Long-term outcome of ABO-incompatible renal transplantation.

Based on the long-term experience with ABO-incompatible kidney transplantation, the following can be concluded: 1. Renal transplantation across ABO incompatibility is an acceptable treatment for patients with end-stage renal failure. [table: see text] 2. Long-term patient and graft survival in ABO-incompatible kidney transplantation is influenced primarily by acute rejection episodes occurring within 1 year. 3. Despite the removal of anti-ABO natural antibodies before transplantation, hyperacute rejection crises may occur in some cases. 4. Humoral rejection is the most prominent type of rejection in ABO-incompatible renal transplantation. Even though most of this rejection is controllable with anti-rejection therapy, the prognosis for a graft that undergoes humoral rejection is significantly poor. 5. The maximum IgG titers of anti-A/B antibody before transplantation may have a harmful effect on graft acceptance in ABO-incompatible kidney transplantation. 6. Renal transplantation across ABO incompatibility is principally the most significant risk factor to affect long-term allograft function in ABO-incompatible living kidney transplantation.     

Tailored desensitization strategies in ABO blood group antibody incompatible renal transplantation

ABO blood group incompatible renal transplantation, using desensitization procedures, is an effective strategy. Efforts have been made to reduce desensitization: these are usually applied to all patients indiscriminately. The Guy's Hospital ABO blood group incompatible desensitization regimen uses a tiered approach, tailoring strategy according to initial antibody titres. Sixty‐two ABO blood group incompatible living donor transplant recipients were compared with 167 recipients of blood group compatible living donor renal transplants. There were no statistically significant differences in allograft survival rates at 1 or 3 years post‐transplant, rejection in the first year post‐transplant or renal function in the first 3 years post‐transplant. There was a higher rate of death in ABO blood group incompatible transplant recipients – this could be associated with differences in age and HLA mismatch between the two groups. Four ABO blood group incompatible patients experienced antibody‐mediated rejection (no episode was associated with a rise in ABO blood group antibodies). Of the patients who received no desensitization, or rituximab alone, none has experienced antibody mediated rejection or experienced allograft loss. Tailoring the use of desensitization in ABO blood group incompatible renal transplantation according to initial ABO blood group antibody titres led to comparable results to blood group compatible transplantation.     

ABO-incompatible kidney transplantation

When a renal transplant candidate's only medically-acceptable living kidney donor is ABO incompatible, the most common practice is to place them on the deceased donor list. Over the past few years, the implementation of paired kidney donor exchange programs and the development of protocols to overcome the ABO blood group barrier have become much more successful and widespread. Here we review the therapeutic options for patients whose only living kidney donor is ABO incompatible, with a specific emphasis on the rationale for and the current outcomes of ABO incompatible living donor kidney transplantation.     

ABO血型不合肝移植研究新进展

复习国外文章关于ABO血型不相同的肝脏移植在A2型供肝使用,移植肝出现受体类型的ABO组织血型抗原,C4d作用和临床治疗上的新进展。A2型供肝能较安全的用于血型不合肝移植,毛细血管内表达r-ABOAg可能是移植物内皮损害和修复的表现,C4d阳性对血型不同肝移植治疗策略上是很好的参考物,但缺乏特异性,采用包括多联免疫抑制药和肝内灌注等综合治疗方法能有效预防排斥反应且能取得良好的预后。     

Eculizumab in renal transplantation

Antibody-mediated rejection, be it acute, subacute or chronic, is currently recognized as the major cause of graft loss in kidney transplant recipients. Anti-HLA donor-specific antibodies are deleterious to the graft fate whether they pre-exist to the transplantation or appear in the course of transplantation. The role of complement is therefore prominent in most instances. As well, the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post-transplantation (aHUS) as well as following ischemia-reperfusion injury leading to delayed graft function.Eculizumab, a fully humanized monoclonal antibody directed against the C5 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria.In the setting of kidney transplantation, there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody-mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant. Studies are currently ongoing to determine its efficacy and safety in ABO incompatible transplantation, in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function.Similar to its efficacy in aHUS on native kidneys, eculizumab prevents or treats recurrence after kidney transplantation.There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies (DSAs) and at risk of HUS recurrence.     

