Conversion from calcineurin inhibitors to mTOR inhibitors as primary immunosuppressive drugs in pediatric heart transplantation

There are only a few reports of successful use of mammalian target of rapamycin (mTORI) as primary immunosuppression in pediatric heart transplantation. Compared to calcineurin inhibitors, mTORI have less side effects, especially nephrotoxicity, infections, and malignancies. A retrospective study was conducted at our institution of all 170 heart transplants from 1995 to 2015. Nineteen patients were switched from tacrolimus (n=15) or cyclosporin (n=4) to everolimus (n=4) or sirolimus (n=15) due to nephrotoxicity (n=5), malignancy (n=8), EBV viremia/reactive plasmacytic changes (n=5), and immune hemolytic anemia (n=1). We monitored for rejection, infection, BUN, creatinine, hyperlipidemia, EBV and CMV copies, CBC, cardiac allograft vasculopathy (CAV), and death. Target trough levels of sirolimus and everolimus were 4‐10. Four treatment failures included debilitating rash, bone marrow suppression, recurrent rejection, and renal transplantation. There were no deaths. One patient had recurrent rejection episodes, and tacrolimus was reinitiated. One patient with preexisting CAV underwent heart retransplantation. One patient, who was treated for PTLD, transformed to CD30+ Hodgkins disease, and was treated with brentuximab. There were three acute rejection episodes. Median creatinine preswitch was higher 0.82 than postswitch 0.78 (P=.016). Median eGFR was lower preswitch, 75.6, than postswitch, 91.2 (P=.0004). These results indicate that conversion to mTORI as primary immunosuppression may be safely accomplished in some pediatric heart transplant patients.     

Anti-TNF-alpha therapy for acute rejection in intestinal transplantation

INTRODUCTION: We present our experience with infliximab rescue therapy for steroid- and OKT3-resistant rejection after intestinal transplantation (ITx). METHODS: Twelve ITx and one multivisceral transplant recipients were immunosuppressed with tacrolimus, rapamycin, daclizumab, steroids (n = 10) or tacrolimus, campath, and steroids (n = 3). RESULTS: In two patients, severe acute rejection did not resolve despite steroid bolus therapy plus 5 to 10 days of OKT3 treatment. Signs of moderate rejection persisted in the distal portions of the grafts. Treatment with infliximab, a chimeric anti-TNF-alpha antibody (four infusions of 3 mg/kg body weight), induced a complete remission of histological and clinical signs of rejection. Two further patients with steroid-resistant rejection received two courses of infliximab (3 mg/kg body weight) as antirejection therapy. All rejection episodes resolved completely. CONCLUSIONS: Infliximab effectively treats steroid and OKT3 resistant acute rejection episodes of intestinal transplantations.     

Infectious complications in kidney transplant recipients: a single-center experience

To determine the patterns of infectious complications in renal transplant recipients in our center, we evaluated 48 patients (29 men and 19 women) who were transplanted between 1994 and 2003. The average age of the patients was 29 years. Thirty (62.5%) and 18 (37.5%) transplants were from living related and cadaveric donors, respectively. Posttransplant immunosuppression consisted of azathioprine or mycophenolate mofetil (MMF), prednisone, antithymocyte globulin (ATG), and cyclosporine or tacrolimus. The acute rejection episodes were treated with pulse doses of methylprednisolone; steroid-resistant rejection was treated with ATG or muromonab (OKT3). All patients received prophylaxis with sulfadoxine-pyrimethamine; none received prophylaxis against cytomegalovirus (CMV) infection. Thirty-nine (81%) recipients developed 77 confirmed episodes of infection; 35 (46%) episodes occurred in the early postoperative period, 28 (36%) in the first month and 14 (18%) after 6 months. According to the type of infection, there were 24 urinary tract, 16 CMV, seven herpetic, nine general septic, six fungal, four pneumonia, one disseminated nocardial, and 10 miscellaneous episodes. All 26 (100%) patients who had acute rejection episodes developed infections compared with 13/22 (59%) who did not have rejection (P < .01). There was a significant correlation between CMV disease and acute rejection and/or tacrolimus or MMF use. CMV infection occurred after the additional immunosuppressive treatment for acute rejection in 10 patients or during the use of tacrolimus or MMF in six patients. We conclude that CMV infection was the most frequent opportunistic pathogen in our renal transplant population and related to the intensive antirejection therapy, followed by urinary tract infections within 3 months after surgery.     

