Cytomegalovirus infection and graft rejection in renal transplantation

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. METHODS: Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. RESULTS: CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CONCLUSION: CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.     

肝移植术后巨细胞病毒感染的防治研究

目的探讨肝移植患者术后巨细胞病毒 (CMV)感染情况及其与急性排斥反应的关系。方法应用PCR和ELISA方法检测 78例肝移植受体手术前后、78例供体及 70例接受上腹部手术的非肿瘤患者血清中的CMV DNA和CMV抗体 ,用免疫组织化学方法检测肝组织中CMV抗原。结果供、受体术中肝脏活体组织学检查的CMV早期抗原 (EA)和晚期抗原 (LA)全部为阴性。术前CMV DNA或CMV IgM阳性的受体术后均为阳性 ;术前CMV DNA或CMV IgM阴性的受体术后CMV DNA或CMV IgM转为阳性的分别有 2 6 %和 10 %。 78例受体CMV DNA阳性率由术前的 5 %增加到术后的 31% ,两者比较差异有显著意义 (P <0 0 5 )。 2 6例患者发生了 33次急性排斥反应 ,16次 (49% )CMV DNA检测阳性、11次 (33% )CMV IgM检测阳性 ,而在术后常规检测血CMV DNA和CMV IgM的阳性率分别不超过 13%和 9% ,两者比较差异有显著意义 (P <0 0 5 )。 2 6例发生急性排斥患者肝脏活体组织学检查CMV EA和CMV LA阳性者均为 9例 (2 7% ) ,与术后的常规肝脏穿刺结果比较差异有显著意义 (P <0 0 5 )。结论 1.肝移植术后CMV感染率明显升高。 2 .CMV感染可能是发生急性排斥反应的危险因素。 3.发生急性排斥反应时 ,应使用抗CMV药物 ;未感染CMV的受体接受感染供体的肝脏时应预防用药。     

An association between cytomegalovirus infection and chronic rejection after liver transplantation

BACKGROUND: Previous studies suggest a link between cytomegalovirus (CMV) infection and chronic rejection. Since these studies, more sophisticated diagnostic methods with high sensitivity and specificity for CMV have been developed and effective therapy/prophylaxis for CMV is now available. We sought CMV prospectively by polymerase chain reaction of serum and urine and by conventional methods in a group of 33 patients undergoing 57 transplants during 1993 or 1994, selected from a larger series. There were 13 grafts lost to chronic rejection. The remaining 44 grafts that did not develop chronic rejection served as controls and comprised 15 successful primary grafts, 15 second transplants, 8 third transplants, and 6 primary grafts that were lost for reasons other than chronic rejection. RESULTS: The combination donor CMV antibody negative with recipient antibody positive and the duration of CMV infection >30 days were associated with an increased relative risk of chronic rejection. In contrast, the presence of CMV infection alone, symptomatic CMV infection, the detection of CMV by PCR of serum or urine, and the peak/cumulative viral load were not predictive. CMV infection occurred earlier in those undergoing a second transplant for chronic rejection than for those undergoing a second transplant for other reasons. In addition, a human leukocyte antigen B mismatch was associated with prolonged CMV infection. CONCLUSION: These data are consistent with the hypothesis that prolonged subclinical cytomegalovirus infection is associated with an increased risk of chronic rejection.     

小肠移植术后巨细胞病毒感染二例的治疗体会

目的 总结小肠移植术后巨细胞病毒(CMV)感染的治疗经验.方法 1994年至2009年间完成15例小肠移植,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1阶段术后未进行CMV感染的预防;第2阶段通过肠镜、病理检查和血清学检查(CMV IgM、CMV pp65和CMV DNA)进行CMV感染的诊断,术后静脉注射更昔洛韦2~3周,口服阿昔洛韦3个月以预防CMV感染;第3阶段在第2阶段的基础上,应用实时定量PCR技术检测CMV DNA,并制定计划性监测方案,术后静脉注射更昔洛韦2~3周,口服更昔洛韦3个月预防CMV感染,采用CMV感染的抢先治疗方案.结果 15例患者中有2例(13.3 %)术后发生CMV感染.其中第2阶段1例术后45 d发生移植肠CMV肠炎,术后64 d并发CMV肺炎,应用更昔洛韦和胸腺肽,并停用他克莫司,最终转为重度排斥反应后死亡;第3阶段1例术后第3个月发生CMV感染,经CMV抢先治疗后治愈.结论 小肠移植术后应进行CMV的预防性治疗,严密监测CMV血清学指标,适时进行抢先治疗.对于CMV侵袭性疾病在进行有效治疗的同时应注意排斥反应的发生.