A new concept of accommodation in ABO-incompatible kidney transplantation

Abstract:  This work focuses on the mechanism of acute antibody-mediated rejection leading to graft loss and the mechanisms of accommodation permitting graft survival in ABO-incompatible kidney transplantation. As previously noted, accommodation occurs only with (i) post-transplant suppression of glycosyltransferase, a product of ABO histo-blood group genes in the graft and (ii) prevention of antigen-antibody reactions and delayed hyperacute rejection due to reduced antigenicity of enzyme-regulated histo-blood group antigens. This article discusses the mechanism of ABO histo-blood group glycosyltransferase suppression. Accommodation is always established in successful ABO-incompatible organ grafts and ABO-minor mismatch bone marrow transplantation. In the former, accommodation develops even though ABO histo-blood types of the recipient and the donor are incompatible. In the latter, infusion of donor-derived bone marrow causes the recipient's blood to be eventually replaced by blood of the donor's type. However, the recipient's organs retain their original tissue type. In successful bone marrow engraftment, accommodation is established regardless of ABO-incompatibility. In organ transplantation the recipient's ABO histo-blood type regulates the graft's ABO histo-blood type, while in bone marrow transplantation the new ABO histo-blood type from the donor suppresses and regulates the ABO histo-blood type in recipient organs. In other words, bone marrow-derived histo-blood type regulates the histo-blood type of the organs.     

Histologic Findings One Year After Positive Crossmatch or ABO Blood Group Incompatible Living Donor Kidney Transplantation

Recent protocols have allowed successful positive crossmatch (+XM) and ABO incompatible (ABOI) kidney transplantation, although their long-term outcome is not clear. To begin to assess this issue we compared protocol biopsies performed 12 months posttransplant in 37 +XM, 24 ABOI and 198 conventional allografts. Although the majority in all three groups had only minimal histologic changes, transplant glomerulopathy (TG) was significantly increased in +XM (22% vs. 13% ABOI vs. 8% conventional, p = 0.015), and correlated with prior humoral rejection (HR) by multivariate analysis (odds ratio 17.5, p < or = 0.0001). Patients with a prior history of HR also had a significant increase in interstitial fibrosis (No HR 54% vs. HR 86%, p = 0.045). In the absence of HR no difference in histologic changes was seen between groups, although all three groups had a demonstrable mild increase in interstitial fibrosis from biopsies performed at the time of transplant. Thus, although HR is associated with an increase in TG, in its absence allograft histology is similar in +XM, ABOI and conventional allografts 1 year posttransplant.     

Rituximab in renal transplantation

Rituximab is a chimeric anti‐CD20 monoclonal antibody that leads to B cell depletion. It is not licensed for use in renal transplantation but is in widespread use in ABO blood group incompatible transplantation. It is an effective treatment for post‐transplant lymphoproliferative disorder, and is also used in both HLA antibody incompatible renal transplantation and the treatment of acute rejection. Recent evidence suggests rituximab may prevent the development of chronic antibody mediated rejection. The mechanisms underlying its effects are likely to relate both to long‐term effects on plasma cell development and to the impact on B cell modulation of T cell responses. Rituximab (in multiple doses or in combination with other monoclonal antibodies and/or other immunosuppressants) may lead to an increase in infectious complications, although the evidence is not clear. Rarely, the drug can cause a cytokine release syndrome, thrombocytopenia and neutropenia. It has been related to an increased risk of progressive multifocal leucoencephalopathy and, recently, deaths from cardiovascular causes. Trials examining the effects of rituximab in induction therapy for compatible renal transplantation and the treatment of chronic antibody mediated rejection are ongoing. These trials should aid greater understanding of the role of B‐cells in the alloresponse to renal transplantation.     

ABO incompatible renal transplantation in an HIV-seropositive patient

To date, there have been no reports of successful ABO blood group incompatible renal transplantation in HIV patients. We describe a case of a 47-year-old African American man with end-stage renal disease secondary to HIV-induced nephropathy who underwent a live unrelated (spouse) donor ABO blood group incompatible transplant using an intravenous immunoglobulin/plasmapheresis preconditioning regimen with interleukin-2 receptor antagonist induction along with tacrolimus and mycophenolate mofetil maintenance. The postoperative course was complicated by two acute cellular rejection (Banff Ia) episodes that were successfully managed with corticosteroid boluses and the addition of corticosteroids to maintenance immunosuppression. Antibody-mediated rejection was not observed on biopsy. The patient reached a serum creatinine nadir of 2.0 mg/dL on postoperative day 20, which has now been maintained for 170 days. His current CD4 count was 410 cells/microL.     