Liver transplantation for primary biliary cirrhosis: influence of primary immunosuppression on survival

INTRODUCTION: Liver transplantation is the only established curative therapy for end-stage primary biliary cirrhosis (PBC). However, the influence of primary immunosuppression on long-term patient and graft survival is still controversial. PATIENTS AND METHODS: Among 1372 patients who underwent liver transplantation from April 1989 to January 2001, 95 (6.9%) suffered from PBC. The primary immunosuppression consisted of cyclosporine (CyA; n = 56) and tacrolimus (FK; n = 39). RESULTS: The median survival of all PBC patients at 5 years was 92% and at 10 years, 90%. There was no difference between the two primary immunosuppression agents. Seven patients died, including five in the cyclosporine group (median = 25 months) and two in the tacrolimus cohort (median = 37 months). One CyA patient group died due to PBC recurrence. Seven patients underwent retransplantation without any difference in primary immunosuppression (CyA 7%; FK 10%). Fifty patients developed an acute rejection episode (CyA 57%; FK 46%); 2 patients, chronic rejection (CyA 2%; FK 4%). Fifty-five patients developed AMA titers after liver transplantation (CyA 66%; FK 46%). Patients presented cyclosporine-based regimens showed significantly (P = .001) more side effects. CONCLUSION: Long-term follow-up after liver transplantation for PBC shows excellent organ and patient survival. The choice of the primary immunsuppressant had no significant influence on patient survival, PBC-related graft loss, or development of acute or chronic rejection episodes.     

Successful infliximab treatment of steroid and OKT3 refractory acute cellular rejection in two patients after intestinal transplantation

Acute rejection resistant to established immunosuppressive rescue protocols remains the most prominent risk factor after intestinal transplantation. In two patients presenting with steroid-resistant severe acute cellular rejection 9 months and 2 years after intestinal transplantation, complete resolution was not achieved despite 5 and 10 days of OKT3 treatment, respectively, and high-dose triple baseline immunosuppression with tacrolimus, rapamycin, and steroids. There was a dissociated course of rejection with persistent moderate to severe rejection in the terminal portion of the graft despite complete recovery from rejection in the proximal parts. Both patients were treated with four subsequent infusions of infliximab (3 mg/kg body weight), a chimeric anti-tumor necrosis factor-alpha antibody. There was an immediate response regarding macroscopic appearance, graft histology, and clinical symptoms. Both patients recovered. In conclusion, infliximab has proven to be an effective rescue therapy in a selected group of patients with steroid and OKT3 refractory severe acute rejection after intestinal transplantation.     

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.     

Evaluation of renal grafts in patients with lupus nephritis as cause of end-stage renal disease

INTRODUCTION: Kidney transplantation is the best option in end-stage renal disease (ESRD). For many years patients affected with lupus nephritis have had poor graft results. However, this has been changing over recent years with the development of new immunosuppressive drugs and a better comprehension of the natural evolution of the entity. METHODS: We studied 20 patients with lupus nephritis who received 22 kidney grafts: 15 women and five men (n = 11) who were treated with cyclosporine or with tacrolimus (n = 11). Secondary immunosuppression included mycophenolate match (MMF) (n = 13) or azathioprine (n = 9). We analyzed human leukocyte antigen, cold ischemia time, acute tubular necrosis, creatinine, cholesterol, triglycerides, glucose, blood pressure, acute rejection episodes, immunosuppression, infections, disease recurrences, as well as graft and patient survival. RESULTS: After a mean cold ischemia time of 22 +/- 4 hours, nine patients displayed delayed graft function of an average duration 9 +/- 4 days. At 36 +/- 35 months nine grafts were lost: two due to acute rejection; five to chronic allograft nephropathy; and two to venous thrombosis. One patient died of hemorrhagic shock. There were five cytomegalovirus infections. Graft survival was dependent on the type of secondary immunosuppression, incidence of acute rejection episodes and occurrence of delayed graft function. CONCLUSIONS: We found no clinical recurrence of lupus nephritis after transplantation and a low incidence of complications, although there was a trend toward thrombosis. The presence of delayed graft function, episodes of acute rejection, and receiving azathioprine instead of MMF as secondary immunosuppression were associated with poorer graft survival.     