Abstract：

Objective Cytomegalovirus (CMV) has remained the most significant pathogen that threatens the outcome of small bowel transplantation (SBTx). This paper To outline preliminary experience of prophylaxis and treatment of cytomegalovirus (CMV) in 15 cases subject to small bowel transplantation (SBTx) and also review current progress of diagnosis and treatment of CMV.Methods Fifteen cases of SBTx were divided into 3 eras: era Ⅰ (1994-1995)-3 SBTx treated with cyclosporine-based immunosuppression; era Ⅱ (2003-2006)-7 SBTx treated with tacrolimus-based immunosuppression; and era Ⅲ (2007-present)-5 SBTx treated with Alemtuzumab induction therapy and maintenance tacrolimus monotherapy. No antiviral prophylaxis after SBTx was applied during era Ⅰ; in era Ⅱ, ileoscopic and pathological diagnosis of CMV graft enteritis was defined, and plasma diagnosis tools including CMV-IgM, CMV pp65 and CMV DNA with PCR were introduced. 2-3 weeks intravenous ganciclovir prophylaxis of CMV was underway, followed by 3 months oral acyclovir; In era Ⅲ, more precise real-time PCR technique was used to detect CMV DNA copies, and the schedule of the CMV surveillance was set up, antiviral prophylaxis therapy was modified to 2-3 weeks intravenous ganciclovir and 3 months oral ganciclovir, and preemptive therapy to halt the progression of asymptomatic infection to clinical disease was also introduced.Results Two of 15 SBTx recipients suffered from CMV with the occurrence rate of 13.3%. One recipient in era Ⅱ suffered from CMV graft enteritis on postoperative day 45, and CMV pneumonia on postoperative day 64, he received intravenous ganciclovir and thymus peptide, paused tacrolimus maintenance, and finally he died from severe acute cellular rejection. 94 100 copies/ml of CMV DNA in periphery blood of a recipient in era Ⅲ was detected with real-time PCR at 3rd month after SBTx, and a preemptive therapy successfully halted the CMV infection.Conclusion Antiviral prophylaxis therapy and close surveillance of CMV infection after SBTx should be performed, and preemptive therapy can also halt the CMV infection. When CMV disease occurs, the recipient should receive effective antiviral therapy, and acute cellular rejection also should be closely monitored at same time.     

Surveillance of alloantibodies after transplantation identifies the risk of chronic rejection

The monitoring of the levels of alloantibodies following transplantation might facilitate early diagnosis of chronic rejection (CR), the leading cause of renal allograft failure. Here, we used serial alloantibody surveillance to monitor patients with preoperative positive flow cytometric crossmatch (FCXM). Sixty-nine of 308 renal transplant patients in our center had preoperative positive FCXM. Blood was collected quarterly during the first postoperative year and tested by FCXM and single antigen bead luminometry, more sensitive techniques than complement-dependent cytotoxic crossmatching. Distinct post-transplant profiles emerged and were associated with different clinical outcomes. Two-thirds of patients showed complete elimination of FCXM and solid-phase assay reactions within 1 year, had few adverse events, and a 95% 3-year graft survival. In contrast, the remaining third failed to eliminate flow FCXM or solid-phase reactions directed against HLA class I or II antibodies. The inferior graft survival (67%) with loss in this latter group was primarily due to CR. Thus, systematic assessment of longitudinal changes in alloantibody levels, either by FCXM or solid-phase assay, can help identify patients at greater risk of developing CR.     