Acute Humoral Rejection in an ABO Compatible Combined Liver–Kidney Transplant—The Kidney Is Not Always Protected

Combined liver–kidney transplantation has become a common practice for the treatment of patients with concurrent end-stage renal disease and end-stage liver disease. Liver transplantation in the setting of multiorgan transplantation is thought to have a protective effect against humoral rejection even when a positive crossmatch is obtained prior to surgery. In most centers, a pre liver–kidney transplant crossmatch is rarely performed because of the known immunoprotective effect of the liver allograft. In this report, a case of acute humoral rejection in the kidney allograft after a combined liver–kidney transplant is described. Although humoral rejection was treated using plasmapheresis, intravenous immunoglobulin and rituximab, the kidney required 3 months to recover function and finally progressed to chronic allograft nephropathy. A heightened index of suspicion for acute humoral rejection of the renal allograft is necessary when performing combined liver–kidney transplants to highly sensitized patients due to previous organ transplants.     

Reversibility from delayed hyperacute rejection in ABO-incompatible renal transplantation: histopathological findings of renal allograft biopsy

ABO-incompatible renal transplantation (ABOIRTx) tend to lead to blood type antibody-mediated rejection, the so-called delayed hyperacute rejection (DHAR), which results in short-term graft loss. To clarify the accurate incidence and prognostic value of DHAR among ABOIRTx, we reviewed biopsy specimens obtained from ABOKTx allografts with abrupt dysfunction during the early period after transplantation. Among 74 ABOIRTx patients, 34 patients displayed allograft dysfunction within 14 days following transplantation. The biopsy specimens were classified based on the Banff schema. The pathological diagnosis of ABO blood type antibody-mediated humoral rejection (ABO-AMHR) was made by the following 3 findings: Specimens with all of above-mentioned findings were categorized as severe ABO-AMHR; those with at least one findings, were categorized as mild ABO-AMHR. All patients were treated with steroid pulse therapy and/or modification of other immunosuppressants. Group 1 consisted of severe ABO-AMHR (n = 6); group 2 consisted of mild ABO-AMHR (n = 5); group 3 consisted of acute cellular rejection (n = 3); group 4 consisted of recovery phase of ATN (n = 11); group 5 consisted of calcineurin inhibitor toxicity (n = 2); and group 6 consisted of normal histology (n = 5). One of 6 patients (16%) in group 1 lost the graft because of DHAR irreversible by antirejection and anticoagulation therapy. However, there has been no clear definition of histpathological criteria for DHAR after ABO-incompatible kidney transplantation. The definition must prognosticate whether the rejection process is reversible.     

心脏死亡器官捐献供肾ABO血型不相容肾移植八例临床分析

目的探讨心脏死亡器官捐献(DCD)供肾ABO血型不相合肾移植临床疗效和安全性。 方法回顾性分析中国人民解放军联勤保障部队第九二四医院移植科2016年12月至2018年6月实施的8例DCD供肾ABO血型不相容肾移植受者临床资料,其中男性6例,女性2例,年龄26～54岁,群体反应性抗体(PRA)阳性4例,二次肾移植2例,供受者Rh(D)血型均为阴性。根据受者初始血型抗体效价及术前PRA抗体水平制定个体化预处理方案。术后常规监测受者免疫抑制剂血药浓度,重点监测尿量、肾功能、凝血状态和血型抗体水平,PRA阳性受者注意监测供者特异性抗体水平。 结果8例受者经个体化预处理后肾移植手术当天血型抗体IgG效价水平均≤1∶16。术后2周内7例受者血型抗体无反弹。截至2018年6月,8例受者平均随访时间6～18个月。病例1于术后第2周发生体液性排斥反应,采用蛋白A免疫吸附及大剂量丙种球蛋白冲击治疗后恢复。病例2术后2 h出现膀胱出血,持续膀胱冲洗保守治疗后止血,移植肾功能恢复正常。病例3术后第5个月并发严重肺部真菌感染,抗真菌治疗失败后并发呼吸衰竭死亡。病例6术后出现移植肾功能延迟恢复,予血液透析处理后恢复。病例7术后尿量少,术后第4天出现右下肢深静脉血栓(移植肾侧),行下腔静脉滤网植入及溶栓抗凝治疗,效果欠佳,移植肾失功后恢复血液透析治疗。病例8术后第2个月并发药物性糖尿病,目前血糖控制较好。其余2例受者移植肾功能恢复良好。 结论根据受者初始血型抗体效价及PRA水平进行个体化预处理,可安全、有效地实施DCD供肾ABO血型不相容肾移植。     

Increasing access to kidney transplantation in countries with limited resources: The Indian experience with Kidney Paired Donation

