Multivariate analysis of antibody induction therapy and their associated outcomes in deceased donor transplants

AIMS: The aims of this study were to describe factors associated with the use of overall induction, classes of induction agents, and to evaluate the incidence of acute rejection, short-term graft survival, and patient survival. METHODS: Of 24,901 transplants reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% received induction therapy including Thymoglobulin (T; n = 3090), Simulect (S; n = 6063), or Zenapax (Z; n = 3755). Propensity scores (PS) were calculated to indicate factors associated with use of induction and for each induction agent. Outcome parameters included graft survival (GS), hazard ratio (HR) for graft loss (GL), and odds ratio (OR) for first-year acute rejection (AR). RESULTS: Pediatric (PS = 1.29; 95% confidence interval [CI] 1.12-1.49, vs adults) and retransplanted recipients (PS = 1.36; 1.23-1.49, vs first) were more likely to receive induction. One-year GS (90.1 vs 88.0%; P < .001), GL = 0.92% (0.86-0.98; P = .01), and AR free = 0.74 (P < .001) were superior in patients receiving induction. Using multivariate analysis, the odds of rejection 0.73 (0.68-0.78), GL 0.91 (0.85-0.97), and death 0.90 (0.82-0.98) were lower in those receiving induction. Among patients given induction, those receiving T were more likely sensitized (PS = 1.50%; 1.31-1.71), retransplanted (PS = 1.51; 1.31-1.75), or had delayed graft function (PS = 1.75; 1.58-1.93). T decreased the odds of rejection compared with S or Z (OR = 0.74; 0.69-0.79), but the type of induction agent did not have an impact on graft outcome HR for T = 1.07 (0.96-1.19). CONCLUSIONS: The use of antibody induction was associated with lower risk of rejection and better GS. There were no differences in GS among individual regimens. Comparative safety data were not analyzed but should be taken into consideration when choosing antibody preparations.     

Multivariate analysis of antibody induction therapy and their associated outcomes in live donor kidney transplantation in the recent era

The majority of kidney transplant recipients in the United States receive antibody induction, but its impact on outcomes in living donor transplant is not well-described. We used Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data as of November 2009 to compare acute rejection (AR) and graft survival among all primary adult living donor kidney recipients of no antibody induction, antithymocyte globulin (ATG) and interleukin-2 receptor antagonists (IL-2RA) in an earlier era (1998-2002; n=21,919) and a later era (2003-2008, n=26,837). The incidence of AR in the overall cohort decreased from 18.5% in 1998 to 8% in 2008. From 1998 to 2002, antibody induction was associated with a decreased risk of acute rejection at six months (RR 0.67, 95% CI 0.62-0.72) and one yr (RR 0.71, 0.65-0.76), while in the recent era, induction was not associated with acute rejection at six months (RR 0.97, 0.88-1.07) or one yr (RR 1.01, 0.91-1.10). There was no difference in graft survival over five yr with antibody induction in either era. Although antibody induction was associated with a decreased risk of AR from 1998 to 2002, it was not associated with a decreased risk of acute rejection from 2003 to 2008, nor was it associated with a difference in graft survival in either era.     

Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches

This study deals with HLA-mismatched kidney transplants that have been removed following rejection. Sera from 27 patients were screened for HLA-specific antibodies by direct complement-dependent lymphocytotoxicity with HLA-typed cell panels. Circulating donor-specific antibodies were detected in 3 cases (11%) before and in 26 cases (97%) after allograft nephrectomy. These findings demonstrate the production of donor-specific antibodies in patients with rejected transplants, but in most cases, they were undetectable before nephrectomy, because the graft had adsorbed them. With an HLAMatchmaker-based serum analysis program, we observed restricted antibody specificity patterns against amino acid triplet-defined epitopes on donor HLA-A,B antigens. Many donor triplets were non-reactive while others were apparently recognized by antibodies. In some patients, the donor triplet specific antibodies persisted for a long time whereas in many other patients, they became undetectable after a few months. The characterization of the antibody specificity profiles of post-allograft nephrectomy sera is clinically useful in defining criteria of HLA mismatch acceptability for sensitized patients awaiting another transplant. It provides also opportunities for determining the relative immunogenicity of mismatched triplets.     

