (FACS) anti-A].ResultsScreening of plasma from 705 donors identified 48 (6.8%) donors with high anti-A isoagglutinin titers in plasma (IAT agglutination score ≥2+ in a 1:200 pre-dilution). Exclusion of plasma from these donors resulted in a one-titer-step reduction of anti-A isoagglutinin in pooled plasma, confirmed by a twofold anti-A isoagglutinin concentration reduction measured by FACS anti-A (1,352 vs. 2,467 µg/g IgG). When the same screening and exclusion were applied to industrial-scale plasma pools (resulting in the exclusion of plasma from 5% of donors), anti-A isoagglutinins were reduced by one titer step in the final IVIG product. Anti-B isoagglutinins were also reduced by one titer step, as many donors with high anti-A isoagglutinins also have high anti-B.ConclusionReduction of anti-A/B isoagglutinin titers in IVIG products on an industrial scale is feasible through implementation of anti-A donor screening, which may reduce the risk of hemolysis following IVIG therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s13554-014-0016-2) contains supplementary material, which is available to authorized users.

Successful ABO Incompatible Living Donor Liver Transplantation in a Patient With High Isoagglutinin Titer Using High-Dose Intravenous Immunoglobulin

The optimal management in living donor liver transplantation using an ABO incompatible donor with a high isoagglutinin titer is still uncertain. Our patient was a 20-year-old woman with fulminant hepatitis. The only available donor was her 54-year-old father-in-law of an incompatible blood type. The initial isoagglutinin titer was 2048×. She received 375 mg/m 2 of anti-CD20 antibody 3 days before the living donor liver transplantation with concomitant splenectomy. Despite daily plasma exchanges after transplantation, the isoagglutinin titer started to shoot up to its maximum value of 2048×, with a sudden decline in the bile output. High-dose intravenous immunoglobulin (0.6 g/kg) was given after the plasma exchanges; thereafter, her liver function tests stabilized without a further increase in the isoagglutinin titer. We showed the effectiveness of high-dose intravenous immunoglobulin for the management of the rebound elevation of isoagglutinin titer. The combination of anti-CD20 antibody and daily plasma exchanges seemed ineffective for such a situation. This strategy might be another management option for ABO incompatible liver transplantation.

ABO‐incompatible kidney transplantation using antigen‐specific immunoadsorption and rituximab: a single center experience

For years ABO-incompatible kidney transplantations were preferentially performed in Japanese centers. In order to overcome the increased risk of humoral rejections, patients were treated with multiple sessions of plasmapheresis, intensified immunosuppressive therapy and splenectomy before transplantation. Despite good long-term results regarding patient and organ survival rates, increased morbidity during the early post-transplant period prevented a broad application of this method. Recently, a new protocol including the anti-CD20-antibody (Ab) rituximab and blood group-specific immunoadsorption instead of splenectomy and plasmapheresis was published with excellent short-term results. From April 2004 to September 2005, 11 patients were prepared for ABO-incompatible transplantation. All patients received 375 mg/m2 rituximab intravenous 3 to 4 weeks before transplantation. Immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and prednisone and was started at least 7 days before transplantation. Intravenous immunoglobulins (0.5 g/kg) were administered the day before transplantation. Immunoglobulin G (IgG)-anti-A or -B Ab titers before starting immunoadsorption treatment ranged between 1 : 4 and 1 : 1024. Immunoadsorption treatment was started in parallel with immunosuppressive medication and was continued until the anti-A or anti -B Ab titers (IgG and IgM) were lowered to the aimed pre-transplant threshold of <1 : 8. During the early postoperative period, additional immunoadsorption treatments were performed, if the titers increased again above 1 : 8 (days 0 to 7) or 1 : 16 (days 8 to 14), respectively. Transplantation could be conducted in eight of 11 patients (two females, six males, mean recipient age 52+/-11 yr). The mean follow-up was 7.0 months (range 4 to 17). The blood group constellation was A1 to 0 in four cases, A2 to 0 in two cases, B to A in one case, and A1 to B in another case, respectively. On average, each patient received seven immunoadsorption treatments. All transplants showed primary function and no humoral rejections occurred. Three of our 11 patients showed rapid increases of isoagglutinin titers after each immunoadsorption treatment and thus could not be transplanted. One patient died 4 months after transplantation with a functioning graft due to sepsis secondary to pseudomembranous enterocolitis. The mean creatinine value of the remaining seven patients now is 1.6 mg/dl. The use of antigen-specific immunoadsorption and an immunosuppressive regimen consisting of a conventional triple immunosuppressive therapy has shown excellent short-term results. The immunoadsorption treatment using antigen-specific columns is highly effective and even patients with high isoagglutinin titers can be transplanted. This protocol is an option for end-stage renal disease patients who have no blood group-compatible donor.

Effect of Anticoagulant and ABO Incompatibility on Recovery of Transfused Human Platelets

Abstract The effects of anticoagulant solutions on the recovery of transfused platelets were studied. Citrate anticoagulants at pH 7.4 or pH 6.5 were found to be equally effective in preserving the viability of platelets when centrifugation of the cells was not required. When centrifugation is required, as in most platelet survival studies, citrate at pH 6.5 gives maximum recoveries. Ethylene diamine tetraacetate (EDTA) caused temporary sequestration of nearly all transfused platelets and reduced maximum recoveries by about 50 per cent. Platelet recovery was lowered by ABO-incompatibility between donor platelets and recipient serum, but survival time of remaining platelets was not altered. Lowest platelet recoveries resulted when group A1 or A1 B platelets were given to group O recipients with high isoagglutinin titers. It is suggested that ABO-compatible platelets prepared in citrate should be used where possible in the treatment of thromboctyopenic disorders.

IMPROVEMENT IN BLOOD TRANSFUSION SERVICE

SELECTION OF NATURAL ANTI-A AND ANTI-B TEST SERUMS OF UNUSUALLY HIGH ISOAGGLUTININ TITER AND IMPORTANCE OF THEIR USE IN GROUPING OF BLOODS PRIOR TO TRANSFUSION With the discovery of the human blood groups by Landsteiner1at the turn of this century, the vast majority of dangerous reactions were eliminated, and the transfusion of blood became a relatively safe procedure. Landsteiner observed that the cells of some bloods when placed with the serums of others would clump together. This phenomenon was called agglutination.2The serum factor in this phenomenon was called the agglutinin, and the cell factor was called the agglutinogen. On the basis of the presence or absence of such serum and cell factors all human bloods can be classified into four groups. Landsteiner was able to divide human blood into three groups.3The fourth and rarest group was added by von Decastello4and Sturli in