Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: One- and two-year outcomes

BACKGROUND: Alemtuzumab (Campath-1H) induction with tacrolimus monotherapy has been shown to provide effective immunosuppression for kidney, liver, lung, and small bowel transplantation. This drug combination was evaluated in pancreas transplant recipients. METHODS: Sixty consecutive pancreas transplants (30 simultaneous pancreas-kidney, 20 pancreas after kidney, and 10 pancreas alone) were carried out under this protocol between July 2003 to January 2005. The mean follow-up was 22 months (range 17-33). RESULTS: One-year patient, pancreas, and kidney allograft survival were 95%, 93%, and 90%, respectively. With 22 months follow-up, patient, pancreas, and kidney survival were 94%, 89%, and 87%, respectively. The rejection rate was 30% (18/60), with four patients (7%) experiencing steroid-resistant rejection. Major infection occurred in three (5%) patients resulting in two (3.3%) deaths from disseminated histoplasmosis and a herpes virus infection. One patient with cryptococcal meningitis was successfully treated. Seven (11.7%) patients experienced cytomegalovirus infection, all of whom responded to treatment with ganciclovir. One (1.7%) case of polymorphic posttransplant lymphoproliferative disease was seen, which regressed with a temporary discontinuation of tacrolimus and high-dose ganciclovir. The mean serum creatinine of the 30 simultaneous pancreas-kidney transplants at one year posttransplant was 1.37+/-0.33 mg/ml. The preexisting creatinine in pancreas after kidney transplants was not adversely affected by this immunosuppressive protocol. CONCLUSION: A single dose of perioperative alemtuzumab followed by daily tacrolimus monotherapy provides effective immunosuppression for pancreas transplantation, but the optimal use of this drug combination is not yet clear.     

Alemtuzumab (Campath 1H) induction with tacrolimus monotherapy is safe for high immunological risk renal transplantation

Immunosuppression for immunologically high-risk renal transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, has shown promise in tolerogenic induction protocols, requiring minimal maintenance immunosuppression. In this prospective, open-label, randomized, controlled trial, we enrolled 21 high immunological risk patients (i.e., panel reactive antibody>20% or previous transplant). Patients received either single-dose alemtuzumab given before graft reperfusion, with tacrolimus monotherapy, or four doses of Thymoglobulin with tacrolimus, mycophenolate, and steroids. Median follow-up was 377 days. One patient in the Thymoglobulin group who suffered primary graft nonfunction died. One-year cumulative graft survival was 85.7% for the alemtuzumab group and 87.5% for the Thymoglobulin group. Two alemtuzumab and three Thymoglobulin patients suffered rejection episodes. Infection rates were similar. Early results of this ongoing study indicate that a tolerogenic protocol with alemtuzumab induction and tacrolimus maintenance monotherapy is safe in immunologically high-risk renal transplant patients.     

Dual antibody induction and de novo use of everolimus enable low-dose tacrolimus with early corticosteroid withdrawal in simultaneous pancreas-kidney transplantation

BackgroundTo be an optimal immunosuppressive regimen after simultaneous pancreas kidney transplantation (SPK), low dose calcineurin inhibitor and early withdrawal of corticosteroids are desired.MethodsImmunosuppressive regimen as such has been conducted consecutively in SPK recipients since 2009 in authors' institute. In addition to tacrolimus in low trough level and early corticosteroid withdraw, dual induction with basiliximab and low-dose thymoglobulin in combination with everolimus are the important components of the protocol.Results25 consecutive primary SPK recipients were included in the study. Lymphocyte depletion by low dose thymoglobulin was limited to two weeks, and CD25 coating with basiliximab was detectable for 4 weeks. The BPAR within the first 12 months was 13%. During a median follow-up of 58 months, new-onset diabetes mellitus and renal function deterioration were rare events. No cytomegalovirus activation was encountered. The patients, pancreas and kidney graft survival at 1-year and 5-year was 100% and 94.4%, 95.8% and 95.8%, 100% and 100% respectively.     

