Nutritional markers in liver allograft recipients

BACKGROUND: Malnutrition is common in patients with end-stage liver disease considered for transplantation, but it is unclear whether this affects the outcome after transplantation. AIM.: To determine whether the severity of malnutrition in liver transplant candidates affects outcome after transplantation. METHODS: We did a prospective study of 61 patients with chronic liver disease accepted for transplantation. FINDINGS: The Child-Pugh and Model for End-Stage Liver Disease (MELD) score correlated significantly but weakly with the mid-arm circumference (MAC) (rho=-0.34 and -0.31, P=0.015 and 0.025, respectively) but not with hand-grip strength, triceps skin-fold thickness (TSFT), or mid-arm muscle circumference. The Child-Pugh score but not the MELD was significantly associated with intensive therapy unit stay but not eventual outcome; there was a weak but statistically significant correlation between death and MAC (rho=+0.29, P=0.04) and TSFT (rho=+0.25, P=0.02). CONCLUSIONS: These findings suggest that nutritional parameters and markers of disease severity do not correlate well with outcomes after transplantation.     

肝移植后采用巴利昔单抗进行免疫诱导治疗

目的 探讨肝移植后采用巴利昔单抗进行免疫诱导治疗预防急性排斥反应的有效性和安全性.方法 160例肝移植患者中,47例术后给予两剂巴利昔单抗(20 mg/剂)进行免疫诱导治疗(研究组),另外113例为对照组,不使用巴利昔单抗.所有患者术后均采用他克莫司、霉酚酸酯和糖皮质激素预防排斥反应.结果 术后1年内,研究组的急性排斥反应发生率为8.5%(4/47),对照组为22.1%(25/113),二者间的差异有统计学意义(P＜0.05);研究组排斥反应活动指数平均为4,对照组为6,两组间的差异无统计学意义(P＞0.05).研究组术后感染发生率为31.9 %(15/47),对照组为26.5%(30/113),两组间的差异无统计学意义(P＞0.05).研究组患者及移植肝1年存活率分别为95.7%和95.7%,对照组分别为96.5%和94.7%,两组间的差异均无统计学意义(P＞0.05).两组间其它不良反应发生率的差异也无统计学意义.结论 在以他克莫司为基础的免疫抑制治疗方案中,采用巴利昔单抗进行诱导治疗可明显降低肝移植后急性排斥反应发生率,且不增加感染和其它不良反应发生率.     

The signal-averaged electrocardiogram in cardiac transplantation. A noninvasive marker of acute allograft rejection.

Cardiac allograft rejection represents a major cause of morbidity and mortality in transplanted patients. Noninvasive markers of rejection have been sought, though transvenous endomyocardial biopsy remains the "gold standard" for the diagnosis of rejection. Sixty-one signal-averaged electrocardiograms (five in patients with rejection and 56 in patients without rejection) were obtained on 41 patients and prospectively analyzed in frequency domain via fast Fourier transform (FFT). Patients with acute allograft rejection demonstrate a significant increase in the high-frequency components of the QRS complex upon FFT analysis (QRS area ratio 203 +/- 57 vs. 66 +/- 10, P = 0.0007) compared with patients without rejection. Thus, frequency domain analysis may be a useful noninvasive marker of acute cardiac allograft rejection.     

The use of extracorporeal photopheresis for allograft rejection in liver transplant recipients