Prevalence and risk factors for early postoperative infection after liver transplantation

OBJECTIVES: To analyze factors related to the development of infection soon after a liver transplant. PATIENTS AND METHOD: Retrospective study of 1000 liver transplants in adults between 1991 and 2004. Pre-, intra- and postoperative variables of recipients were analyzed in 2 groups according to whether infection did or did not develop. RESULTS: Infection developed in 151 patients. Bacterial infections were the most common type. Significant risk factors for infection in the multivariate analysis were sex (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.33-0.90); Child-Pugh stage (OR, 1.89; 95% CI, 1.29-2,77); hepatitis C virus cirrhosis (OR, 0.58; 95% CI, 0.34-0.99); post-reperfusion syndrome (OR, 1.82; 95% CI, 1.03-3.21); vena cava preservation technique (OR, 0.43; 95% CI, 0.22-0.84); history of diabetes mellitus (OR, 2.38; 95% CI, 1.34-4.22); respiratory distress syndrome (OR, 6.60; 95% CI, 1.16-37.45); pulmonary edema (OR, 2.36; 95% CI, 1.44-3.86); renal dysfunction (OR, 3.25; 95% CI, 1.89-5.60); acute renal insufficiency (OR, 20.24; 95% CI, 9.88-41.46); neurological alterations (OR, 3.36; 95% CI, 1.94-5.821); postoperative bleeding (OR, 2.80; 95% CI, 1.32-5.97); graft dysfunction (OR, 2.07; 95% CI, 1.21-3.53); primary graft failure (OR, 0.07; 95% CI, 0.01-0.33). CONCLUSION: Infection is a serious complication that continues to be difficult to control. Certain risk factors can be improved with careful management (kidney failure, pulmonary edema) or appropriate donor-recipient matching (initial dysfunction). Others, however, are inherent to the procedure (post-reperfusion syndrome, sex) or to immunosuppression, which acts as a true mediator of infection with regard to both its appearance and its clinical manifestation.     

Circumocular exanthema associated with chronic rejection after kidney transplantation

A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross-reacted with unknown pathogens on the skin and contributed to inflammation.     

Isolated pulmonary rejection after combined heart-lung transplantation

Severe pulmonary rejection without cardiac rejection in a patient after combined heart-lung transplantation is presented with the clinical and pathological findings. Acute lung rejection after heart-lung transplantation cannot be excluded by normal cardiac biopsy results.     

Per- and postoperative risk status in pulmonary surgery

Better understanding of pulmonary physiology over the last few years has permitted a more effective control of gaz exchanges during pulmonary surgery. The introduction of one-lung anesthesia offers a greater margin of safety to the patient and improved surgical conditions, and helps avoid hypoxic episodes. Modern management of ventilation during pulmonary surgery unquestionably requires the use of full invasive monitoring: central venous pressure, pulmonary pressures (in specific situations) and radial arterial pressure (systolic, mean and diastolic pressures). Pulse oximetry and measurement of end-tidal carbon dioxide are also indispensable. Complete monitoring and frequent determinations of arterial blood gases allow continuous adjustments of the ventilation of the dependent and independent lungs. Placement of epidural thoracic catheters for postoperative analgesia represents another improvement. This technique alone permits rapid and complete recovery of pulmonary function after pulmonary surgery.     

Rat cytomegalovirus and Listeria monocytogenes infection enhance chronic rejection after allogenic rat lung transplantation

The role of infection in the pathomechanism of obliterative bronchiolitis (OB) after human lung transplantation is controversial. In a rat lung transplantation model, we analyzed the effect of viral [rat cytomegalovirus (RCMV)] and bacterial infection [Listeria monocytogenes (LM)] on the development of chronic allograft rejection. Fisher rats underwent single left lung transplantation with allografts from Lewis rats. Postoperatively, animals were infected with either RCMV or LM, or served as noninfected controls. Animals were killed on day 120 and both lungs were evaluated histopathologically for chronic airway and chronic vascular rejection. Infection with RCMV produced a significant increase in the incidence of chronic airway rejection (66.7% vs. 20%), compared with noninfected long-term surviving animals. In rats with bacterial infection (LM) a similar increase of chronic airway changes as in viral infection (50% vs. 20%) was observed. Chronic rejection of allografts infected with either RCMV or LM was associated with significantly enhanced expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelium. More infiltrating leukocytes (CD18, CD11a, CD44) and ED1-positive macrophages were found in allografts of infected animals. In this experimental model of chronic airway rejection in long-term surviving rats, not only viral but also bacterial infection resulted in enhanced development of chronic airway and vascular rejection. These results support our hypothesis that infectious complications have a substantial influence on the development of OB in human lung allografts.     

