Six‐year outcomes in broadly HLA‐sensitized living donor transplant recipients desensitized with intravenous immunoglobulin and rituximab

Desensitization with intravenous immunoglobulin (IVIG) and rituximab can improve transplantation rates in broadly sensitized kidney transplant recipients. However, long‐term outcomes are lacking. Here we analyze long‐term outcomes in living donor kidney transplant recipients desensitized with this regimen and compare them to low‐risk recipients. Living donor kidney transplants that took place between July 2006 and December 2010 were considered retrospectively. The primary end point of the study was death‐censored allograft survival at last follow‐up. Secondary end points included patient survival, incidence of rejection, glomerular filtration rate (GFR), and proteinuria. There were 66 sensitized and 111 low‐risk patients included. Average follow‐up was 68 months. There was no difference in long‐term patient or graft survival. The rate of rejection was similar in the groups with more early rejection in the sensitized group and more late rejection in the low‐risk group. There was more antibody‐mediated rejection in the sensitized group. Estimated GFR was similar during the follow‐up period. Risk factors for rejection included a positive cross‐match (HR: 2.4 CI: 1.35–4.40) and age (HR: 0.97 CI: 0.95–0.99). Desensitization with IVIG and rituximab has good long‐term results with graft outcomes similar to non‐HLA‐sensitized patients despite higher immunologic risk.     

Treatment of acute antibody-mediated rejection: a single-center experience

Introduction

Acute antibody-mediated rejection (AMR) leads to graft loss. The combination of plasmapheresis (PP), intravenous immunoglobulin (IVIG), and rituximab (RTX) has been reported to be effective therapy.

Patients and methods

Between October 2005 and September 2009, 8 (4.7%) kidney transplant recipients developed AMR, diagnosed by severe acute rejection and extensive C4d staining in peritubular capillaries.

Results

All patients were treated with two to six sessions of PP with IVIG added after the last PP. In two patients, RTX was prescribed after PP and IVIG. Baseline immunosuppression was based on steroids, mycophenolate mofetil or azathioprine, and tacrolimus or cyclosporine or everolimus. The presence of subsequent significant decrease in anti-HLA class I antibodies was demonstrated in a highly sensitized patient before and after transplantation with PP treatment. An increase was observed before the diagnosis of AMR. After a mean follow-up of 10 months (range = 1-23), patient and graft survivals were 100% and 50%, respectively. Three patients lost their transplants to AMR refractory to treatment and one patient, due to interstitial fibrosis and tubular atrophy at 23 months after AMR. Finally, four patients recovered renal function, showing a mean serum creatinine of 2.2 ± 0.45 mg/dL.

Conclusions

Early diagnosis and treatment with PP, IVIG, and RTX may resolve AMR. PP before and after transplantation in high-risk patients may result in anti-HLA class I and class II antibody removal from plasma and prevention of AMR.     

Effect of Induction Therapy Protocols on Transplant Outcomes in Crossmatch Positive Renal Allograft Recipients Desensitized with IVIG

Here we retrospectively examine the efficacy of two antibody induction regimens using Zenapax or Thymoglobulin in patients with positive complement-dependent cytotoxicity crossmatches (CDC-CMXs) desensitized with IVIG (intravenous immunoglobulin). Between January 1999 and March 2005, 97 patients with (+) CDC-CMXs received kidney transplants (43 deceased donors/54 living donors). All patients received at least 2 g/kg IVIG (maximum four doses) until an acceptable CMX was obtained. Patients were divided into two groups: 1. IVIG + Zenapax (n = 58), 2. IVIG + Thymoglobulin (n = 39). A total of 94% of patients in Group 1 and 84% in G2 have at least 2 years of follow up. Patient and graft survival was 96%/84% in Group 1 and 100%/90% in Group 2, p = NS. The number and severity of AR episodes were similar (36% Group 1 vs. 31% Group 2, p = NS) as was the incidence of C4d (+) antibody-mediated rejection (AMR) (Banff Grade II/III) (22% Group 1 vs. 21% Group 2). Mean serum creatinines (SCrs) at 24 months were similar (Group 1: 1.4 +/- 0.7 vs. G2: 1.5 +/- 0.7 mg/dL). Induction therapy with Zenapax or Thymoglobulin results in excellent patient, graft survival and graft function at 2 years. There was no increased risk of viral infections or malignancies with either agent. Neither agent was effective in reducing the incidence of AMR.     