According to the Indian chronic kidney disease registry, in 2010 only 2% of end stage kidney disease patients were managed with kidney transplantation, 37% were managed with dialysis and 61% were treated conservatively without renal replacement therapy. In countries like India, where a well‐organized deceased donor kidney transplantation program is not available, living donor kidney transplantation is the major source of organs for kidney transplantation. The most common reason to decline a donor for directed living donation is ABO incompatibility, which eliminates up to one third of the potential living donor pool. Because access to transplantation with human leukocyte antigen (HLA)‐desensitization protocols and ABO incompatible transplantation is very limited due to high costs and increased risk of infections from more intense immunosuppression, kidney paired donation (KPD) promises hope to a growing number of end stage kidney disease patients. KPD is a rapidly growing and cost‐effective living donor kidney transplantation strategy for patients who are incompatible with their healthy, willing living donor. In principle, KPD is feasible for any centre that performs living donor kidney transplantation. In transplant centres with a large living donor kidney transplantation program KPD does not require extra infrastructure, decreases waiting time, avoids transplant tourism and prevents commercial trafficking. Although KPD is still underutilized in India, it has been performed more frequently in recent times. To substantially increase donor pool and transplant rates, transplant centres should work together towards a national KPD program and frame a uniform acceptable allocation policy.     

Humoral and cellular rejection after combined liver–kidney transplantation in low immunologic risk recipients

Combined liver–kidney transplantation is considered a low risk for immunologic complication. We report an unusual case of identical ABO liver–kidney recipient without preformed anti-human leukocyte antigen (HLA) antibodies, transplanted across a T- and B-cell-negative cross-match and complicated by early acute humoral and cellular rejection, first in the liver then in the kidney. While analyzing the immunologic complications in our cohort of 12 low-risk combined liver–kidney recipients, only one recipient experienced a rejection episode without detection of anti-HLA antibody over time. Although humoral or cellular rejection is rare after combined kidney-liver transplantation, our data suggest that even in low-risk recipients, the liver does not always systematically protect the kidney from acute rejection. Indeed, the detection of C4d in the liver should be carefully followed after combined liver–kidney transplantation.     

The emerging role of rituximab in organ transplantation

Long-term acceptance of solid organ allografts remains a challenge. While many acute rejection episodes can be treated, new mechanisms of allograft damage are now being defined especially in kidney transplantation. Unexpected clusters of CD20(+) cells have been discovered in renal biopsies performed for clinical rejection. C4d deposition is now routinely seen in refractory rejection. Despite the rapid introduction of new immunosuppressive agents in transplantation, the search for an efficacious anti-B-cell agent remains. With novel mechanisms of allograft damage now being defined, it is important to consider how an anti-B-cell agent might fit into an immunosuppressive regimen. Rituximab is a high-affinity CD20 specific antibody that depletes the B-cell compartment by inducing cellular apoptosis. Thus, it is a rational choice for therapy in transplantation to abrogate B-cell mediated events. In this review, we will discuss the mechanisms of action of rituximab, and its use in for a variety of indications in solid organ transplantation. There are emerging case reports that show that rituximab may be an effective agent to treat antibody-mediated rejection, and post-transplant lymphoproliferative disorder. Rituximab has been frequently cited as an important adjunct therapy in desensitization protocols for highly sensitized transplant recipients as well as recipients of ABO incompatible transplants. Rituximab demonstrates promise in this regard and warrants additional consideration in prospective clinical trials.     

Accommodation in ABO‐incompatible organ transplants

Accommodation refers to a condition in which a transplant (or any tissue) appears to resist immune‐mediated injury and loss of function. Accommodation was discovered and has been explored most thoroughly in ABO‐incompatible kidney transplantation. In this setting, kidney transplants bearing blood group A or B antigens often are found to function normally in recipients who lack and hence produce antibodies directed against the corresponding antigens. Whether accommodation is owed to changes in anti‐blood group antibodies, changes in antigen or a change in the response of the transplant to antibody binding are critically reviewed and a new working model that allows for the kinetics of development of accommodation is put forth. Regardless of how accommodation develops, observations on the fate of ABO‐incompatible transplants offer lessons applicable more broadly in transplantation and in other fields.     