小肠移植中应用Campath 1H诱导和低剂量他克莫司维持抗排斥治疗

目的 报告Campath 1H诱导和单用低剂量他克莫司维持的免疫抑制方案在2例小肠移植应用的经验.方法 小肠移植术中给予Campath 1H 30 mg及甲泼尼龙2 g.移植肠血管开放后给予他克莫司,术后早期从静脉途径给药,逐渐过渡至通过移植肠给予他克莫司.术后前3个月他克莫司血药浓度维持在10～15μg/L,术后第4个月开始,他克莫司血药浓度减低至5μg/L左右.结果 2例患者生存期均已超过1年,其中1例患者于术后第13个月时行移植肠末端造口关闭、还纳手术.2例患者各发生一次病理学检查证实的不确定(IND级)至轻度(1级)排斥反应,给予小剂量甲泼尼龙治疗后排斥反应消失;1例患者于术后8个月发生一次轻至中度排斥,给予大剂量激素冲击治疗后病理证实排斥反应消失.Campath 1H应用后淋巴细胞和单核细胞计数明显下降,其后缓慢回升.无明显感染及移植物抗宿主反应(GVHD)征象发生.移植肠功能良好,分别于术后第21天和第14天摆脱静脉营养,依赖口服饮食维持营养状态.结论 小肠移植中应用Campath 1H诱导,单用低剂量他克莫司、无激素维持方案,能有效地控制排斥反应,不增加感染发生的机会,未发生GVHD.患者移植肠功能良好,能尽早摆脱静脉营养.     

Alemtuzumab induction in deceased donor kidney transplantation

BACKGROUND: The use of alemtuzumab for induction therapy in kidney transplantation has been increasing. Herein is a report of graft outcomes associated with alemtuzumab induction from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. METHODS: A total of 14,362 deceased donor kidney transplants from 2003 to 2004 received no induction (n=4,364), antithymocyte globulin (ATG; n=4,930), interleukin-2 receptor antagonists (IL-2RA; n=4,378), or alemtuzumab (n=690). Acute rejection within the initial hospitalization, 6 months, and 1 year; graft survival; and rejection-free survival were examined. Graft and rejection-free survival of alemtuzumab recipients maintained with tacrolimus (FK) or cyclosporine (CSA), mycophenolate mofetil (MMF), and steroids versus no calcineurin inhibitors (CNI), MMF, and steroids were compared. RESULTS: Alemtuzumab recipients had less acute rejection during the initial hospitalization (2.3%) than no induction, ATG, and IL-2RA (7.6%, 3.4%, and 4.8%, respectively; P<0.001). There was increased acute rejection at 6 months and 1 year with alemtuzumab (14.5% and 19.2%) compared to no induction (12.7% and 14.8%, P<0.001), ATG (8.2% and 10.2%, P<0.001), and IL-2RA (11.1% and 13.0%, P<0.001) with no difference in adjusted relative risk for graft loss. Alemtuzumab recipients receiving FK or CSA, MMF, and steroids had increased graft (FK/MMF/steroids, P<0.001, CSA/MMF/steroids, P=0.007) and rejection-free survival (FK/MMF/steroids, P<0.001, CSA/MMF/steroids, P=0.006) over 24 months compared to no CNI, MMF, and steroids. CONCLUSIONS: Despite reduced early rejection, acute rejection rates at 6 months and 1 year with alemtuzumab induction exceeded other forms of induction therapy. Maintenance with CNI-based immunosuppression may improve graft and rejection-free survival compared to CNI-free regimens among alemtuzumab recipients.     

Alemtuzumab induction in deceased donor kidney transplantation

Purpose

Alemtuzumab (Campath-1H), a humanized monoclonal antibody directed against CD52, is a lymphocyte-depleting agent currently being evaluated as an induction agent in solid organ transplantation. This study analyzed the clinical outcomes and effects on peripheral blood lymphocyte subset counts in adult deceased donor renal transplant recipients who received an alemtuzumab-based induction protocol.

Methods

Eleven kidney alone or simultaneous pancreas-kidney transplant recipients received 20 mg alemtuzumab on postoperative days 0 and 1, followed by calcineurin inhibitor-based maintenance immunosuppression after postoperative day 5. We collected 1-year data including recipient and donor demographic features, renal function and adverse events including endocrine impact, incidence of acute rejection episodes, infections or malignancies as well as hematologic and late immunologic parameters for correlation with patient or graft survival.

Results

Mean HLA mismatch was 3.6 and 8/11 deceased donors were of the extended criteria type. Only 2 (18%) recipients displayed delayed graft function with a failure of the serum creatinine to decrease by 25% on the first day; however, their long-term outcomes were similar to other nonaffected patients. Serious adverse events were absent; there was no hyperlipidemia or new-onset diabetes. We failed to observe an acute rejection. The 3 (27%) recipients with infectious complications experienced pericardial tuberculosis, urinary tract infection, or invasive pulmonary aspergillosis. Two (18%) cases of posttransplantation lymphoproliferative disease were diagnosed in this study during the follow-up. Overall patient and graft survival rates were both 91%.