Therapy Modalities for Antibody Mediated Rejection in Renal Transplant Patients

Introduction: The aim of our study was to determine the effectiveness of immunoglobulin, rituximab and plasmapheresis in renal transplant patients with antibody mediated rejection (AMR). Patients and Methods: Fourteen renal transplant patients with AMR were included in this study. The mean age of the patients was 33.9 ± 10.3 years and 10 (71.4%) of them were male. Lymphocyte cross match was negative for all patients and 10 (71.4%) of them were living donor transplants. Six patients were administered tacrolimus, three patients cyclosporine, two patients everolimus, and three patients sirolimus for immunosuppression. The patients with AMR were administered IVIG, rituximab and plasmapheresis. Results: Patient survival rate was 100%, graft survival rate after AMR was 50% in the first year and 33% in the 2nd and third years. AMR developed 31.9 ± 25.9 months after transplantation. Seven (50%) patients lost their grafts. Delayed graft function was observed in 28.6%, chronic allograft dysfunction in 78.5%, diabetes after transplantation in 14.3%, and cytomegalovirus infection in 7.1% of the patients. At the last follow-up, the mean blood creatinine was 3.1 ± 1.4, the mean proteinuria was 2300 (1300–3300) mg/day and the mean GFR was 34.5 ± 17.6 ml/min. C4d was positive in peritubullar capillaries in all patients, while neutrophil accumulation in peritubular and glomerular capillaries was observed in 8 patients. Chronic allograft vasculopathy was observed in 12 patients. Conclusion: AMR leads to progressive loss of renal function and has low graft survival. More effective treatment alternatives are needed for this clinical issue.     

Clinical course and pathologic findings of successful second ABO-incompatible renal transplantation in a patient with donor-specific anti-HLA antibody

Abstract:  Donor-specific anti-HLA antibody and anti-blood group antibody could cause antibody-mediated rejection (AMR). Here, we report a successful second ABO-incompatible (ABO-I) renal transplantation in a patient with donor-specific anti-HLA antibody and its pathologic findings. A 50-yr-old woman underwent second ABO-I (A1 to O) renal transplantation. She had received the first renal graft from her mother following splenectomy in July 2003; however, graft function was lost 50 d after transplantation because of AMR. The patient received the second renal graft in November 2005, from her husband whose blood type was also A1. The recipient had donor-specific anti-HLA antibody because flow panel reactive antibody and flow cytometry crossmatch were strongly positive prior to the plasmapheresis (PP) therapy. Pre-transplant intensive immunosuppression, PP, and low dose (100 mg/m²) anti-CD20 antibody (rituximab) administration were performed as desensitization therapy. The recipient clinically developed acute rejection, and allograft biopsy specimen at day 6 post-transplant revealed AMR type II according to the Banff 2003 classification. However, the graft function was rescued by PP/low dose (100 mg/kg) intravenous immunoglobulin (IVIG) therapy, and the biopsy specimen at day 43 post-transplant showed border-line change without AMR. Rituximab and PP/low-dose IVIG therapy might improve the clinical course and pathologic findings in this AMR-related high-risk transplantation.     

Advances in diagnosing and managing antibody-mediated rejection

Antibody-mediated rejection (AMR) is a unique, significant, and often severe form of allograft rejection that is not amenable to treatment with standard immunosuppressive medications. Significant advances have occurred in our ability to predict patients at risk for, and to diagnose, AMR. These advances include the development of newer anti-human leukocyte antigen (HLA)-antibody detection techniques and assays for non-HLA antibodies associated with AMR. The pathophysiology of AMR suggests a prime role for antibodies, B cells and plasma cells, but other effector molecules, especially the complement system, point to potential targets that could modify the AMR process. An emerging and potentially larger problem is the development of chronic AMR (CAMR) resulting from de novo donor-specific anti-HLA antibodies (DSA) that emerge more than 100 days posttransplantation. Therapeutic options include: (1) High-dose intravenously administered immunoglobulin (IVIG), which has many potential benefits. (2) The use of IVIG + rituximab (anti-CD20, anti-B cell). (3) The combination of plasmapheresis (PP) + low-dose IVIG with or without rituximab. Data support the efficacy of all of the above approaches. Newer approaches to treating AMR include using the proteosome inhibitor (bortezomib), which induces apoptosis in plasma cells, and eculizumab (anti-C5, anticomplement monoclonal antibody).     