抗体诱导治疗在肝移植中的应用进展

应用生物蛋白制剂——抗体作为器官移植早期实施免疫抑制覆盖治疗的方法,可显著减少器官移植术后早期急性排斥反应的发生,且未显著增加移植后感染发生率,同时可延迟或减少CNI的应用,有利于保护肾功能、促进移植物功能恢复及受者长期存活。本文通过总结常见抗体免疫诱导剂的特点及作用机制,分析不同抗体诱导治疗应用于肝移植的临床获益与风险,为肝移植抗体诱导剂的合理使用提供参考。     

Selective management of gastroschisis according to the degree of visceroabdominal disproportion.

OBJECTIVE: This study analyzed the factors influencing the postoperative results after the repair of gastroschisis defects during the past 27 years. SUMMARY BACKGROUND DATA: The clinical results after the repair of gastroschisis abdominal defects have improved appreciably during the past 25 years, with the long-term survival rate in most large children's centers currently being approximately 90%. The improvement in survival has been largely attributed to advances in perioperative care, frequent use of parenteral nutrition, and better techniques of surgical repair. METHODS: Between 1965 and 1992, 84 infants with gastroschisis underwent surgical repair. The management of 52 infants after 1979 was compared with that of 32 during the previous 14 years. Associated anomalies were present in 29%. The average birth weight was 2412 g. In 31%, primary fascial closure was performed. In another 31% with moderate visceroabdominal disproportion (VAD), a silastic chimney was used initially, and complete repair was performed at a second operation. For 25% who had severe VAD, more than two operative reconstructions were necessary. Seven of 52 infants with moderate VAD underwent initial skin-flap closure and secondary repair within 12 days. RESULTS: Almost all complications (27%) and deaths (4%) occurred in infants with severe VAD and were largely unrelated to associated malformations or birth weight. The length of postoperative mechanical ventilation, need for parenteral nutrition, need for multiple operations, and length of hospitalization were all directly related to the severity of the VAD. CONCLUSIONS: Complete repair of gastroschisis at the initial operation is the optimal goal; however, the severity of VAD has permitted this approach in only one third of patients in this study. Delayed repair with a silastic chimney and one or more reconstructive procedures has provided excellent long-term survival with low morbidity and mortality rates. Although skin-flap closure is no longer used initially, this technique has been helpful for the residual defect in infants with severe VAD who have had multiple silon chimney repairs (Applied Biomaterial, Silverdale, WA).     

小肠移植中应用单克隆抗体免疫诱导治疗的临床疗效观察

目的 研究人源化抗CD52单克隆抗体(阿来佐单抗)与抗CD25单克隆抗体(达利珠单抗)在小肠移植诱导治疗中的临床疗效.方法 回顾性分析2007年至2012年间1 1例小肠移植受者的临床资料,其中6例在小肠移植时使用了阿来佐单抗(阿来佐单抗组),5例应用了达利珠单抗(达利珠单抗组).观察术前和术后12周内受者外周血淋巴细胞及单核细胞的变化情况,术后3个月内排斥反应、感染的发生情况,以及受者肝、肾功能的变化情况.结果 阿来佐单抗组受者中,1例因发生急性心功能衰竭于术后13 d死亡,余5例术后8周内外周血淋巴细胞、单核细胞显著下降,8周后开始缓慢上升,外周血CD3+、CD4+及CD8+T淋巴细胞的百分比下降至给药前的5％,并在给药后8周内维持在稳定的低水平.达利珠单抗组受者中,1例因曲霉感染于术后25 d死亡,余4例受者淋巴细胞、单核细胞计数在给药后1d明显增加,1周后持续稳定在正常水平.术后3个月内,阿来佐单抗组检出轻度排斥反应1例,达利珠单抗组检出轻、中、重度排斥反应各1例,经及时抗排斥反应治疗后成功好转.11例受者术后3个月时血肌酐、尿素氮、丙氨酸转氨酶、胆红素总量与术前相比,无明显差异.结论 应用阿来佐单抗或达利珠单抗均可成功进行小肠移植免疫诱导,但阿来佐单抗诱导后的感染发生率更低.     

