Effect of early EBV and/or CMV viremia on graft function and acute cellular rejection in pediatric liver transplantation

Indolfi G, Heaton N, Smith M, Mieli‐Vergani G, Zuckerman M. Effect of early EBV and/or CMV viremia on graft function and acute cellular rejection in pediatric liver transplantation.
Clin Transplant 2012: 26: E55–E61.
© 2011 John Wiley & Sons A/S. Abstract: Background: The clinical impact of Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections in the early post‐transplantation period are poorly documented. We investigated the prevalence and timing of EBV and CMV infections during the first 21 d post‐transplantation in relation to graft function and acute cellular rejection in a large cohort of pediatric liver transplantation recipients. Patients and methods: Clinical, biochemical, virological, and histopathological data of 62 consecutive children who received a liver transplant were reviewed retrospectively. Results: Seventeen patients (27%) developed EBV and 11 (18%) CMV viremia (mean interval from surgery: 7.6 d, SD 3.6 and 8.7 d, SD 6.4, respectively). EBV and CMV viremia were more common as a consequence of reactivation than of primary infection. EBV viremic recipients had more often abnormal bilirubin levels [p = 0.01; OR 5.8: 95% CI 1.3–25.5]. Acute rejection was diagnosed in 20 recipients (32.3%). No correlation was found between rejection and EBV and CMV serology before transplantation and viremia after transplantation (mean interval between the diagnosis of rejection and the detection of EBV DNA and CMV DNA: one d, SD 4.4 and five d, SD 9.2, respectively). Conclusion: EBV and CMV viremia occur at a very early‐stage post‐transplantation and do not appear to affect the short‐term outcome of the transplant.     

Cytokine gene polymorphisms and acute human liver graft rejection

Interindividual differences exist in the capacity to produce cytokines. It has been reported that levels of in vitro cytokine production measured after stimulated cell culture are associated with polymorphisms in cytokine genes. Moreover, a correlation between heart, kidney, liver, and lung graft rejection or survival with cytokine gene polymorphisms has been described. In the present study, we analyzed the association of gene polymorphisms in T helper subtype 1 (T_H1-), T_H2-, and regulatory-type cytokines with human liver allograft rejection. Patients who received a primary liver graft from 1992 onward and were seen at the transplant outpatient clinic since then were included on this study (n = 89). Patients were HLA typed routinely. Biopsy-proven acute rejection occurred in 41 of 89 patients. After informed consent, blood was collected and DNA was obtained. Using amplification-refractory mutation system polymerase chain reaction, the following cytokine gene polymorphisms were determined: IL-2+166, IL-2-330, IL-15+13689, IL-15-80, TNF-A-308, TNFd3, IFN-G+874 (T_H1-type cytokines), IL-4+33, IL-4-590, IL-6-174, IL-10-592, IL-10-819, IL-10-1082, IL-13+2043, IL-13-1055 (T_H2 type cytokines), TGF-B1+869, and TGF-B1+915 (regulatory-type cytokines). Univariate analysis showed that polymorphisms of IL-10-1082, TGF-B1+869, and HLA-DR6 were significantly related to liver graft rejection. Multiple logistic regression analysis was used to assess which variables remained significantly predictive of acute rejection. Multivariate analysis showed that TGF-B1+869 and HLA-DR6 were independently associated with the occurrence of acute rejection. These findings suggest a role for the regulatory-type cytokine transforming growth factor-β1 in human liver graft rejection. (Liver Transpl 2002;8:603-611.)     