Failure to remove de novo donor‐specific HLA antibodies is influenced by antibody properties and identifies kidney recipients with late antibody‐mediated rejection destined to graft loss – a retrospective study

Current research is focusing on identifying bioclinical parameters for risk stratification of renal allograft loss, largely due to antibody‐mediated rejection (AMR). We retrospectively investigated graft outcome predictors in 24 unsensitized pediatric kidney recipients developing HLA de novo donor‐specific antibodies (dnDSAs), and treated for late AMR with plasmapheresis + low‐dose IVIG + Rituximab or high‐dose IVIG + Rituximab. Renal function and DSA properties were assessed before and longitudinally post treatment. The estimated GFR (eGFR) decline after treatment was dependent on a negative % eGFR variation in the year preceding treatment (P = 0.021) but not on eGFR at treatment (P = 0.74). At a median follow‐up of 36 months from AMR diagnosis, 10 patients lost their graft. Altered eGFR (P < 0.001) and presence of C3d‐binding DSAs (P = 0.005) at treatment, and failure to remove DSAs (P = 0.01) were negatively associated with graft survival in the univariable analysis. Given the relevance of DSA removal for therapeutic success, we analyzed antibody properties dictating resistance to anti‐humoral treatment. In the multivariable analysis, C3d‐binding ability (P < 0.05), but not C1q‐binding, and high mean fluorescence intensity (P < 0.05) were independent factors characterizing DSAs scarcely susceptible to removal. The poor prognosis of late AMR is related to deterioration of graft function prior to treatment and failure to remove C3d binding and/or high‐MFI DSAs.     

Splenic Irradiation for the Treatment of Severe Antibody‐Mediated Rejection

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody‐mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long‐term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor‐specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short‐ or medium‐term adverse effects of the radiation therapy. One‐year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.     

IVIG and rituximab for treatment of chronic antibody‐mediated rejection: a prospective study in paediatric renal transplantation with a 2‐year follow‐up

Chronic antibody‐mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. We report the results of a prospective pilot study on an antihumoral therapy (AHT) consisting of high‐dose intravenous immunoglobulin G (IVIG) and rituximab in 20 paediatric renal transplant recipients. Donor‐specific HLA antibodies (HLA DSA) were quantified by Luminex‐based bead array technology. Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m² during 6 months prior to AHT to 2.1 ml/min/1.73 m² (P = 0.0013) during 6 months after AHT. Fourteen patients (70%) responded: nine of nine patients (100%) without and five of 11 (45%) with transplant glomerulopathy (P = 0.014). C4d positivity in PTC decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P = 0.002) in the follow‐up biopsy. In four of nine biopsies (44%) C4d staining turned negative. During 2 years of follow‐up, the median loss of eGFR in each of the four 6‐month periods remained significantly lower compared with prior to AHT. Class I DSA declined in response to AHT by 61% (p = 0.044), class II DSA by 63% (p = 0.033) 12 months after intervention. AHT with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation.     

Donor‐Specific HLA Antibodies in a Cohort Comparing Everolimus With Cyclosporine After Kidney Transplantation

Donor‐specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody‐mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3–4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow‐up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log‐rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log‐rank: p = 0.036). Four of 10 patients with AMR—all in the everolimus group—lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus‐based immunosuppression is associated with an increased risk for the development of DSA and AMR.     

Comparison of clinical outcome between high and low baseline anti-ABO antibody titers in ABO-incompatible kidney transplantation

High baseline anti-ABO antibody titer is still an important obstacle for successful ABO-incompatible kidney transplantation (ABO IKT). This study aims to investigate the clinical outcome of ABO IKT in patients with a high baseline titer in comparison with patients with a low baseline titer. Fourteen patients who received ABO IKT at our center were classified as the high-titer group (≥1:256, n = 8) or the low-titer group (≤1:128, n = 6). We used a protocol composed of rituximab, plasmapheresis, and intravenous immunoglobulin (RTX/PP/IVIG). We compared the intensity of preparation, complications, and clinical outcome between the two groups. The high-titer group required more sessions of pretransplant (10.5 ± 3.5 vs. 6.0 ± 1.3 times, p = 0.01) and posttransplant (1.6 ± 1.8 vs. 0 ± 0 times) PP/IVIG than the low-titer group did. All patients from both groups showed immediate recovery of graft function. The antibody titer and allograft function in the high-titer group were stable and did not differ significantly from those of the low-titer group up to 1 year after kidney transplantation. There was no antibody-mediated rejection in either group during follow-up, but three cases of acute cellular rejection developed in the high-titer group. The high-titer group showed two cases of opportunistic viral infection (herpes gingivitis and cytomegalovirus viremia) and one case of graft loss due to postoperative bleeding. ABO IKT can be safely performed even in patients with a high baseline anti-ABO antibody titer, but the risk for infection and bleeding should be considered before transplantation.     