BACKGROUND: Originally introduced for cutaneous T-cell lymphomas and autoimmune diseases, extracorporeal photopheresis (ECP) has been proven effective to reverse allograft rejection. The aim of the present work was to show the results of a single-center experience with ECP for the treatment of biopsy-proven rejection in selected liver transplant (LT) recipients. PATIENTS AND METHODS: A retrospective review of five LT patients (M:F=4:1; median age 51 years) undergoing ECP for biopsy-proven allograft rejection between January 1996 and December 2003. In this period 476 LT were performed on 441 patients. RESULTS: The indications for LT were three cases of HCV-related cirrhosis, complicated by hepatocellular carcinoma in two; one HBV-HDV-alcoholic cirrhosis; and one fulminant HBV hepatitis. All patients received calcineurin-inhibitor (CNI)-based immunosuppression with induction using anti-IL2R monoclonal antibodies. Indications for ECP were: ductopenic rejection in one patient with HCV recurrence; steroid-resistant acute rejection in two; acute rejection in a major ABO-mismatched liver graft; and one acute rejection in a patient with a proven allergy to steroids. The median interval from LT to inception of ECP was 43 days. The median number of ECP sessions per patient was 20. During the course of ECP, two patients tested positive for CMV antigenemia, associated in one case with bacterial pneumonia. All patients tolerated ECP and there were no procedure-related complications. At a median follow-up of 7.9 months after start of ECP, neither rejection relapses nor HCV/HBV recurrences have been observed. Three patients are off ECP with complete reversal and low-dose immunosuppression. Two patients are still receiving ECP with full-dose immunosuppression: one has achieved normal liver function but ECP is indicated due to a major ABO-incompatible liver graft, while the other patient's liver functions have not yet returned to baseline values.     

Value of urinary polyamines as noninvasive markers of cardiac allograft rejection in the dog

A noninvasive marker of cardiac allograft rejection would be useful clinically. Lymphocyte proliferation and organ rejection may cause changes in urinary polyamine excretion. To test this hypothesis, cervical heterotopic heart transplantations were performed in a group of 6 nonimmunosuppressed dogs and in a group of 9 dogs treated with cyclosporine (N = 3) or cyclosporine and steroids (N = 6). A group (N = 3) having a sham operation was also studied. Serial biopsies of the transplanted hearts were performed. Urinary polyamine levels were measured daily by high-pressure liquid chromatography of urine specimens. Between 2 and 4 days after transplantation, the transplanted hearts of all animals without immunosuppression demonstrated histological rejection. An early increase in putrescine levels and in total urinary polyamine levels was observed in this group. In the treated groups, histological rejection appeared from the second to the eighth day after transplantation. Each episode of rejection occurred from 1 day to 4 days after a significant increase in urinary polyamine levels compared with the preoperative baseline level (p less than 0.01). In contrast, polyamine excretion in 3 dogs after sham operations remained unchanged. Thus, urinary excretion of polyamines increases before the appearance of histological rejection; this suggests that changes in urinary polyamine levels may be a useful marker of cardiac allograft rejection.     

Banff schema for grading liver allograft rejection: utility in clinical practice.

An accurate and functional system for grading acute liver allograft rejection is important for patient management, research, and communication. The Banff schema is a consensus document designed to provide an internationally accepted standard for this purpose. The aim of this study is to determine if application of the Banff schema would significantly alter the grading of acute liver allograft rejection compared with the Birmingham system. One hundred twenty-four post-liver transplantation biopsies performed by the Western Australian Liver Transplantation Service between 1992 and 1997 were retrospectively analyzed by a pathologist and a hepatologist. Each was supplied with a brief clinical history before applying the Banff and Birmingham criteria. Results were compared with each other and to the diagnosis made at the time of the biopsy, which was based on the European grading system. Rejection was diagnosed by the reviewers in 61 of 124 biopsy specimens according to the criteria of Snover. The Banff schema and Birmingham system agreed on the grade of rejection in 22 of the 61 biopsy specimens. The Banff schema elevated the grade of rejection in 39 specimens by an increment of one. In no instance did the Banff schema reduce the grade. Comparison between the Banff schema and diagnosis made at the time of biopsy showed agreement in 39 specimens, whereas the Banff schema elevated the grade in 15 specimens and reduced the grade in 23 specimens. In comparison to the Birmingham system, the Banff schema elevated the grade of liver allograft rejection in the majority of biopsy specimens, and this has the potential to alter clinical management with the adoption of the Banff schema or if the systems are used interchangeably.     

