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.     

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.     

An economic assessment of contemporary kidney transplant practice

Kidney transplantation is the optimal therapy for end‐stage renal disease, prolonging survival and reducing spending. Prior economic analyses of kidney transplantation, using Markov models, have generally assumed compatible, low‐risk donors. The economic implications of transplantation with high Kidney Donor Profile Index (KDPI) deceased donors, ABO incompatible living donors, and HLA incompatible living donors have not been assessed. The costs of transplantation and dialysis were compared with the use of discrete event simulation over a 10‐year period, with data from the United States Renal Data System, University HealthSystem Consortium, and literature review. Graft failure rates and expenditures were adjusted for donor characteristics. All transplantation options were associated with improved survival compared with dialysis (transplantation: 5.20‐6.34 quality‐adjusted life‐years [QALYs] vs dialysis: 4.03 QALYs). Living donor and low‐KDPI deceased donor transplantations were cost‐saving compared with dialysis, while transplantations using high‐KDPI deceased donor, ABO‐incompatible or HLA‐incompatible living donors were cost‐effective (<$100 000 per QALY). Predicted costs per QALY range from $39 939 for HLA‐compatible living donor transplantation to $80 486 for HLA‐incompatible donors compared with $72 476 for dialysis. In conclusion, kidney transplantation is cost‐effective across all donor types despite higher costs for marginal organs and innovative living donor practices.     

ABO incompatible kidney transplantation

PURPOSE OF REVIEW: Although ABO incompatible kidney transplantation is increasingly recognized as effective, the procedure is still evolving. The purpose of this review is to summarize recent advances in this area. RECENT FINDINGS: Short to intermediate-term outcome appears good, although long-term results are still preliminary. Pretransplant risk stratification based on antidonor antibody titer may be of limited value. Splenectomy, previously reported to be an important component of ABO incompatible transplantation, appears to be avoidable under many circumstances. The wider implementation of A2 blood group incompatible transplantation shortens waiting time for deceased donor transplantation of blood group B recipients without significantly disadvantaging others. The diagnosis of acute humoral rejection has become clearer following the recognition that C4d deposition commonly occurs in well functioning ABO incompatible allografts. The long-term implications of acute humoral rejection appear substantial even following successful acute therapy, with a significant percentage of patients developing chronic humoral rejection manifested as transplant glomerulopathy. Finally, although ABO incompatible transplantation entails increased expense, when compared with maintenance dialysis and taking into account the health related quality of life benefits of a successful transplant, it is clearly cost effective. SUMMARY: ABO incompatible kidney transplantation is an effective therapy, and will become more widely implemented in the future.     

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.     

Four years of experience with the Australian kidney paired donation programme

New approaches to increase kidney transplantation rates through expansion of live donor kidney transplantation have become necessary due to ongoing shortage of deceased donor organs. These strategies include desensitization in antibody‐incompatible transplants to overcome the barrier of blood group incompatibility or human leucocyte antigen antibodies between recipient and donor and kidney paired donation (KPD) programmes. In KPD, a kidney transplant candidate with an incompatible live donor joins a registry of other incompatible pairs in order to find potentially compatible transplant solutions. To match the largest possible number of donor–recipient pairs while minimizing immunologic risk, KPD programmes use sophisticated algorithms to identify suitable matches with simultaneous two‐way or more complex multi‐way exchanges as well as including non‐directed anonymous donors to start a chain of compatible transplantations. Because of the significant immunologic barriers when fewer donor options are available, the optimal solution for difficult‐to‐match, highly sensitized patients is access to more potential donors using large multi‐centre or national KPD registries. This review focuses on the first 4 years of experience with the Australian multi‐centre KPD programme that was established in October 2010.     

The Dutch National Living Donor Kidney Exchange Program

The wait time for deceased-donor kidney transplantation has increased to 4-5 years in the Netherlands. Strategies to expand the donor pool include a living donor kidney exchange program. This makes it possible that patients who cannot directly receive a kidney from their intended living donor, due to ABO blood type incompatibility or a positive cross match, exchange donors in order to receive a compatible kidney. All Dutch kidney transplantation centers agreed on a common protocol. An independent organization is responsible for the allocation, cross matches are centrally performed and exchange takes place on an anonymous basis. Donors travel to the recipient centers. Surgical procedures are scheduled simultaneously. Sixty pairs participated within 1 year. For 9 of 29 ABO blood type incompatible and 17 of 31 cross match positive combinations, a compatible pair was found. Five times a cross match positive couple was matched to a blood type incompatible one, where the recipients were of blood type O. The living donor kidney exchange program is a successful approach that does not harm any of the candidates on the deceased donor kidney waitlist. For optimal results, both ABO blood type incompatible and cross match positive pairs should participate.     

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.     