CMV, EBV, HHV6, and HHV7 infections after intestinal transplantation without specific antiviral prophylaxis

PURPOSE: To analyze the incidence and relevance of viral infections after intestinal transplantation (ITx) without specific antiviral prophylaxis. METHODS: Eleven patients (median age 34 years; range 26 to 58 years) who underwent ITx received no CMV/EBV prophylaxis but rather preemptive treatment. Viral monitoring for CMV or EBV polymerase chain reactions (PCR) in peripheral blood and graft biopsies, for HHV6-, and HHV7-PCR; for adeno-/rotavirus antigen and serology was performed based on clinical indications. RESULTS: Median time under risk was 19 months (range 2 to 39). CMV: The donor (D)-to-recipient (R) status prior to ITx was: D+/R+ (4); D+/R- (3); D-/R- (2); D-/R+ (2). Eight patients showed no positive CMV-PCR. Three episodes of tissue invasive CMV disease occurred in two patients. There were two asymptomatic CMV infections but no episodes of CMV disease. None of the R(-) recipients developed CMV infection or enteritis irrespective of the donor status. EBV: Four patients experienced six episodes of transient significant EBV-viremia. Two patients developed EBV enteritis concurrently with CMV enteritis during acute rejection. There were no PTLD. CMV and EBV enteritis only occurred during or immediately after steroid and OKT3 therapy. None of the patients developed significant HHV6 and HHV7 infection or viremia. There was one episode of adeno- and rotavirus enteritis. CONCLUSIONS: Despite witholding specific antiviral prophylaxis against CMV and EBV, we observed no such infections in 60% to 80% of patients. Donor-recipient matching regarding CMV was not predictive for the occurrence of CMV-related complications. HHV6 and HHV7 have not contributed to posttransplant morbidity.     

Gastrointestinal perforations following kidney transplantation

This study reports major gastrointestinal (GI) complications among a group of 1611 patients following kidney transplantation. The immunosuppressive regimen changed somewhat during the course of the study but included azathioprine, prednisolone, antilymphocyte globulin, cyclosporine, tacrolimus, mycophenolate mofetil, and sirolimus. Perforations occurred in the colon (n=21), small bowel (n=15), duodenum (n=6), and stomach (n=4). Nearly 50% of the complications occurred while patients were being given high-dose immunosuppression to manage either the early postoperative period or acute rejection episodes. Of the 46 patients affected, 11 (24%) died as a direct result of the GI complication. This high mortality appeared to be related to the effects of the immunosuppression and the associated response to sepsis. Reduction of these complications may be achieved by improved surgical management, preventive measures, prompt diagnosis, and a reduced immunosuppressive protocol.     

Improved efficacy of basiliximab over antilymphocyte globulin induction therapy in paediatric renal transplantation.