两种血流动力学管理策略术后早期对肝移植受者的影响

目的 探讨采用Swan-Ganz导管与中心静脉导管监测血流动力学参数指导治疗对肝移植患者术后早期的影响.方法 107例肝移植受者中102例入选,随机数字表法分为肺动脉导管(PAC)组(52例),中心静脉导管(CVC)组(50例).两组均监测中心静脉压、平均肺动脉压、心率、平均动脉压、肺动脉嵌顿压、心输出量和氧输送量等,按既定血流动力学管理方案用血管活性药物或持续静脉-静脉血液滤过治疗控制各项指标在目标范围内.结果 两组患者的基本资料的差异无统计学意义.PAC组住重症监护病房期间死亡率为7.7%,CVC组为4.0%.PAC组术后28 d死亡率为11.5%,CVC组为8.0%.PAC组ICU住院时间中位数为2.5 d,CVC组为2 d.PAC组机械通气时间中位数为26.5 h,CVC组为24 h.以上各项指标的差异均无统计学意义(P＞0.05).两组术前及术后第1、5天肾功能和肝功能以及术后第1、2、3天血乳酸的差异均无统计学意义(P＞0.05).PAC组发生-过性室性心律失常共26例;CVC组发生2例.结论 肝移植术后采用Swan-Ganz导管监测血流动力参数指导治疗并不优于采用中心静脉导管监测中心静脉压的方法,反而增加-过性室性心律失常的发生率.     

Significance of biochemical markers in early detection of canine lung allograft rejection

To evaluate the significance of bronchoalveolar lavage fluid, levels of tumor necrosis factor-alpha (TNF), gamma-interferon, interleukin 2, and soluble IL-2 receptor in early detection of canine lung allograft rejection, bronchoalveolar lavages were performed serially in mongrel dogs before and after single lung transplantation. The dogs were divided into three groups. Group 1 (control group) consisted of one in which neither donor nor recipient dogs were treated with cyclosporine. In group 2 (CsA-pretreated group) only donors were treated with CsA orally at a single dose of 20 mg/kg/day for 3 days prior to single lung transplantation. In group 3 only recipients were treated with CsA orally at a single dose of 20 mg/kg/day for a short period of 9 days after single-lung transplantation. Marked elevation was found of TNF, IFN-gamma, IL-2, and IL-2R in BALF obtained from the grafted lungs in group 1 and group 2 dogs. The levels of these markers were significantly higher than those obtained from the normal, native lungs (P less than 0.05). Two of three recipients in group 2 had pneumonia in the native lungs on day 10 after single-lung transplantation. All markers except IFN-gamma in BALF obtained from the infected native lungs were also increased, but the titers were less than those obtained from the grafted lungs at the same time. There were significantly higher levels of TNF, IL-2, and IL-2R present in the BALF of grafted lungs of dogs in group 1 than group 2 (P less than 0.05). In group 3, BALF levels of these markers from the grafted lungs were not significantly different from those of the normal and native lungs during the period of CsA treatment after single-lung transplantation. On various days after discontinuation of CsA treatment, BALF levels of all markers began to rise. Abnormal levels of BALF markers obtained from the grafted lungs heralded the appearance of abnormalities detected by chest x-ray films. Our study suggests that serially measuring BALF levels of TNF, IFN-gamma, IL-2, and IL-2R may serve as a useful means in monitoring the immunologic status of canine lung allografts and in the early detection of lung allograft rejection. The role of BALF IFN-gamma in distinguishing lung allograft rejection from pulmonary infection needs further studies.     

Pseudorejection: factors mimicking rejection in renal allograft recipients.

Serum creatinine level is used as a major measure of post-transplant renal function at most centers. A significant elevation of creatinine level suggests allograft rejection. However, other factors affect renal function in the transplant recipient and each may cause an elevation in serum creatinine level, suggesting a rejection episode. It is important to make the correct diagnosis and not treat these episodes with anti-rejection therapy. We reviewed the course of patients transplanted between 1969 and 1974 to determine the pathogenesis of creatinine elevations retrospectively found to be due to causes other than rejection. Six distinct causes were found: hyperglycemia, ureteral obstruction, infection, lymphocele, arterial stenosis, and recurrence of the original disease. Each of these is discussed individually. In order to make the diagnosis of pseudorejection, a high index of suspicion is necessary.     