Conclusion

This study demonstrated that preconditioning with antibody-depletion using alemtuzumab was efficient with satisfactory patient and graft survivals at 1 year. Alemtuzumab induction was safe even for recipients of extended criteria donor renal transplantation.     

Diabetic ketoacidosis following development of de novo diabetes in renal transplant recipient associated with tacrolimus

Although drugs used in renal transplant recipients such as steroids, cyclosporine, and particularly, tacrolimus have diabetogenic potential, diabetic ketoacidosis is uncommon. There are few data concerning the long-term follow-up of these patients. Diabetic ketoacidosis occurred in a renal transplant recipient following de novo development associated with tacrolimus.     

肾移植术后新发恶性肿瘤临床分析

探讨肾移植术后新发恶性肿瘤的临床特征.方法 回顾性分析2001年6月至2005年1月在中山大学附属第五医院行肾移植术后生存半年以上并能接受定期随访的236例受者中新发恶性肿瘤患者的临床资料.结果 在236例肾移植受者中,共有新发恶性肿瘤5例,发生率2.1%(5/236).患者均为男性,新发肿瘤类型分别为直肠癌2例、肺癌1例、移行细胞癌1例、非霍奇金淋巴瘤1例.患者肾移植时年龄为46 ~70岁,平均年龄61岁,肿瘤确诊时的年龄为48 ~73岁,平均年龄65岁;从接受肾移植手术至发生肿瘤的时间为14 ~ 77个月,平均时间46个月.5例患者经确诊为新发恶性肿瘤后,给予手术治疗和(或)化学药物治疗及减少免疫抑制剂或者转换免疫抑制方案治疗,均未发生肾功能异常和排斥反应.其中2例患者死于肿瘤进展和多器官功能衰竭,3例存活.结论 肾移植术后新发恶性肿瘤进展隐匿迅速,早期诊断、早期治疗是提高其疗效的关键措施.     

Alemtuzumab (Campath-1H) combined with tacrolimus in intestinal and multivisceral transplantation

BACKGROUND: We combined alemtuzumab (Campath-1H, Berlex Laboratories, Montville, NJ) and tacrolimus (Tac) immunosuppression for intestinal and multivisceral transplantation. MATERIALS AND METHODS: A total of 21 adult patients received 24 grafts: 14 intestinal, nine multivisceral, and one liver-intestinal graft. Alemtuzumab was administered perioperatively in four doses with low-dose Tac (levels 10-15 ng/dL) and no maintenance steroids. Tac was substituted with sirolimus in case of Tac-related complications. Suspected or mild rejections were treated with steroids. Moderate rejections were treated with steroids or OKT3. Severe rejections were treated with OKT3. RESULTS: Of the 16 patients that were followed up for an average of 9 months, 12 are alive with functioning grafts. Two patients experienced severe rejection, three experienced moderate rejection episodes, and seven experienced mild acute rejection episodes. Four patients never developed acute rejection. Infectious complications included a cytomegalovirus enteritis and four fungal infections (related to central venous access). CONCLUSIONS: The combination of alemtuzumab and Tac therapy without steroid use seems to efficiently prevent acute rejection in a significant number of patients without causing frequent opportunistic infections.     

Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation

BACKGROUND: Corticosteroid-free maintenance immunosuppression after organ transplantation eliminates the well-known corticosteroid-related side effects and may help to improve long-term outcome. We investigated whether a corticosteroid-free tacrolimus (Tac)/mycophenolate mofetil (MMF) regimen, in combination with daclizumab (Dac) induction therapy, provides adequate immunosuppression after renal transplantation. METHODS: This 6-month, open-label, multicenter, parallel-group study involved 538 renal patients randomized (1:1) to a Dac/Tac/MMF regimen (n = 260) or a Tac/MMF/corticosteroids regimen (n = 278) as a control group. RESULTS: Of the patients who completed the study, 88.8% in the Dac/Tac/MMF group were free from corticosteroid therapy at month 6. The incidence of biopsy-proven acute rejection was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5.0% with Tac/MMF/corticosteroids and Dac/Tac/MMF, respectively (P = NS for both comparisons). Renal function was also similar in both groups: median serum creatinine at month 6 was 125.0 micromol/L (Tac/MMF/corticosteroids) and 131.0 microml/L (Dac/Tac/MMF), P = 0.277. The overall safety profile was similar with both regimens. However, compared with the Tac/MMF/steroid regimen, a significantly reduced incidence of new-onset insulin-dependent diabetes mellitus (5.4% vs. 0.4%, P = 0.003) was found with steroid-free immunosuppression. Moreover, mean total cholesterol concentrations increased from baseline in the Tac/MMF/corticosteroids group by 0.19 mmol/L, whereas in the Dac/Tac/MMF group, levels decreased by 0.19 mmol/L, P = 0.005. CONCLUSIONS: Corticosteroid-free immunosuppression with a Dac/Tac/MMF regimen is as effective at preventing acute rejection after renal transplantation as a standard triple regimen of Tac/MMF/corticosteroids. Furthermore, the safety benefits reported with Dac/Tac/MMF treatment may help improve the long-term outcome for renal-transplant patients.     