BACKGROUND: Basiliximab is a chimeric human/mouse monoclonal antibody directed against the alpha chain of the IL-2 receptor, CD25, which has been reported as successfully reducing rejection in adult renal transplant recipients. Reported clinical experience of basiliximab in paediatric renal transplantation is limited. METHODS: Using two intravenous doses on day 0 (pre-operatively) and day 4 with prednisolone and cyclosporin A (dual) maintenance immunosuppression in 42 children undergoing renal transplantation in our unit (SIM group), we have compared patient and graft outcome, rejection rates in the first 6 months, renal function and the incidence of Cytomegalovirus (CMV) infection with 42 consecutive children who previously received antilymphocyte globulin immunoprophylaxis with prednisolone, cyclosporin A and azathioprine (triple) maintenance immunosuppression (ALG group). The two groups were similar, including HLA mismatching, apart from age and size at transplantation (SIM=10.3+/-5.4 years vs ALG=12.4+/-4.2 years, P<0.05). RESULTS: One patient in the SIM group died from food inhalation with a functioning kidney and one patient in the ALG group from Pneumocystis pneumonia and post-transplant lymphoproliferative disorders with a rejecting graft. Both 1- and 2-year actuarial graft survivals were 93% for the SIM group and 86% for the ALG group (NS). Three grafts were lost in the SIM group-none from rejection (thrombosis 2, death 1)-and seven in the ALG group-three from rejection. Occurrence of biopsy documented rejection in the first 6 months after transplantation was 0.15+/-0.22 for the SIM group and 0.35+/-0.51 episodes per pt-month at risk for ALG treatment (P<0.04). Early rejection within 30 post-operative days occurred in only four SIM patients, three of whom had undergone retransplantation. Forty-seven per cent of rejection episodes occurred between days 30 and 44 in SIM treated patients. Switching to tacrolimus was similar in both groups; 24% of the SIM groups were prescribed triple therapy. Estimated glomerular filtration rate was 46.0 and 46.2 ml/min for SIM and ALG groups, respectively, six months after transplantation. Ten per cent of SIM and 19% of ALG treated patients developed clinically significant CMV infection (NS) but none of 16 (R(+)) SIM children had CMV infection compared with 8 out of 15 (R(+)) ALG patients (P<0.01). CONCLUSIONS: Basiliximab immunoprophylaxis and dual therapy reduces rejection episodes in the first six months and maintains graft survival and function after paediatric renal transplantation. Seventy-six per cent of children receiving basiliximab immunoprophylaxis were successfully maintained on long-term dual immunosuppression. This immunosuppressive protocol reduces CMV disease in CMV(+) recipients compared with ALG induction and triple therapy.     

Epstein-Barr virus infection after pediatric living-related liver transplantation--management and risk factors

Introduction

Posttransplant lymphoproliferative disorder (PTLD) is one of the severe complications after pediatric liver transplantation. Epstein-Barr virus (EBV) infection is a major risk factor developing PTLD. This study evaluates the risk factors, incidence, and clinical presentation of EBV infection at our institute.

Patients and Methods

This study examines 81 children who underwent living-related liver transplantation (LRLT) from November 2005 to December 2009. The immunosuppression protocol consisted of tacrolimus and low-dose steroids, which were withdrawn by 3 months after LRLT. Additional immunosuppression was indicated for the selected cases because of recurrent rejection or renal insufficiency. Fifteen ABO blood type incompatible LRLTs were enrolled into this study. EBV was periodically monitored by the use of a real-time quantitative polymerase chain reaction (cut-off value, >10² copies/μg DNA). The median follow-up period was 637 days (range, 85 to 1548 days). These patients were divided into two groups: EBV infection versus EBV noninfection, for analysis of risk factors by univariate analysis.

Results

The incidence of EBV infection was 50.6% (n = 41) with the mean onset of 276 ± 279 postoperative days (range, 7 to 1229 days). Nine cases (22.5%) presented clinical symptoms related to EBV infection, consisting of adenoid hypetrophy (n = 5), Evans's syndroms (n = 2), hemophagocytic syndrome (n = 1), and erythema nodosum (n = 1). There was no case of PTLD. The combination of a preoperative EBV seropositive donor and an EBV seronegative recipient was a high risk factor for postoperative EBV infection among the recipients (56.1% versus 26.8%, P < .05). The mean age at operation among the EBV infection group was younger than that of the EBV noninfection group (22 ± 30 months versus 62 ± 68 months; P < .05). The incidence of acute rejection episodes and cytomegalovirus infections; ABO blood type incompatible LRLT, and the length of steroid treatment and the additional immunosuppression were not significantly different between the two groups.

Conclusion

There were various clinical presentations related to EBV infection; however, none of our patients developed PTLD. Careful monitoring of EBV infection especially for cases with donor seropositivity is important to prevent disease progression.     