Therapeutic effect of 15-deoxyspergualin on acute graft rejection in canine liver transplantation

Abstract Therapeutic effect of 15-deoxyspergualin (DSG) on acute rejection was investigated by examining hepatic functions and histological findings in a model of canine liver transplantation. When acute rejection (defined as an acute rise of hepatic functions) occurred, the recipients were treated with DSG alone or combined with a small amount of methyl-prednisolone (MP). The recipients in group 1 were administered no basic immunosuppressant, and those in groups 2 and 3 received cyclosporine as the basic drug. The rejections in groups 1 and 2 were treated with DSG combined with MP and those in group 3, with DSG alone. Amelioration or healing of hepatic dysfunction and histological abnormalities as seen in all groups except for one case in group 3. The observations in this study were quite similar to those in renal transplantation. Therefore, DSG therapy is expected to be useful for treating graft rejection even in clinical liver transplantation.     

The significance of parenchymal changes of acute cellular rejection in predicting chronic liver graft rejection

BACKGROUND: Chronic rejection (CR) in liver allografts shows a rapid onset and progressive course, leading to graft failure within the first year after transplantation. Most cases are preceded by episodes of acute cellular rejection (AR), but histological features predictive for the transition toward CR are not well documented. METHODS: We assessed the predictive value of centrilobular necrosis, central vein endothelialitis (CVE), central vein fibrosis, and lobular inflammation in the development of CR. One-week and one-month biopsy specimens of 12 patients with CR were compared with those of a control group consisting of 17 patients, who experienced AR without developing CR. The progress of the histological changes was further evaluated in follow-up biopsy specimens of the CR group taken at 2 months and beyond 3 months after transplantation. RESULTS: Centrilobular necrosis, CVE, central vein fibrosis, and lobular inflammation were common features in both groups at 1 week. At 1 month, the incidence declined in the control group. The CR group showed an increased incidence and persistence of these features in the follow-up biopsy specimens. The incidence and median grade of severity of CVE was significantly higher in the CR group (P=0.04 and P<0.001). The severity of portal and lobular inflammation was also more pronounced in the CR group (P=0.01 and 0.068). Conversely, in the control group, the incidence of the lobular features decreased and the severity of CVE declined significantly (P=0.03). CONCLUSION: The shift from a predominantly portal-based process toward lobular graft damage represents the early transition of AR to CR, for which a modification of immunosuppression might be necessary to prevent graft loss.     

The relative influence of delayed graft function and acute rejection on renal transplant survival

Three hundred and eight cadaveric renal transplants were analysed to establish the effects of acute rejection in the first 90 days and delayed graft function (DGF) on graft outcome. There were 120 patients (39%) with no DGF and no rejection (group 1), 101 patients (33%) with rejection but no DGF (group 2), 41 patients (13%) with DGF but no rejection (group 3) and 46 patients (15%) with both rejection and DGF (group 4). The actuarial 4-year graft survival rates for groups 1,2,3 and 40.4%, respectively. The acute rejection rate was 101/221 (46%) in patients with initial graft function compared with 46/87 (53%) for those with DGF (²=1.02, P=0.31). Cox stepwise logistic regression analysis demonstrated that DGF was a more powerful predictive factor for poor graft survival (P=0.001) than acute rejection occurring in the first 90 days post-transplant (P=0.034). Further efforts at improving graft outcome should concentrate on reducing the incidence of DGF.     

Cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis.

In the field of liver transplantation, 7 reports have been published investigating the association between polymorphisms in cytokine genes and the occurrence of acute rejection in liver graft recipients. However, most of the individual studies lack the statistical power to detect a small-to-moderate effect of cytokine gene polymorphisms on the acute rejection rate. To overcome this problem, we performed a quantitative meta-analysis of 7 gene-association studies that were comparable with regard to definition of acute rejection and the type of immunosuppression used. In the overall analysis, the interleukin (IL)-10 polymorphism at position -1082 was identified as a genetic risk factor for acute liver graft rejection; liver transplant recipients carrying the IL-10 -1082.A allele displayed a lower rejection rate (common odds ratio [OR], .6; 95% confidence interval [CI], .4-.9). For the tumor necrosis factor (TNF)-A -308 polymorphism, a common OR could not be calculated due to significant heterogeneity of ORs between the studies (mean OR, 1.4; 95% CI, .8-2.6). No associations were found between acute liver graft rejection and single nucleotide polymorphisms in the IL-6 (position -174) and transforming growth factor (TGF)-beta1 (positions +869 and +915) genes. In conclusion, results from this meta-analysis suggest a role for the IL-10 -1082 polymorphism in human liver graft rejection.     