Recurrent or de novo IgA nephropathy with crescent formation after renal transplantation

IgA nephropathy is the most common glomerular disease in China, accounting for 38.8% of primary glomerular disease. It has been reported that 20.8% patients of IgA nephropathy had a different degree of crescent formation. From January 1995 to December 2004, 1000 patients had undergone cadaveric renal transplantation, and 1742 allograft renal biopsies were reviewed in the Department of Nephrology at Jinling Hospital, Nanjing University. Among them, 18 cases were found with crescent formation, in which 10 patients were diagnosed as recurrent or de novo IgA nephropathy because their immunofluorescence showed strong IgA deposition in mesangial area and capillary. The initial treatment protocol was CsA+Azp+Pred, except in two cases of CsA+MMF+Pred. There were 8 males and 2 females, with ages from 25 to 69 (mean of 37.1) years old. All of them showed progressive renal dysfunction with increasing level of serum creatinine ranged from 1.48 to 6.25 mg/dL. Seven cases presented edema with an increasing level of proteinuria (1.36 to 3.58 g/24hr), and nine cases presented with hematuria ranging from 50 to 1250 x 10(4)/mL (one showed gross hematuria). In pathological examinations, they showed mesangial proliferation and matrix expansion with 10% to 66.7% crescents (mean of 37.5%) in their allograft renal biopsy's samples. All patients changed their immunosuppressive regimens; however, nine of them eventually advanced to ESRD and returned to hemodialysis after 6 to 36 months. Two cases received second renal transplantation after six months to five years, and one kept stable renal function with 2.5 mg/dL of serum creatinine after three years of follow-up. IgA nephropathy with crescentic formation was not rare in renal allografts or native glomerulonephritis in Chinese patients. These patients showed rapidly progressive renal dysfunction, and most of them lost graft function and needed hemodialysis therapy.     

A case of de novo glomerulonephritis with electron-dense deposits following renal transplantation

Abstract:  We present here a case of de novo glomerulonephritis (GN) two yr after kidney transplantation. The patient was a 13-yr-old girl who had renal insufficiency because of bilateral hypoplastic kidneys. She received a renal allograft from her father at the age of 11 yr. Immunosuppressive treatment was started with tacrolimus, mizoribine (MZB), basiliximab, and methylprednisolone (mPSL). There were no findings of GN at the one-h biopsy (first biopsy). Two yr after transplantation, she showed proteinuria, hematuria and increased serum creatinine level with no apparent trigger. The biopsy specimen (fourth) showed mesangial proliferative GN with electron-dense deposits in a variety of regions and borderline changes indicating acute rejection. She was treated with mPSL pulse therapy, deoxyspergualin, replacement of MZB with mycophenolate mofetil, an increase of the mPSL dose, and candesartan. Her serum creatinine and urinary protein excretion levels improved after the treatment. One month later, she developed deterioration in her renal function again. Renal biopsy findings (fifth) were almost the same as the lesions observed in the fourth allograft biopsy. After she recovered from these episodes, she appeared to improve in clinical findings of GN. Protocol biopsies at three yr and five months after transplantation (sixth) showed no evidence of acute rejection, but we still observed the features of de novo GN. We could not resolve the underlying causes by reference to the clinical history and serological findings. We speculate that some kind of immunological reactions might be associated with the pathophysiology.     