Underutilization of A2 ABO incompatible kidney transplantation

Redfield RR, Parsons RF, Rodriguez E, Mustafa M, Cassuto J, Vivek K, Noorchashm H, Naji A, Levine MH, Abt PL. Underutilization of A2 ABO incompatible kidney transplantation.
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01543.x.
© 2011 John Wiley & Sons A/S. Abstract: Background: ABO compatibility creates a disadvantage for O and B renal allograft candidates. A2 ABO incompatible transplant may decrease waiting times and generate equivalent graft survival to an ABO compatible transplant. Methods: Death‐censored graft survival was compared between A recipients and O, B, and AB recipients of an A2 allograft with multivariate Cox regression models utilizing data from the United Network of Organ Sharing (UNOS) between 1997 and 2007. Results: Eighty‐five percent of A2 kidneys were transplanted into ABO compatible recipients vs. 15% into ABO incompatible recipients. Rates of A2 incompatible kidney transplants did not increase over the study period (14.8% to 14.6%). Mean wait time for A2→O kidneys was 337 vs. 684 d for O→O and for A2→B kidneys, 542 vs. 734 d for B→B. Adjusted relative risk of graft loss at five‐yr was similar between O, B, and AB recipients compared to A recipients of an A2 allograft, corresponding to a five‐yr graft survival of 84%, 86.2%, 86.1%, and 86.1%, respectively. Conclusion: A2 incompatible kidney transplantation is underutilized. Graft outcomes are similar among A2 compatible and incompatible recipients. Shorter waiting time and improved access might be achieved if A2 kidneys are considered in all blood groups.     

Prolonged cardiac allograft survival in presensitized rats after a high activity Yunnan-cobra venom factor therapy

Complement-dependent antibody-mediated acute humoral rejection is the major obstacle of clinical transplantation across ABO incompatibility and human leukocyte antigen presensitization. We previously demonstrated that Yunnan-cobra venom factor (Y-CVF) could almost completely abrogate complement activity and successfully prevent hyperacute rejection in some xenotransplant models without any obvious toxicity. In this study we investigated whether depletion of complement by Y-CVF prevented acute humoral allograft rejection in presensitized rats thereby prolonging graft survival. METHODS: Presensitization was achieved in Lewis rats by sequential grafting of three full-thickness skin pieces from Brown Norway rats. Serum cytotoxic alloantibody titers were determined by a modified in vitro complement-dependent microcytotoxicity assay. After presensitization, each Lewis rat received a heterotopic Brown Norway cardiac allograft. Fifteen recipients were divided into two groups: (1) no treatment control (n = 7); (2) Y-CVF therapy group (86 u/kg, IV, day -1) (n = 8). After cessation of the heart beat, allograft rejection was confirmed by pathologic as well as IgG and C3 immunohistochemical examinations. RESULTS: The mean graft survival time was significantly prolonged to 99.50 +/- 38.72 hours among rats that received Y-CVF vs 12.71 +/- 13.94 hours in nontreated controls (P < .001). Upon pathological and immunohistochemical examination, acute humoral rejection was mainly exhibited in the control group, whereas acute cellular rejection was mainly displayed in the Y-CVF therapy group. CONCLUSIONS: Our study demonstrated that complement depletion by Y-CVF significantly inhibited acute humoral allograft rejection in presensitized rats. As a therapeutic immunointervention tool for complement, Y-CVF has shown potential efficacy across ABO incompatible and positive cross-match barriers.     

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. METHODS: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1-2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone+/-azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. RESULTS: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF-associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One-yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One-year patient survival was 93 and 100%, respectively (p>0.05). CONCLUSIONS: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year.     

Donor Kidney Exchanges

Kidney transplantation from live donors achieves an excellent outcome regardless of human leukocyte antigen (HLA) mismatch. This development has expanded the opportunity of kidney transplantation from unrelated live donors. Nevertheless, the hazard of hyperacute rejection has usually precluded the transplantation of a kidney from a live donor to a potential recipient who is incompatible by ABO blood type or HLA antibody crossmatch reactivity. Region 1 of the United Network for Organ Sharing (UNOS) has devised an alternative system of kidney transplantation that would enable either a simultaneous exchange between live donors (a paired exchange), or a live donor/deceased donor exchange to incompatible recipients who are waiting on the list (a live donor/list exchange). This Regional system of exchange has derived the benefit of live donation, avoided the risk of ABO or crossmatch incompatibility, and yielded an additional donor source for patients awaiting a deceased donor kidney. Despite the initial disadvantage to the list of patients awaiting an O blood type kidney, as every paired exchange transplant removes a patient from the waiting list, it also avoids the incompatible recipient from eventually having to go on the list. Thus, this approach also increases access to deceased donor kidneys for the remaining candidates on the list.