ABO incompatible living donor kidney transplantation in Korea: highly uniform protocols and good medium‐term outcome

The organ shortage is as serious in Korea as in other parts of the world. As about one‐third of the potential living donors are ABO incompatible (ABOi), transplantation across the blood group barrier can help overcome this shortage. One hundred and twenty‐five ABOi kidney transplantations (KTs) were performed between 2007 and 2010 in Korea. We collected the perioperative and follow‐up data for 118 of these patients until September 2011. The preconditioning and immunosuppressive protocols were almost identical across the different transplant centers, with rituximab but no splenectomy; pre‐transplant plasmapheresis (PP) with target anti‐A/B titer 8 or 16 on transplant day, on‐demand, rather than routine, post‐transplant PP, and tacrolimus‐based immunosuppressants. The number of patients and participating centers showed a rapid increase over time, and in 2010, ABOi KT (n = 79) comprised 10% of all the living donor KTs in Korea. The mean follow‐up period was 21 months (range, 1–56 months). Sixteen (14%) patients developed acute rejection, and three of these had antibody‐mediated rejection (AMR). Two‐yr patient and graft survival were 99.2% and 97.5%, respectively. No graft was lost due to AMR. ABOi KT is rapidly expanding in Korea with excellent medium‐term outcome and will help mitigate the organ shortage.     

Determinants of Poor Graft Outcome in Patients with Antibody-Mediated Acute Rejection

This study analyzes the incidence and course of antibody-mediated rejection (AMR) in a cohort of 237 renal transplant patients followed for 30 +/- 20 months. Among these, 32 patients were considered to be at risk for AMR and received intravenous immunoglobulin (IVIg), either as preconditioning (Group A, n = 18) or at the time of transplant (Group B, n = 14). The prevalence of AMR was 27.8% in Group A, 57.1% in Group B and 3.9% in the remainder of the population. Although graft loss remains greater among AMR than for acute cellular rejection (ACR) or the overall transplant population, we have identified a good outcome group (GFR > 15 mL/min/1.73 m(2)) (n = 13), whose renal function at the end of follow-up was comparable to that of the general transplant population. The factors associated with bad outcome are: (1) immunologic: presence and/or persistence of donor-specific anti-HLA antibodies post-transplantation and (2) histologic: neutrophilic glomerulitis, peritubular capillary dilatation with neutrophil infiltrates and interstitial edema at the time of first biopsy; and at the time of late biopsy (3-6 months): lesions of vascular rejection, and monocyte/macrophage infiltrates in glomeruli and dilated peritubular capillaries. Persistence of C4d does not predict outcome. This study outlines for the first time the immunologic and histologic profiles of AMR patients with poor prognosis.     

A Survey of Current Practice for Antibody‐Mediated Rejection in Heart Transplantation

No evidence based management guidelines exist for antibody mediated rejection (AMR) in heart transplantation. The International Society for Heart and Lung Transplantation (ISHLT) recently introduced standardized pathologic based diagnostic criteria for AMR (pAMR 0–3). We evaluated international practice for the management of AMR focusing on pAMR grade, donor specific antibody (DSA) and allograft function. On‐line survey data were analyzed from 184 ISHLT members (physicians‐78%, surgeons‐20%). The majority were from adult‐transplant (84%), medium‐large volume centres (transplants/year: 10–25, 61%; 25–50, 19%) across North America (60%) and Europe (26%). Irrespective of pAMR grade and DSA, 83–90% treated a drop in ejection fraction (EF ≤45% or >25% decrease). In the presence of stable EF, an increasing number elected treatment for progressively severe pAMR grade (p < 0.001) and for accompanying DSA (p < 0.05, pAMR 1–3). Intravenous steroid was the most commonly used therapy followed by intravenous immunoglobulin (IVIG) or plasmapheresis, rituximab and thymoglobulin. Plasmapheresis and rituximab were favored for positive versus negative DSA (p < 0.05). Using a threshold of ≥70% consensus among respondents, treatment for AMR may be considered for a drop in EF, asymptomatic pAMR 3 or asymptomatic pAMR 2 with DSA. Combination steroid, IVIG and plasmapheresis are suggested as initial therapies.     

Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody‐mediated rejection: a pilot study

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B‐cell targeting molecules represent a rational strategy to treat TG during chronic antibody‐mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post‐biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24‐month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor‐specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody‐mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.     

Prognosis and Treatment for Active and Chronic Antibody-Mediated Rejection in Renal Transplant Recipients; Single Center Experience

BackgroundThe aim of the study was to evaluate the prognostic factors and treatment alternatives of antibody-mediated rejection (ABMR) in renal transplant patients.MethodsThree thousand renal transplant patients were included in the study. The patients were first divided into 2 groups. Group 1: ABMR [-] recipients (n = 2871), Group 2: ABMR (+) recipients (n = 129). ABMR patients were compared among themselves by dividing them into 3 subgroups (early-active, late-active, chronic-active). The study was performed retrospectively. Different combinations of methylprednisolone, intravenous immunoglobulin (IVIG), rituximab, plasmapheresis (PP), anti-thymocyte globulin (ATG) were used in the treatment and the results were compared.ResultsGraft survival and functions were worse and the rates of CAD, delayed graft function, BK virus, and cytomegalovirus higher in patients with ABMR. Also, graft survival was lower in patients with serum creatinine ≥3 (P = 0.001), GFR <30 (P <0.001), and spot urine protein to creatinine ratio ≥1 (P = 0.042) at the time of diagnosis. High interstitial fibrosis and tubular atrophy scores in chronic ABMR cases and high intimal arteritis scores in active ABMR cases were poor prognostic factors.ConclusionsThe study showed that ABMR has a poor prognosis in terms of clinical parameters, and treatment should be individualized according to pathologic findings and graft functions at the time of diagnosis. Pulse methylprednisolone and IVIG should be used in the treatment of all ABMR patients, but PP, rituximab, and ATG should be used in selected cases. ABMR has a poor prognosis and treatment should be individualized.     

Isolated Donor Specific Alloantibody-Mediated Rejection after ABO Compatible Liver Transplantation

Antibody-mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno-transplantation, but its role after ABO compatible liver transplantation is controversial. We report a case of ABO compatible liver transplantation that demonstrated clinical, serological and histological signs of AMR without evidence of concurrent acute cellular rejection. AMR with persistently high titers of circulating donor specific antibodies resulted in graft injury with initial centrilobular hepatocyte necrosis, fibroedematous portal expansion mimicking biliary tract outflow obstruction, ultimately resulting in extensive bridging fibrosis. Immunofluorescence microscopy demonstrated persistent, diffuse linear C4d deposits along sinusoids and central veins. Despite intense therapeutic intervention including plasmapheresis, IVIG and rituximab, AMR led to graft failure. We present evidence that an antibody-mediated alloresponse to an ABO compatible liver graft can cause significant graft injury independent of acute cellular rejection. AMR shows distinct histologic changes including a characteristic staining profile for C4d.     