不同的免疫抑制方案对脾移植排斥与存活的影响

目的　通过总结 11例脾移植的免疫抑制治疗的经验 ,分析不同的免疫抑制方案对脾移植排斥反应 ,移植物抗宿主反应 (GVHR)和移植物存活的影响。方法　分两组 ,Ⅰ组 6例 ,术前无预处理 ,术后采用常规三联用药CsA 6 8mg/ (kg·d) Aza 2mg/ (kg·d) Pred 30mg/d ;Ⅱ组 5例 ,术前供受者均行预处理 ,供者用CsA 8mg/ (kg·d) ALG 5 0 0mg/d ,连用 3d。受者术前 1d给予静脉CsA 3mg/(kg·d) Aza 10 0mg。术后受者免疫抑制为CsA 6 8mg/ (kg·d) ALG 5 0 0mg/d Pred 30mg/d ,10d后改为CsA 5 8mg/ (kg·d) Pred 2 0mg/d维持。结果　Ⅰ组 6例均发生多次排斥反应和 (或 )GVHR。移植脾功能维持在 1年以内。Ⅱ组仅 1例因供脾过大发生 1次GVHR ,全部病例有功能存活超过 1年 ,但伴随不同程度的移植脾萎缩。结论　脾移植免疫抑制治疗有自己的特色 ,选择合适的免疫抑制方案 ,对抑制排斥反应和防止移植脾萎缩十分重要。     

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = _1.031.68_2.72). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = _1.452.09_3.02; PFNC = _1.672.40_3.46; PCC = _1.482.24_3.37). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = _1.341.62_1.95) than CLDKT (aHR = _1.962.29_2.67) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.     

Sensitivity of graft rejection in rats to local immunosuppressive therapy

In this study we investigated whether allograft rejection is sensitive to local immunosuppressive therapy. In rats, cardiac transplantations (BN----Lewis) were performed with venous return on the portal vein of the recipient. For local treatment the topical steroid budesonide was infused with an osmotic minipump directly into the carotid artery of the transplant. Budesonide is rapidly cleared by the liver, and cardiac tissue binding of the drug is high. Hence, local budesonide administration, 120 micrograms/kg/day, resulted in high drug levels within the graft (29.6 ng/mg) and low systemic drug levels (0.34 ng/ml). Systemic drug levels were so low that systemic biological effects of the drug during local administration were not measurable. In contrast systemic drug delivery, via the jugular vein of recipient, resulted in similar drug levels within the graft (31.0 ng/mg), but with high systemic drug levels within the graft (31.0 ng/mg), but with high systemic drug levels (1.65 ng/ml) and important systemic side effects. Both local and systemic administration of budesonide, 120 micrograms/kg/day for 13 days, resulted in significant prolongation of graft survival; median graft survival time was respectively 19.5 days and 20.0 days, compared with 7 days in controls. These results demonstrate that allograft rejection can be treated locally without significant systemic immunosuppression.     