Steroid-free tacrolimus monotherapy after pretransplantation thymoglobulin or Campath and laparoscopy in living donor renal transplantation

Living donor renal transplantation was performed under a regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning. From October 9, 2002, to December 31, 2004, 196 consecutive, unselected laparoscopic live donor nephrectomies resulting in 196 living donor renal transplantations were performed. Recipients were pretreated with rabbit antithymocyte globulin (thymoglobulin; 24 patients or [12%]) or Campath 1H (alemtuzumab; 166 patients [85%]), or were not in protocol (6 patients [3%]), and were given postoperative steroid-free low-dose tacrolimus immunosuppressive monotherapy with subsequent weaning. There was no donor mortality. Major and minor donor morbidities were 2.6% and 4.2%, respectively. Laparoscopic live donor nephrectomy recipient outcomes with a mean follow-up of 401 days included (1) recipient and graft survival of 99.0% and 97.4%, respectively; (2) no ureteral stenosis; (3) 0.5% delayed graft function, from recurrent focal segmental glomerulosclinosis; and (4) no vascular thrombosis. The incidence of acute rejection at 30, 90, and 401 days was 1.5%, 3.8%, and 11.2% (all 196 recipients), 0%, 25%, and 29.2% (thymoglobulin recipients), and 1.8%, 3.9%, and 8.4% (Campath 1H recipients), respectively. Sixty-six patients (33.7%) are receiving spaced-dose immunosuppressive monotherapy. The mean creatinine concentration in all recipients was 1.5 +/- 1.1 mg/dL. There were no instances of cytomegalovirus tissue invasive disease or posttransplantation lymphoproliferative disease. The incidence of new-onset posttransplantation insulin-dependent diabetes was 0.5%. At current follow-up, the use of Campath 1H rather than thymoglobulin for pretreatment seems to have significantly improved the efficacy of our regimen.     

肾移植受体术后新发恶性肿瘤临床分析

目的  总结肾移植受体术后新发恶性肿瘤的特点和治疗要点。方法  回顾性分析759例肾移植受体中43例术后新发恶性肿瘤患者的临床资料,总结肾移植术后新发恶性肿瘤的发病特点、治疗方法及预后。结果  肾移植受体术后新发恶性肿瘤发生率为5.7%。发病年龄（52±11）岁,肿瘤确诊时间为移植术后60（13~193）个月。43例恶性肿瘤中包括原肾肾癌9例、膀胱癌7例、肺癌6例、淋巴瘤5例、大肠癌4例、乳腺癌4例、皮肤癌2例、肾上腺癌1例、胃癌1例、原发性肝癌1例、胰腺癌1例、头皮血管肉瘤1例和脑膜瘤1例,确诊后采取手术、调整免疫抑制方案、放射治疗或化学药物治疗等方案治疗。术后1、5年存活率分别为81%和63%。结论  肾移植受体术后恶性肿瘤发生率高于正常人,且以泌尿系统肿瘤最常见。治疗应以根治性手术切除为主,无法手术者采用抗肿瘤综合治疗,同时减少免疫抑制剂用量并调整用药方案,可有效延长患者存活时间。     

阿来佐单抗行肾移植免疫诱导治疗的有效性和安全性

目的 评价阿来佐单抗行肾移植免疫诱导治疗的有效性和安全性.方法 将89例肾移植受者随机分为试验组(43例)和对照组(46例).试验组于肾移植术前和术后24 h内分别静脉滴注阿来佐单抗15 mg,对照组不接受免疫诱导治疗.受者术后常规应用环孢素A(或他克莫司)+吗替麦考酚酯+泼尼松预防排斥反应.统计两组术后12月内的移植肾功能、急性排斥反应发生率、感染发生率、移植肾功能延迟恢复发生率、移植肾存活率及淋巴细胞计数,并用ImmuKnowTM免疫细胞功能测定法检测受者CD4+T淋巴细胞的三磷酸腺苷(ATP)值.结果 术后12个月内试验组7.0%(3/43)的受者发生病理证实的急性排斥反应,明显低于对照组的23.9%(11/46,P＜0.05).试验组和对照组总体的感染发生率为别为39.5%(17/43)和30.4%(14/46,P＞0.05),两组机会性感染的发生率分另为23.2%(10/43)和17.4%(8/46,P＞0.05).术后3个月内,试验组淋巴细胞计数低于对照组;术后6个月内,试验组CD4+T淋巴细胞ATP值低于对照组.结论 阿来佐单抗行肾移植免疫诱导治疗可维持受者的免疫抑制状态,未见严重不良反应.