Infectious complications after multivisceral transplantation in adults

It is thought that multivisceral transplantation requires high levels of immunosuppression and therefore, patients run an increased risk of infection. We retrospectively reviewed our center's experience with clinically relevant infectious complications. PATIENTS: Between 2000 and 2005, 10 adult patients underwent multivisceral transplantation. Two immunosuppression protocols were used: between 2000 and 2003, a high immunosupression protocol (six patients; daclizumab induction, tacrolimus trough levels >20 ng/mL and steroids) and an immunomodulatory, low imunosuppression scheme from 2003 onward (four patients; ATG induction, tacrolimus levels 5 to 10 ng/mL, no steroids). Standard antimicrobial prophylaxis consisted of vancomycin, meropenem, and amphotericin B. Cytomegalovirus (CMV) prophylaxis was used in all but first two cases. Donor and recipient CMV status were D+/R+ (n = 7), D+/R- (n = 2), D-/R+ (n = 1). RESULTS: The median follow-up period was 627 days (range, 19 to 2207 days). A total of 47 infectious episodes were recorded in all patients (range 1 to 14 per patient). The etiology was bacterial in 32 (69%), viral in 8 (17%), and fungal in 7 (14%) cases. The most frequent were catheter related (n = 13) followed by respiratory (n = 7), intraabdominal (n = 6), and wound infections (n = 5). Symptomatic viral infection of the graft (CMV gastritis or enteritis, adenoviral enteritis) was also encountered. Epstein-Barr virus was transiently detected in the serum of nine patients, one of whom later developed posttransplant lymphoproliferative disorder (PTLD). Three deaths all among patients receiving high immunosuppression were owing to infectious complications: pulmonary PTLD at 4 months posttransplantation, ruptured mycotic aneurysm after 8 weeks, and sepsis after 3 weeks. CONCLUSIONS: Infections accounted for a high morbidity after multivisceral transplantation, representing the leading cause of mortality. Exhaustive monitoring, early antimicrobial intervention, and lower immunosuppression may improve the outcome.     

Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: a protocol with early elimination of steroids and reduction of tacrolimus dosage.

A prospective evaluation was performed to study the potential benefits of the use of interleukin-2 receptor antibody (IL-2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty-one liver transplant recipients who underwent right-lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL-2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL-2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new-onset diabetes (0% vs 28%, P =.011), acute cellular rejection (6% vs 27%, P =.038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P =.011) in the IL-2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL-2Rab group (median, 4.0 vs 4.4 mmol/L, P =.007). On follow-up, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL-2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long-term follow-up are required to document their potential benefits on hepatitis B and HCC recurrences.     

Use of tacrolimus and mycophenolate mofetil as induction and maintenance in simultaneous pancreas‐kidney transplantation

Abstract Clinical trials using quadruple immunosuppression that include the combination of tacrolimus and mycophenolate mofetil have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas‐kidney (SPK) transplantation. In an attempt to obtain a low rejection rate without antibody induction therapy, we undertook a prospective study of combined tacrolimus and mycophenolate mofetil and steroids as primary immunosuppression for SPK transplantation. In this study, we analyzed 17 patients who received low‐dose intravenous tacrolimus as induction therapy. This was combined with oral tacrolimus, mycophenolate mofetil, and steroids as the primary immunosuppression regimen. There was a significant reduction of empirically and biopsy‐proven rejection with an incidence of 23 % (4 patients). Leukopenia, gastroparesis, and gastrointestinal side‐effects were the cause of discontinuation of mycophenolate mofetil, or low tacrolimus trough level in those patients who developed rejection. All rejection episodes were easy to treat, and none of them required antibody therapy. The combination of tacrolimus with mycophenolate mofetil without antibody induction therapy is effective in preventing early acute rejection. This combination is safe and effective as an alternative immunosuppressive regimen after SPK transplantation.     