无皮质激素的免疫抑制方案对肝移植后近期急性排斥反应发生率的影响

目的 探讨无皮质激素的免疫抑制方案对原位肝移植术后近期急性排斥反应发生率的影响.方法 采用随机数字表法将186例肝移植受者分为两组.无皮质激素组(研究组)术后均采用他克莫司(Tac)[或环孢素A(CsA)]+吗替麦考酚酯(MMF)的免疫抑制方案,未使用皮质激素;有皮质激素组(对照组)术后均采用Tac(或CsA)+MMF+皮质激素的三联免疫抑制方案.观察术后6个月内两组间急性排斥反应发生率的差异.急性排斥反应的诊断参照Banff标准.结果 两组受者间性别、年龄、原发病、Child-Pugh评分、终末期肝病模型(MELD)评分、手术时间、术中出血量、输注红细胞悬液及供肝热、冷缺血时间等基本资料的比较,差异均无统计学意义(P＞0.05).观察期内,研究组和对照组接受移植肝穿刺活检各9例次,诊断为急性排斥反应者分别为5和4例,发生率分别为5.3％ (5/94)和4.4％(4/92),两组间比较,差异有统计学意义(P＜0.05).结论 肝移植术后采用无皮质激素的免疫抑制方案不会增加近期(半年内)急性排斥反应的发生率.     

The influence of late acute rejection episodes on long-term graft outcome after liver transplantation

Acute cellular rejection represents the most important single risk factor for the occurrence of chronic rejection after organ transplantation. We correlated late acute rejections with the occurrence of chronic graft failure after liver transplantation. We followed 1426 liver transplants for late acute rejection episodes defined as occurring >3 months after OLT. The overall incidence of chronic rejection in our patient population was 3.7%. In summary, we observed a predictive increase of transaminase levels prior to routine biopsies among patients with histologic evidence of late acute rejections. In contrast to other organ systems, late acute rejection episodes were not associated with the occurrence of chronic graft deterioration in liver grafts.     

Non-invasive diagnosis of acute rejection in kidney transplants with delayed graft function

Delayed graft function (DGF) often occurs in kidney transplants from deceased donors. We wanted to provide studies giving more accurate non-invasive tests for acute rejection (AR). Using real-time PCR, we examined the expression of cytolytic molecules such as perforin, granzyme B, and fas-ligand along with serpin proteinase inhibitor-9. We also measured the expression of FOXP3, a characteristic gene of T-regulatory cells known to be involved in AR. These studies were conducted on peripheral blood monocytes, urinary cells, and 48 surveillance kidney biopsies taken from a total of 35 patients with DGF. Of these patients, 20 had a histopathological diagnosis of AR, whereas other 28 had characteristics of acute tubular necrosis (ATN). Expression of cytolytic and apoptotic-associated genes in the biopsy tissue, peripheral blood leukocytes, and urinary cells was significantly higher in patients with AR than that in patients with ATN. Diagnostic parameters associated with FOXP3 gene expression were most accurate in peripheral blood leukocytes and urine cells with sensitivity, specificity, positive and negative predictive values, and accuracy between 94 and 100%. Our study shows that quantification of selected genes in peripheral blood leukocytes and urinary cells from renal transplant patients with DGF may provide a useful and accurate non-invasive diagnosis of AR.     

Effect of graft steatosis on liver function and organ survival after liver transplantation

BACKGROUND: It was the aim to determine the effect of graft steatosis on intraoperative organ blood flow, postoperative liver function, and organ survival. METHODS: A total of 225 consecutive liver transplants were reviewed. Liver blood flow, hepatic function (AST, ALT, prothrombin time), and organ survival were determined. Donor liver grafts were categorized into 2 subgroups: mild (<30%) (n = 175) and moderate to severe (>/=30%) (n = 50) macrovesicular steatosis. RESULTS: Moderate to severe steatosis was associated with significantly increased AST and ALT levels and significantly diminished prothrombin time on the first and second postoperative day. By day 7 differences in liver function were no longer evident. Organ blood flow was not affected by steatosis. After adjustment for potential confounders, organ survival did not depend on the degree of donor steatosis (5-year-survival rates: 68% and 58% with steatosis <30%, or >/= 30%, respectively) (hazard ratio .754, confidence interval .458-1.242, P = .268). CONCLUSION: Steatotic livers can be transplanted safely with good results for long-term organ survival if other contraindications are absent.     