Cytomegalovirus infection and development of biliary complications after liver transplantation

BACKGROUND: Cytomegalovirus (CMV) infection is known to cause ulceration and mucosal hemorrhage in the gastrointestinal tract. Gastroduodenal and biliary complications were prospectively evaluated in 100 consecutive liver transplant patients in whom CMV was monitored during the first posttransplant year. METHOD: Gastroduodenal biopsy specimens were taken from 36 patients by endoscopies and in 28 patients by endoscopic retrograde cholangiopancreatography, and bile duct specimens were taken from three patients who underwent surgical reconstruction because of biliary complication. CMV was demonstrated from blood by the pp65 antigenemia test and from frozen sections of tissue specimens by immunohistochemistry and in situ hybridization. RESULTS: Symptomatic CMV infection, treated with ganciclovir, developed in 49 recipients: 13 (100%) of CMV seropositive donor (D+) seronegative recipient (R-) cases, 29 (45%) D+/R+ cases, and 7 (32%) D-/R+ cases. Duodenal ulcer developed in three and hemorrhagic gastritis in three recipients. CMV antigens were found from the gastroduodenal mucosa in 37 (69%) of the 54 studied recipients. The biliary complication rate was 24%. Preceding or concomitant CMV antigenemia was demonstrated in 75% of patients with a biliary complication (68% in CMV D+/R+ or D-/R+ and 100% in D+/R- recipients). The biliary complication rate was higher among recipients with CMV antigenemia, compared with recipients without (P<0.05). CMV antigenemia, CMV infection, or both in the duodenal mucosa was found in 96% of patients with a biliary complication. In two patients who underwent surgical reconstruction, CMV antigens and DNA were demonstrated in the bile ducts. CONCLUSIONS: Liver transplant patients are at risk of developing biliary complications after CMV infection, especially those with primary CMV infection.     

Cytomegalovirus infection of the native ureter after liver-kidney transplantation

We report a case of invasive cytomegalovirus (CMV) infection in the native ureter of a patient 7 years after liver-kidney transplantation. Previous reports of CMV ureteritis in transplant patients have involved only the allograft ureter, usually within 3 months of transplantation. The common characteristics of these patients, the possible risk factors, and the diagnostic findings of CMV ureteritis are discussed. Combined surgical and medical intervention are required for successful treatment.     

Cytomegalovirus infection after organ transplantation: an update with special emphasis on renal transplantation

Abstract. Cytomegalovirus infections are still the most important infectious complications after organ transplantation. Besides historical notes this review will deal with new aspects concerning the epidemiology of the CMV, diagnostic modalities of CMV infection, the delicate counterbalance between the immune system and the CMV, as well as the symptomatology of this infection. Furthermore, aspects like prophylaxis and new, promising therapeutic regimes for treatment of infection will be dealt with. Although this update is applicable for all types of solid organ transplantation, emphasis will be on renal transplantation.     

Cytomegalovirus infection after renal transplantation: selective prophylaxis and treatment

We have reviewed our experience in selective cytomegalovirus (CMV) infection prophylaxis and treatment in our renal transplant population. Between 1996 and 2001, 263 cadaveric renal transplant recipients had at least 6 months follow up. Immunosuppression was based on cyclosporine Neoral (n=108) or tacrolimus (n=155). CMV infection prophylaxis (oral acyclovir or gancyclovir at half usual doses) was only prescribed in recipients receiving a CMV positive ve kidney and in recipients treated with OKT3. CMV infection was diagnosed by a positive pp65 antigenemia upon appearance of CMV-related symptoms, leading to specific treatment (IV ganciclovir) only if symptoms were intense or there was visceral involvement. Thus, no preemptive treatment or programmed or periodic antigenemia was performed in any case. Nineteen episodes of symptomatic CMV infection were diagnosed (prevalence 7.2%). The frequency was similar for all immunosuppressive regimens. Only 9 of 19 (47%) of patients were given IV ganciclovir; the others were not treated. All patients survived without apparent complications, relapses, or recurrences. No oral gancyclovir was delivered after IV treatment. Our CMV prophylaxis protocol was limited to high-risk patients, using lower gancyclovir dosages than those usually advocated. It does not include programmed or scheduled search for CMV antigenemia in asymptomatic renal transplant patients. Despite these factors, our CMV infection rate and severity were similar to those reported with more aggressive protocols, with extended prophylaxis, preemptive therapy, or intense surveillance.     