Equivalent Outcomes for Pediatric Heart Transplantation Recipients: ABO‐Blood Group Incompatible versus ABO‐Compatible

ABO‐blood group incompatible infant heart transplantation has had excellent short‐term outcomes. Uncertainties about long‐term outcomes have been a barrier to the adoption of this strategy worldwide. We report a nonrandomized comparison of clinical outcomes over 10 years of the largest cohort of ABO‐incompatible recipients. ABO‐incompatible (n = 35) and ABO‐compatible (n = 45) infant heart transplantation recipients (≤14 months old, 1996–2006) showed no important differences in pretransplantation characteristics. There was no difference in incidence of and time to moderate acute cellular rejection. Despite either the presence (seven patients) or development (eight patients) of donor‐specific antibodies against blood group antigens, in only two ABO‐incompatible patients were these antibodies implicated in antibody‐mediated rejection (which occurred early posttransplantation, was easily managed and did not recur in follow‐up). Occurrence of graft vasculopathy (11%), malignancy (11%) and freedom from severe renal dysfunction were identical in both groups. Survival was identical (74% at 7 years posttransplantation). ABO‐blood group incompatible heart transplantation has excellent outcomes that are indistinguishable from those of the ABO‐compatible population and there is no clinical justification for withholding this lifesaving strategy from all infants listed for heart transplantation. Further studies into observed differing responses in the development of donor‐specific isohemagglutinins and the implications for graft accommodation are warranted.     

Allocation and matching in kidney exchange programs

Living donor kidney transplantation is the preferred treatment for patients suffering from end‐stage renal disease. To alleviate the shortage of kidney donors, many advances have been made to improve the utilization of living donors deemed incompatible with their intended recipient. The most prominent of these advances is kidney paired donation (KPD), which matches incompatible patient–donor pairs to facilitate a kidney exchange. This review discusses the various approaches to matching and allocation in KPD. In particular, it focuses on the underlying principles of matching and allocation approaches, the combination of KPD with other strategies such as ABO incompatible transplantation, the organization of KPD, and important future challenges. As the transplant community strives to balance quantity and equity of transplants to achieve the best possible outcomes, determining the right long‐term allocation strategy becomes increasingly important. In this light, challenges include making full use of the various modalities that are now available through integrated and optimized matching software, encouragement of transplant centers to fully participate, improving transplant rates by focusing on the expected long‐run number of transplants, and selecting uniform allocation criteria to facilitate international pools.     

Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO‐incompatible pancreas and kidney transplantation

Summary We describe the presumably first intentional ABO‐incompatible deceased‐donor kidney and pancreas transplantation with a severe antibody‐mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement‐related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.     

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.     

Single‐Center Kidney Paired Donation: The Methodist San Antonio Experience

Many potential kidney transplant recipients are unable to receive a live donor transplant due to crossmatch or blood type incompatibility. Kidney paired donation increases access to live donor transplantation but has been significantly underutilized. We established a kidney paired donation program including consented incompatible donor/recipient pairs as well as compatible pairs with older non‐human leukocyte antigen identical donors. Over a 3‐year period, a total of 134 paired donor transplants were performed, including 117 incompatible pairs and 17 compatible pairs. All transplants were done with negative flow cytometry crossmatches and five were done with desensitization combined with paired donation. Kidney paired donation transplants included two‐way and three‐way exchanges as well as three chains initiated by nondirected donors. Of the sensitized recipients transplanted by paired donation, 44% had calculated panel reactive antibody levels greater than 80%. Transplantation of females and prior transplant recipients was significantly higher with paired donation. Only three episodes of rejection occurred and no transplants were lost due to rejection. These data highlight the potential of kidney paired donation and suggest that all transplant centers should be actively engaged in paired donation to increase access to live donor transplantation.     

Increasing the opportunity of live kidney donation by matching for two- and three-way exchanges

BACKGROUND: To expand the opportunity for paired live donor kidney transplantation, computerized matching algorithms have been designed to identify maximal sets of compatible donor/recipient pairs from a registry of incompatible pairs submitted as candidates for transplantation. METHODS: Demographic data of patients who had been evaluated for live donor kidney transplantation but found to be incompatible with their potential donor (because of ABO blood group or positive crossmatch) were submitted for computer analysis and matching. Data included ABO and HLA types of donor and recipient, %PRA and specificity of recipient alloantibody, donor/recipient relationship, and the reason the donor was incompatible. The data set used for the initial simulation included 29 patients with one donor each and 16 patients with multiple donors for a total of 45 patients and 68 donor/patient pairs. In addition, a simulation based on OPTN/SRTR data was used to further assess the practical importance of multiple exchange combinations. RESULTS: If only exchanges involving two patient-donor pairs were allowed, a maximum of 8 patient-donor pairs in the data set could exchange kidneys. If three-way exchanges were also allowed, a maximum of 11 pairs could exchange kidneys. Simulations with OPTN/SRTR data demonstrate that the increase in the number of potential transplants if three-way exchanges are allowed is robust, and does not depend on the particular patients in our sample. CONCLUSIONS: A computerized matching protocol can be used to identify donor/recipient pairs from a registry of incompatible pairs who can potentially enter into donor exchanges that otherwise would not readily occur.     