激素最小化免疫抑制方案在肝移植术后的应用

目的 探讨肝移植术后激素最小化免疫抑制方案的安全性及可行性.方法 2005年1月至2008年6月共收治经手术治疗并符合入选条件的成人肝移植患者116例,根据术后免疫抑制方案中激素使用的不同分为三组:3个月撤离组(n=40),7 d撤离组(n=40)及24 h撤离组(n=36),比较各组患者术后生存、感染、急性排斥反应包括耐激素治疗的排斥反应、切口愈合不良、肝炎和肝癌复发、新发糖尿病、高脂血症及高血压的发生情况.结果 各组间患者术后生存、急性排斥反应、高脂血症、乙型肝炎复发及肝癌复发无明显区别(P>0.05);24 h撤离组的术后切口愈合不良及发生高血压的例数明显低于7 d撤离组及3个月撤离组(P<0.05),术后感染及新发糖尿病例数明显少于3个月撤离组(P<0.05),但与7 d撤离组无明显差异(P>0.05).结论 激素最小化的免疫抑制方案(激素7 d撤离,甚至24 h撤离)在肝移植术后的应用是安全的,在不影响患者及移植物预后的同时可以明显减少激素相关的不良反应.     

Renal graft irradiation in acute rejection

To evaluate the effect of graft irradiation in the treatment of acute rejection of renal transplants, a randomized study was conducted from 1978 to 1981. Patients with acute rejection were given standard medical management in the form of intravenous methylprednisolone, and were chosen randomly to receive either graft irradiation (175 rads every other day, to a total of 525 rads) or simulated (sham) irradiation. Eighty-three rejections occurring in 64 grafts were randomized to the protocol. Rejection reversal was recorded in 84.5% of control grafts and 75% of the irradiated grafts. Recurrent rejections were more frequent and graft survival was significantly lower in the irradiated group (22%) than in the control group (54%). Graft irradiation does not appear to be beneficial in the treatment of acute rejection of renal transplants when used in conjunction with high-dose steroids.     

Delayed graft function complicated by spontaneous renal allograft rupture without acute rejection

We report a young male patient who developed spontaneous renal allograft rupture 7 days after cadaveric renal transplant, complicated by delayed graft function, without evidence of rejection on allograft biopsy.     

Silent acute rejection during prolonged delayed graft function reduces kidney allograft survival

BACKGROUND: The relationship between the effects of early, silent, acute rejection (AR) and delayed graft function (DGF) on kidney allograft survival remain controversial, and the role of protocol biopsies during DGF is unclear. We hypothesized that protocol biopsies during DGF would reveal a high incidence of silent AR that may adversely affect long-term allograft survival. METHODS: We routinely carried out protocol biopsies in patients requiring dialysis 7 to 10 days posttransplant. We retrospectively examined the extent to which silent AR, diagnosed by protocol biopsies during prolonged DGF, may mediate the adverse effects of DGF on graft survival in 410 consecutive transplants using Cox proportional hazards analysis. RESULTS: By 40 days posttransplant, the cumulative incidence of AR was 57.2% among 65 patients who had a protocol biopsies during DGF, while it was only 15.1% among the 345 who did not need a protocol biopsy. Mild DGF (n=30) requiring one or two dialysis treatments had no effect on graft survival, but the unadjusted risk ratio (and 95% confidence interval) associated with more prolonged DGF (n=104) was 3.08 (2.09-4.52, P<0.0001). The risk for graft failure from AR detected on protocol biopsy was 2.91 (1.60-5.27, P=0.0004) and was similar to the risk from early AR in patients without DGF, 2.95 (1.72-5.07, P<0.0001). After taking the effects of AR into account, the risk of graft failure attributable to prolonged DGF was reduced to 1.76 (1.06-2.94, P=0.0294), suggesting that much of the risk of DGF was because of the risk of AR. CONCLUSIONS: Silent AR is common during DGF. Prolonged DGF is associated with reduced graft survival after kidney transplantation, and much of this association can be explained by silent AR. In the absence of data from randomized trials, protocol biopsies and treatment of silent AR during prolonged DGF appear to be warranted.