Combined use of myeloid-related protein 8/14 and procalcitonin as diagnostic markers for acute allograft rejection in kidney transplantation recipients

The myeloid-related proteins 8 and 14 exist as a dimeric complex (MRP 8/14) and serve as early and highly specific markers for inflammatory processes, such as allograft rejection and non-viral (bacterial or fungal) infections. An elevated procalcitonin (PCT) concentration in serum also serves as a diagnostic indicator of non-viral infection. Therefore, by measuring both MRP 8/14 and PCT serum concentrations, one may be able to distinguish between acute allograft rejection and non-viral infections in non-rejection transplant recipients. Here, we investigated whether MRP 8/14 and PCT can function as prognostic (Study I) or diagnostic (Study II) markers for allograft rejection in renal transplant recipients. In Study I, the serum concentrations of MRP 8/14 and PCT during the first 2 weeks after transplantation did not differ between patients who did and did not suffer organ rejection within 1 year post-transplantation; these findings suggest that the MRP 8/14 and PCT parameters are not valid prognostic markers. However, in Study II, patients with acute rejection or non-rejection/non-viral infection groups displayed a significant increase in serum MRP 8/14 concentration, and non-rejection patients with non-viral infections only had elevation in the PCT serum concentrations. These results indicate that the combined use of MRP 8/14 and PCT serum concentrations can allow one to distinguish between allograft rejection and other inflammatory processes, such as infection.     

Characteristics of cadaveric renal allograft recipients developing chronic rejection.

As the early results of renal transplantation improve, chronic rejection is increasing in relative importance as a cause of graft loss. The aetiology of the condition is unknown. In order to identify possible predisposing factors, the characteristics of 22 patients with chronic rejection were compared with those of 50 patients with stable graft function 2 years or more after transplantation. Patients with chronic rejection had significantly more acute rejection episodes in the first 6 months after transplant (P less than 0.01), a higher incidence of acute rejection with vascular features (P less than 0.01), and longer ischaemic times (P less than 0.05) compared to patients with stable graft function. In a logistic regression analysis both frequency and severity of acute rejection episodes were significantly associated with the subsequent development of chronic rejection. Thus chronic rejection is associated with early injury to the transplanted kidney.     

Day-5 protocol liver allograft biopsies document early rejection episodes and are predictive of recurrent rejection.

METHODS. The day-5 posttransplant protocol biopsy specimens and clinical courses of 27 consecutive orthotopic liver transplant recipients followed up at least 6 months were reviewed. RESULTS. Twelve (44%) of 27 patients had histologic evidence of rejection on the day-5 biopsy; 8 (67%) of these 12 patients required OKT3 for reversal of the rejection. No significant differences in biochemical liver test results, bile output, or cyclosporine levels were observed between this group and the 15 patients (56%) without histologic evidence of rejection on day 5. Eight (67%) of the 12 patients with rejection had recurrent rejection episodes, with one recurrence each in six patients, two recurrences in one patient, and three recurrences in one patient. Of the 15 patients without rejection on day 5, nine (60%) subsequently had rejection at 10 days, 14 days, and 1 1/2, 3 1/2, 4, 5, and 11 months after transplantation. Only one (11%) of these nine patients had a recurrent rejection episode. There were no differences in the incidence of posttransplant cytomegalovirus infections between the two groups. Two cases of posttransplant lymphoma were seen; they developed in two patients without rejection on the day-5 biopsy. No patients or allografts were lost to acute or chronic rejection. No complications occurred as a result of the day-5 protocol biopsy. CONCLUSION. The day-5 protocol biopsy is useful in detecting rejection episodes that may not otherwise be clinically apparent.     

Cytokine gene polymorphism and early graft rejection in liver transplant recipients

Cytokines, which play important roles in allograft rejection, show variable production among individuals. These variations may be related to genetic polymorphisms within the regulatory regions of the cytokine genes. We investigated the association between the role tumor necrosis factor alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interferon gamma (IFN-gamma), interleukin (IL)-10 and IL-6 gene polymorphisms and early graft rejection among liver transplant recipients. Forty-three liver transplant recipients enrolled in this study were divided into 2 groups based on events in the first 2 months posttransplantations, namely, those experiencing at least 1 rejection episode (n = 26) or those without any episode (n = 17). The allele or genotype frequencies of cytokine gene polymorphisms showed no difference between liver recipients with or without nonrejection. In conclusion, there was no significant correlation between early graft rejection and cytokine gene polymorphism of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma in liver transplant recipients.