Cytomegalovirus infection does not increase the risk of vanishing bile duct syndrome after liver transplantation

Abstract  Cytomegalovirus (CMV) infection and HLA-DR sharing have been reported to be associated with the development of vanishing bile duct syndrome (VBDS) after liver transplantation. We retrospectively analyzed the importance of these risk factors for VBDS in 126 consecutive recipients of a first transplant. In contrast to previous studies, CMV was monitored strictly using the antigenemia assay, a quantitative marker of the viral load. Patient and graft survival were comparable in patients with and without CMV infection. The incidence of VBDS was low, regardless of the CMV infection status or degree of HLA-DR sharing. Improvements in the early diagnosis and treatment of CMV infection may have eliminated its negative influence on graft survival.     

Cytomegalovirus infection after organ transplantation: an update with special emphasis on renal transplantation

Cytomegalovirus infections are still the most important infectious complications after organ transplantation. Besides historical notes this review will deal with new aspects concerning the epidemiology of the CMV, diagnostic modalities of CMV infection, the delicate counterbalance between the immune system and the CMV, as well as the symptomatology of this infection. Furthermore, aspects like prophylaxis and new, promising therapeutic regimes for treatment of infection will be dealt with. Although this update is applicable for all types of solid organ transplantation, emphasis will be on renal transplantation.     

Exploratory analysis of time-dependent risk for infection, rejection, and death after cardiac transplantation

Data from 95 heart transplantations performed at The Johns Hopkins Hospital from July 1983 to October 1988 were analyzed to detect patterns of morbidity and mortality. Using nonparametric techniques, hazard functions were determined for all deaths and for deaths due to infection or rejection. The rates of rejection and infection (episodes per patient-month) were determined within each of ten intervals following transplantation. A total of 19 deaths, 281 rejection episodes, and 180 distinct infections were available for analysis during a follow-up of 1 to 62 months. The hazard function for rejection appeared biphasic, with a rapidly decelerating early phase during the first year followed by a constant late phase. The hazard function for infection was triphasic, with a delayed, decelerating early phase, a period of increased risk approximately 2 years after operation, and finally a late constant phase. Both infection and rejection rates (episodes per patient-month) were biphasic, with rapidly decelerating early phases and constant late phases. Multiple regression analysis demonstrated that eventually nonsurviving patients had significantly higher rates of rejection and infection during both the early and late phases compared with survivors. The increased rate of rejection among nonsurvivors was evident throughout follow-up, although no deaths were attributable directly to rejection after the first 8 months. These data suggest that a complex interrelationship between infection and rejection determines late survival after cardiac transplantation and that aggressive treatment of late rejection predisposes toward death from infection.     

肾移植术后远期急性排斥反应与巨细胞病毒感染

目的探讨肾移植术后远期急性排斥反应与巨细胞病毒感染的关系。方法检测４５例移植肾有功能存活１年以上后发生急性排斥反应者外周血白细胞中巨细胞病毒ＤＮＡ（ＣＭＶＤＮＡ）,并给予激素冲击治疗,对激素冲击无效的部分患者给予更昔洛韦抗病毒治疗。结果３２例激素冲击有效,１３例无效。无效者外周血白细胞内可测到ＣＭＶＤＮＡ,８例用更昔洛韦治疗后ＣＭＶＤＮＡ转阴,２例肾功能好转,６例恢复正常,另５例未用更昔洛韦者ＣＭＶＤＮＡ持续阳性,肾功能损害加重。结论部分肾移植受者发生的远期急性排斥反应与ＣＭＶ感染有一定关系;临床上对用激素冲击治疗无效的远期急性排斥可给予抗病毒治疗