Prolonged cold ischemia time obviates the benefits of 0 HLA mismatches in renal transplantation

HYPOTHESIS: Recipients of 0 HLA mismatch kidneys with prolonged cold ischemia times of longer than 36 hours do not have superior outcomes compared with recipients of kidneys with 1 or more mismatches. DESIGN: Retrospective review. SETTING: Transplanation centers. PATIENTS AND METHODS: A total of 63,688 recipients who underwent transplantation between January 1, 1990, and July 31, 1998. MAIN OUTCOME MEASURES: Delayed graft function, serum creatinine level, and patient and renal graft survival. RESULTS: Recipients of 0 HLA mismatch kidneys with fewer than 36 hours of cold ischemia time had better 5-year graft survival (75%) when compared with recipients with 1 or more mismatches (67%) (P<.001). However, recipients of 0 HLA mismatch kidneys with longer than 36 hours of cold ischemia time did not have any graft survival advantage (71% in 0 HLA mismatch kidneys vs 72% in 1 or more mismatches, P =.24). CONCLUSIONS: Cold ischemia times of longer than 36 hours obviate the benefits of better graft survival conferred by better matching.     

The influence of HLA mismatches and immunosuppression on kidney graft survival: an analysis of more than 1300 patients

New immunosuppressive drugs used in kidney transplantation decreased the incidence of acute rejection. It was hypothesized that, with their power, the importance of HLA matching was decreased. To evaluate the influence of HLA matching, immunosuppression, and other possible risk factors, we analyzed data of 1314 consecutive deceased donor kidney transplantation. We divided the patient population into 4 cohorts, according to the era of transplantation: era 1, before 1990, azathioprine (Aza) and cyclosporine (Csa) no microemulsion; era 2, between 1990 and 1995, Csa microemulsion; era 3, between 1996 and 2000, wide use of mycophenolate mofetil (MMF) and anti-thymocyte globulin (ATG); and era 4, after 2000, marked by sirolimus and tacrolimus (TAC) use. Multivariate analysis compared death-censored graft survival. Using as reference the results obtained with 0 HLA mismatches, we verified, during era 1 and era 2, an increased risk of graft loss for all of the subgroups with HLA mismatch >0. However, during era 3 and era 4, the number of HLA mismatches did not influence graft survival. Although acute rejection and delayed graft function, which decreased in the later periods, remained as prognostic factors for graft loss. Considering the immunosuppressive protocol with Csa+Aza+Pred as reference, protocols used after 1995 with Pred+Csa+ATG, with Pred+Csa+MMF, and with Pred+Tac+MMF presented better survival results. Results showed that the significance of HLA matching decreased while the results improved with the new immunosuppressant drugs. These observations support the hypothesis that the weakened importance of HLA matching may be a consequence of the increasing efficacy of the immunosuppression.     

Arthroscopic subacromial decompression: Results according to the degree of rotator cuff tear

We evaluated the results of arthroscopic subacromial decompression according to the degree of rotator cuff tear in 71 patients, available for follow-up for at least 1 year (average 19 months). Of the patients with stage II disease, 82% were satisfied regardless of whether they had no rotator cuff tear (nine of 11) or had a partial tear (28 of 34) of the rotator cuff. Of patients with stage III disease (complete rotator cuff tear), 88% (23 of 26) were satisfied. An acceptable objective UCLA shoulder rating greater than or equal to 28 points was seen in 82% (nine of 11) of the patients without a rotator cuff tear, 76% (26 of 34) with a partial tear, and 77% (20 of 26) with a complete tear. All four of the patients with complete tears less than 1 cm obtained excellent results. Three of the six failures were in patients with complete tears who had a narrowed acromial-humeral distance of less than 7 mm. The average UCLA pain score showed significant improvement from 2.8 (constant pain) to 8.6 (occasional pain) at 1-2 years postoperatively. The function, strength, and active forward flexion scores also increased at 1-2 years from their preoperative values. The overall patient satisfaction rate of 85% and the objective success rate of 77% are within the range of that seen with open rotator cuff repair.     