OKT3 and ganciclovir treatments are possibly related to the presence of Epstein–Barr virus in serum after liver transplantation

The development of Epstein-Barr virus (EBV) associated lymphoproliferative disorder (PTLD) is related to EBV genome numbers in serum or plasma and B-cells, and the level of immunosuppression. EBV DNA viremia, defined as presence of EBV genomes in serum or plasma, is common in immunodeficiency. This survey of EBV viremia was performed by real-time polymerase chain reaction (PCR) on consecutive serum samples of 21 patients with acute (n = 3) or chronic liver disease (n = 18) during the first year after liver transplantation (LTX). Cytomegalovirus (CMV) DNA was analyzed with PCR in serum or leukocytes. The levels of EBV and CMV viremia were related to PTLD and the effect of different anti-rejection regimens. All patients were EBV-seropositive pre-LTX. In total, 24 of 152 (16%) samples from 10 of 21 (48%) individuals were EBV positive [five of 11 cyclosporin A (CsA); five of 10 tacrolimus treated cases]. EBV viremia was demonstrated in five of seven patients with OKT3 therapy. The number of EBV DNA positive samples was highest (26%) at 14 days after LTX. In the OKT3 treated groups, the medians of EBV DNA copy numbers were 1600/ml (range 230-7200) and 380/ml (range 120-860) in the CsA and tacrolimus patients, respectively (P < 0.02). One patient developed EBV lymphoma and another one EBV hepatitis 13 months and 24 days post-LTX, respectively. Both patients had received OKT3. Their EBV genome load was not significantly different from what was found in other patients. After ganciclovir therapy, EBV DNA was eradicated from serum in four of five patients for several months. EBV DNA load was not affected by CMV infection or disease. We conclude that presence of EBV in serum is a possible marker of an active infection and an early ganciclovir therapy may be beneficial. Quantification of EBV load offers the potential to implement pre-emptive interventions.     

小肠移植术后内镜引导下移植肠黏膜活检的时机及诊断价值

目的 总结小肠移植术后内镜引导下移植肠黏膜活检的时机及该技术对急性排斥反应和感染的诊断价值.方法 根据免疫抑制方案的不同,将15例小肠移植受者分为3个阶段.1994-1995年为第1阶段(3例),2003-2006年为第2阶段(7例),2007年以后为第3阶段(5例).第3阶段进行计划性内镜引导下移植肠黏膜活检的监测,既术后第3天进行首次内镜引导下移植肠黏膜活检,此后活检的频次在术后第1个月为2次/周,术后第2～3个月为1次/周,术后第4～6个月为1次/2周,术后7个月以后为1次/月,在受者出现排斥反应的临床症状和抗排斥反应治疗期间,也进行内镜引导下移植肠黏膜活检.结果 15例共进行内镜引导下移植肠黏膜活检255次,移植肠腹壁造口肉眼直视下取材活检21次.以上276份样本中,诊断排斥反应共51份(18.5%),其中诊断不确定急性排斥反应至轻度排斥反应32份(11.6%)、中度排斥反应9份(3.3%)、重度排斥反应10份(3.6%),巨细胞病毒(CMV)感染2份(0.7%),细菌感染2份(0.7%).15例共发生病理证实并需l临床治疗的排斥反应20次,其中不确定急性排斥反应至轻度排斥反应11次、中度5次、重度4次,发生细菌性和CMV肠炎各1次.结论 内镜引导下移植肠黏膜活检及其病理学检查是小肠移植术后诊断排斥反应和感染的重要手段,有计划的进行该检查对排斥反应有术后监测、早期诊断、鉴别诊断和指导治疗的价值.     

Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus

AIMS: The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease. RESULTS: Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21). CONCLUSIONS: SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.     

Blood monitoring of granzyme B and perforin expression after intestinal transplantation: considerations on clinical relevance