Economic Impacts of ABO‐Incompatible Live Donor Kidney Transplantation: A National Study of Medicare‐Insured Recipients

The infrequent use of ABO‐incompatible (ABOi) kidney transplantation in the United States may reflect concern about the costs of necessary preconditioning and posttransplant care. Medicare data for 26 500 live donor kidney transplant recipients (2000 to March 2011), including 271 ABOi and 62 A2‐incompatible (A2i) recipients, were analyzed to assess the impact of pretransplant, transplant episode and 3‐year posttransplant costs. The marginal costs of ABOi and A2i versus ABO‐compatible (ABOc) transplants were quantified by multivariate linear regression including adjustment for recipient, donor and transplant factors. Compared with ABOc transplantation, patient survival (93.2% vs. 88.15%, p = 0.0009) and death‐censored graft survival (85.4% vs. 76.1%, p < 0.05) at 3 years were lower after ABOi transplant. The average overall cost of the transplant episode was significantly higher for ABOi ($65 080) compared with A2i ($36 752) and ABOc ($32 039) transplantation (p < 0.001), excluding organ acquisition. ABOi transplant was associated with high adjusted posttransplant spending (marginal costs compared to ABOc ‐ year 1: $25 044; year 2: $10 496; year 3: $7307; p < 0.01). ABOi transplantation provides a clinically effective method to expand access to transplantation. Although more expensive, the modest increases in total spending are easily justified by avoiding long‐term dialysis and its associated morbidity and cost.     

ABO blood group incompatible kidney transplantation: a case report and review of the literature

A patient with end-stage renal failure, two previously failed kidney transplants and high serum lymphocytotoxic antibody levels was transplanted electively with an ABO-mismatched, HLA-identical kidney from his sibling. Immunosuppression consisted of pretransplant splenectomy and plasma exchange, followed by rabbit antithymocyte serum, azathioprine, prednisone and plasma exchange in the early post-transplant period. He is now 3 years post-transplant with normal renal function on conventional immunosuppressive therapy. This case, and a review of the literature, suggest that ABO blood group incompatibility need not be an absolute barrier to successful kidney transplantation. ABO incompatible kidney transplantation may be a potentially fruitful area for further research as the demand for donor organs continues to outstrip the supply.     

The low dose of rituximab in ABO-incompatible kidney transplantation without a splenectomy: a single-center experience

Shirakawa H, Ishida H, Shimizu T, Omoto K, Iida S, Toki D, Tanabe K. The low dose of rituximab in ABO‐incompatible kidney transplantation without a splenectomy: a single‐center experience.
Clin Transplant 2011: 25: 878–884. © 2010 John Wiley & Sons A/S. Abstract: Purpose: A new protocol for ABO‐incompatible (ABO‐i) kidney transplantation including rituximab was introduced in January 2005 in our institute. This study reviewed the results and evaluated the use of low‐dose rituximab in ABO‐i kidney transplantation. Material and methods: Seventy‐four de novo ABO‐i kidney transplantations were performed at Tokyo Women’s Medical University between January 2005 and August 2010. The immunosuppressive protocol was consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone. All the patients received induction therapy with basiliximab. The pre‐conditioning protocol included double‐filtration plasmapheresis and a single dose of rituximab. A dose of 500 mg/body rituximab was initially employed and yielded excellent results (Group I, n = 24). Afterward, the dose of rituximab was reduced to 200 mg/body in January 2007 (Group II, n = 50). Results: Seventy‐four de novo ABO‐i recipients were treated with this protocol, and all patients underwent kidney transplantation successfully. Effective elimination of the peripheral blood CD19 cells was observed in both groups. However, the peripheral blood CD19 levels were still low in both groups at 24 months after treatment. Conclusion: The patients in Group II showed excellent results similar to Group I. These results suggest that the low dose of rituximab (200 mg/body) is the sufficient dose in ABO‐i kidney transplantation.     

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。     

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.     

Pilot conversion trial from mycophenolic acid to everolimus in ABO‐incompatible kidney‐transplant recipients with BK viruria and/or viremia

Immunosuppression using everolimus (EVR) plus low‐dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long‐term outcomes and impacts of Tac‐EVR on the BK virus are reported in ABO‐incompatible kidney‐transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34–529) days post‐transplantation, seven stable ABO‐incompatible kidney‐transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO‐incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow‐up, clinical and biological parameters were monitored. The median time from conversion to the last follow‐up was 784 (398‐866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti‐HLA antibodies). At last follow‐up, median eGFR was similar in the Tac‐MPA versus Tac‐EVR group (40 [range: 14–56] vs. 54.5 ml/min/1.73 m² [range: 0–128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO‐incompatible kidney‐transplant recipients with an active BK virus infection may benefit from conversion to EVR.