动态分析HLA和MICA特异性抗体对移植肾功能的影响

目的 探讨肾移植前后人类白细胞抗原(HLA)和主要组织相容性一类相关链A基因(MICA)抗体特异性对移植后排斥反应和移植肾功能的影响. 方法采用免疫荧光液相芯片技术检测27例肾移植(尸供22例,亲属活体供肾5例)受者手术前后抗HLA抗体和MICA抗体的特异性和阳性值变化,并结合供受者的基因分型,区分供体特异性抗体和非供体特异性抗体.取同期的临床资料和SCr水平进行分析. 结果 27例移植患者中带肾存活26例,移植肾失功1例.移植后1、3、6、12个月时动态随访24例,失访2例.27例患者移植前预存抗体7例(25.9%),其中HLA抗体阳性2例、MICA抗体阳性3例,HLA和MICA抗体均阳性2例.肾移植前HLA和MICA抗体均阴性者中移植后3～6个月产生新生抗体3例.1例新生HLA-Ⅱ类特异性抗体者,移植半年后出现慢性排斥反应,经治疗术后1年SCr>200 btmol/L.3例肾移植前MICA抗体阳性者,术后MICA抗体的特异性均无改变,但抗体的阳性分值呈现2～8分的变化,1年后均升高到移植前(4～8分)水平.移植前预存低阳性率HLA-Ⅱ类特异性抗体者1例,移植后2周有发热等排斥反应,巨细胞病毒检测阳性,移植后1个月时SCr为171μmol/L,3个月升高到236μmol/L.24例分为抗体阴性组(14例)和抗体阳性组(10例).移植后1个月和1年时SCr水平2组间比较差异有统计学意义(P=0.03,0.05). 结论 移植后3～6个月是新生抗体变化的重要随访时间,可根据HLA和MICA抗体的特异性和阳性分值变化,尽早采取有效方法预防排斥反应和减少移植肾功能减退的发生和发展.     

Mycophenolic mofetil reduces the HLA antibody response of children to valved allograft implantation

BACKGROUND: Valved allografts induce a brisk, broadly reactive human leukocyte antigen (HLA) antibody response in children after implantation. Mycophenolic mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of both T cells and B cells and has been reported to possibly reduce HLA panel reactive antibody (PRA) in sensitized transplant recipients. METHODS: The purpose of this study was to determine whether MMF can blunt the HLA antibody response to valved allografts in children. Eight patients completed (of 28 approached) a pilot study to determine the effects of 3 months of twice daily MMF (600 mg/m(2)/dose) on the HLA antibody response measured before surgery, at 1 month, and at 3 months after implantation. Patients were 7.5 +/- 4 yrs old (mean +/- standard deviation [SD]), with 5 patients undergoing repair of tetralogy of Fallot, 2 Ross procedures, and 1 aortic valve replacement. RESULTS: In contrast to historical controls with a virtual 100% HLA class I PRA response to valved allograft implantation, MMF markedly decreased the HLA class I antibody response at 1 and 3 months postimplantation. In 6 cases where the HLA type of the donor was defined, PRA specificity correlated with incompatible antigens on the allograft. One patient withdrew after 2 weeks due to a sinus infection that was successfully treated with oral antibiotics, and 3 patients had a transient adverse effect of postoperative vomiting. CONCLUSIONS: This study demonstrates the ability to pharmacologically abrogate the HLA class I antibody response to valved allograft implantation in children using MMF.     

The impact of induction therapy in low-immunological risk kidney transplant recipients regardless of HLA matching

BackgroundInduction agents have proved to reduce the rate of acute rejection (AR) in kidney transplant recipients (KTRs) without improving long-term graft and patient survival (PS).ObjectiveThis study evaluates the utility of induction therapy in low immunological risk KTRs regardless of donor-to-recipient HLA matching.MethodsWe retrospectively reviewed the records of 218 patients undergoing kidney transplantation (KT). These patients were divided into two groups according to the usage of induction therapy: 82 did not receive any induction therapy (Group I), and 136 patients received either Anti-IL2 receptor antibodies or anti-thymocyte globulin (Group II). All patients had panel reactive antibody (PRA) < 20% and absence of donor-specific antibodies (DSA). The difference in outcomes were assessed at different intervals following KT.ResultsThe rate of bacterial infections at one year (p-value = 0.032) and the frequency of CMV disease (p-value = 0.044) were significantly higher in Group II (with induction therapy). The duration of hospital stay, the rate and severity of acute rejection, the occurrence of delayed graft function, the rate and type of surgical complications at one year, and the graft function and survival at one and three years were similar between the two groups (p-value = NS). In addition, the financial burden is much less in Group I (without induction therapy), reducing the total cost of the transplant procedure.ConclusionWe conclude that induction therapy in low-immunological risk kidney transplant patients is not a must regardless of donor-to-recipient HLA matching. Therefore, induction therapy did not yield significant health results, but had negative financial consequences.