ABO血型不合肝移植术前脱敏治疗方案的网状荟萃分析

目的评价ABO血型不合肝移植(ABO-ILT)术前不同脱敏治疗方案的疗效。 方法以利妥昔单抗(Rb)为关键药物,将脱敏治疗方案分为：Rb＋全血血浆置换(去除)组(Rb＋TPE/PP组)、Rb组、Rb＋静脉注射免疫球蛋白组(Rb＋IVIG组),以ABO血型相合肝移植受者作为对照组,对比4组不同结局事件。计算机检索PubMed、EMbase、MEDLINE、Cochrane Library、Scopus、CNKI、WanFang Data、VIP数据库。检索年限为2003年1月至2018年5月20日。采用NOS文献质量评价量表评价纳入文献质量。采用Excel 2007软件,加载NetMetaXL宏命令,调用WinBUGS 14.3软件,选择贝叶斯随机效应模型实现网状荟萃分析。P<0.05为差异有统计学意义。 结果共纳入9篇文献。分别有6、4篇文献报道了不同脱敏治疗方案肝移植受者术后1、3年生存率,3种方案组间对比以及与血型相合肝移植对照组相比,差异均无统计学意义(P均>0.05)。9篇文献报道了不同脱敏治疗方案肝移植受者术后抗体介导排斥反应(AMR)和急性细胞排斥反应(ACR)发生率,3组方案组间对比以及与血型相合肝移植对照组对比,差异均无统计学意义(P均>0.05);但Rb＋TPE/PP组、Rb组和Rb＋IVIG组ACR的SUCRA值分别为0.3562、0.7767和0.7092,均高于血型相合肝移植对照组(0.1579),差异均有统计学意义(P均<0.05)。分别有8、7篇文献报道了不同脱敏治疗方案肝移植受者术后弥漫性肝内胆管狭窄和非肝内胆道并发症(胆漏、胆道狭窄)发生率,3组方案组间对比以及与血型相合肝移植对照组对比,差异均无统计学意义(P均>0.05)。ABO-ILT术前采用不同脱敏治疗方案的受者术后AMR和ACR发生率漏斗图均分布在垂直线周围,无明显不对称,可能不存在小样本效应。 结论Rb脱敏疗效等同于Rb＋IVIG及Rb＋TPE/PP。若肝移植术前无充分准备时间,可实施Rb＋IVIG脱敏治疗;时间充分且受者经济负担重时,可予Rb脱敏治疗。     

Diagnosis and treatment of antibody mediated rejection in lung transplantation: A retrospective case series

IntroductionAntibody mediated rejection (AMR) has been identified as an entity that may lead to graft dysfunction. Optimal means for diagnosis and treatment of AMR have not been established.Material and methodsWe reviewed the medical records of all patients receiving lung transplantation at Henry Ford Hospital from March 2006 to December 2011. For each patient, we identified potential markers of AMR (immunopathology, histopathology, and serology). Immunopathology was defined as linear c4d immunostaining, histopathology was defined as capillaritis, and serology was defined as identification of donor specific antibody (DSA). We identified all treatment regimens, and we identified clinical and serological outcomes.ResultsOf 62 patients, 14 were identified with at least one marker of AMR. Only two patients had all three potential markers; immunopathology, histopathology, and serology. Both patients received plasmapheresis (PP) and intravenous immunoglobulin followed by clinical improvement and ultimate elimination of DSA. 4 patients had positive DSA without clinical symptoms, and did not receive treatment with PP, IVIG, or rituximab. DSA has not persisted in these patients, and they remain clinically asymptomatic at up to 803 days after identification.DiscussionDiagnosis of AMR is difficult due to poorly defined diagnostic markers and confounding factors such as infection. Outcomes are highly variable following treatment that may include therapeutic plasma exchange, intravenous immunoglobulin, and/or rituximab. It is not clear when any or all of these therapies are beneficial. In some cases, symptomatic patients with isolated positive DSA (latent humoral response) can remain asymptomatic and convert to negative DSA without antibody targeted therapy.ConclusionsFirm conclusions are difficult due to the small number of patients and the retrospective nature of the study. Further study is warranted.     

Therapy with plasmapheresis and intravenous immunoglobulin for acute humoral rejection in kidney transplantation

BACKGROUND: Acute humoral rejection (AHR) is characterized by acute graft dysfunction associated with de novo production of donor-specific alloantibodies (DSA) and C4d deposition in peritubular capillaries of the renal allograft. It has been reported the combination of plasmapheresis (PP) and intravenous gamma globulin (IVIG) as effective rescue therapy for established AHR. METHODS: Between 1999 and 2004, seven kidney allografts recipients suffered from AHR diagnosed by severe rejection and C4d staining in peritubular capillaries. All patients had a negative cross-match before renal transplantation. RESULTS: All patients were treated with daily sessions of PP and in four cases IVIG was added after the last PP session. Tacrolimus and mycophenolate mofetil were employed as maintenance immunosuppressive regimen. In one case, rituximab was added to PP and IVIG owing to refractory humoral rejection. At 1 year, patient survival was 100%, allograft survival was 70%, and the mean serum creatinine was 201 micromol/L. CONCLUSIONS: AHR is a severe form of rejection associated with a poor prognosis, but its early diagnosis and treatment with PP and IVIG allows reversal of AHR reaching a 70% graft survival at 1 year.