BACKGROUND: The use of biomarkers for rejection monitoring represents a major goal in intestinal transplantation. We analyzed the blood expression of Granzyme B (GB) and Perforin (PF) in the following pathological conditions after intestinal transplantation: acute rejection (AR), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD). The diagnostic accuracy and the clinical utility of these tests are finally discussed. METHODS: GB and PF levels were measured by real time polymerase chain reaction on peripheral blood samples from 32 intestinal recipients. Blood samples (n=494) after comparison of clinical, histological, and microbiological data were assigned to the following groups: normal (n=307), AR (n=30), EBV infection (n=107), CMV infection (n=25), and PTLD (n=25). RESULTS: Mean levels of GB and PF in the AR (GB=279.7; PF=256.7), PTLD (GB=199; PF=185.9), EBV (GB=133.2; PF=143.7), and CMV (GB=151.3; PF=144) groups were significantly higher than in the normal group (GB=100.1; PF=101.1) (all P<0.05, except for PF in CMV infection). The best accuracy was obtained for the diagnosis of AR with sensitivity and specificity of 80% and 79% for GB and 70% and 79% for PF, respectively. The area under the receiver-operator characteristics curve was 0.87 for GB and 0.82 for PF. CONCLUSIONS: GB and PF are diagnostic molecular markers of AR. GB and PF blood levels are also increased in case of viral infections or PTLD. Serial blood testing for GB and PF might be predictive of early intestinal graft dysfunction and should be interpreted in the context of the histological and virological analyses.     

Incidence of graft rejection in small bowel transplanted pigs after immunosuppression withdrawal

As intestinal grafts require heavy immunosuppression, there are no reports of immunosuppression withdrawal after clinical small bowel transplantation. In this large-animal study, we investigated the occurrence of graft rejection in intestinal-transplanted pigs after withdrawal. Large-White unrelated piglets were transplanted and divided in three groups: group 1 (n = 5), intestinal transplantation (ITx) with no immunosuppression; group 2 (n = 7), Itx and 60 days of treatment with tacrolimus and mycophenolate mofetil; group 3 (n = 5), Itx and donor bone marrow infusion (DBMi) and 60 days of treatment with tacrolimus and mycophenolate mofetil. Follow-up time after withdrawal was 120 days. Group 1 pigs died of graft acute cellular rejection (ACR) after a median of 11 days. In group 2, two pigs died of ACR-related infection and another two of ACR within 90 days. The remaining three animals (43%) were sacrificed at day 180, and their grafts showed no signs of ACR. In group 3, two pigs died of ACR-related infection and one of graft versus host disease within 80 days; at day 180 the two surviving animals showed signs of chronic rejection in the allograft. This study demonstrates that total withdrawal after ITx is followed by sudden and lethal ACR (or ACR-related infection) in more than 50% of the recipients. When a tolerance-inducing strategy as DBMi is applied, lethal graft versus host disease may also occur. In group 3, the intestinal allograft, to which the recipients were partially tolerant, developed chronic rejection that was probably associated with a decline with time of donor-leukocytes chimerism, as recently demonstrated in rats.     

Growth after intestinal transplant in children

Intestinal transplantation has been more frequent in children with intestinal failure. However, the growth after intestinal transplantation has not been well documented. The demographics, transplant information, postoperative complications, heights, and weights were obtained retrospectively from medical records on 23 children who underwent intestinal transplantation. Z-scores were calculated from the STAT Growth-BP, based on Centers for Disease Control and Prevention growth chart (2000). Transplantations were performed between 1999 and 2004. Patient median age was 1.1 years (range 0.5 to 6.9 years). Twelve were boys and 11 girls. Seventeen children received multivisceral transplantations, one modified multivisceral transplantation, and five isolated intestinal transplantations. Baseline immunosuppression consisted of tacrolimus and corticosteroids. Daclizumab was used as induction agent in 18 patients; alemtuzumab, in five patients. Median pretransplant Z-scores were median -1.67 (n = 23) in weight, and median -3.36 (n = 21) in height. Pretransplant growth was significantly retarded. We analyzed significantly retarded patients with Z-score <-2.0. The change of weight Z-score from pretransplant was: 1.25 at 6 months (n = 11), 1.46 at 12 months (n = 10), and 2.21 at 24 months (n = 7). The change of height Z-score: 1.9 at 6 months (n = 16), 1.42 at 12 months (n = 13), and 1.51 at 24 months (n = 10). Z-score significantly improved (P < .002, ANOVA). Among the analyzed factors sex, age at transplant, length of stay, and rejection within 6 months, were not associated with catch-up growth. Children with retarded growth showed significant catch-up after successful intestinal transplantation.