Chronic graft rejection represents the single most important risk factor for unsatisfactory long-term results after organ transplantation. In addition to various alloantigen dependent and independent factors, acute rejection episodes have been cited as a major immunological risk factor. However, the effects of acute rejection episodes on long-term graft outcome remains unknown. To examine the influence of a single early rejection event on ultimate graft outcome, acutely rejecting rat kidney grafts were retransplanted sequentially into syngeneic rats and their functional and structural behavior assessed over time. LEWxBNF1 kidney allografts and LEW isografts were removed from their LEW recipients after three, four, five and seven days (N = 12/group/time period) and retransplanted into donor strain hosts. The grafts were followed functionally and harvested four, eight, and 32 weeks later. Urinary protein excretion was measured weekly. Kidneys were examined morphologically and immunohistologically using monoclonal antibodies (mAbs) against macrophages (ED-1), T cells and their subsets (CD5, CD4, CD8), MHC class II expression (OX3) and adhesion molecules (ICAM-1 and LFA-1alpha). The mean standard time +/- SD of non-retransplanted allografts was 14.5 +/- two days; isografts functioned indefinitely. At five and seven days, acutely rejecting allografts showed massive cellular infiltrates associated with extensive necrosis. These changes could not be reversed by retransplantation and the syngeneic recipients later died of renal failure. In contrast, most allografts retransplanted earlier in the process recovered completely when retransplanted after three (12 of 12 allografts) and four (7 of 12 allografts) days. During the subsequent follow-up period, urinary protein excretion was comparable in retransplanted allografts and isografts. The increased mononuclear cell infiltration in non-retransplanted allografts seen at three and four days was only occasionally observed during the follow-up period after retransplantation. Only a few sclerosed glomeruli (approximately 15%), mild arterial changes and minimal cellular infiltrates were observed by 32 weeks, which were similar to that seen in retransplanted isografts. A single acute rejection episode was completely reversible and did not progress to chronic rejection if retransplanted into syngeneic donors when the inflammatory changes are still early. Those results demonstrate the critical effect of alloantigen-dependent events on chronic graft deterioration, and indicate that prompt and aggressive treatment of initial acute rejection episodes are beneficial to protect against late deleterious changes in the graft.

Animals↗

PubMed1998

[The diagnosis and imaging of the a. hepatica after orthoptic liver transplantation--a comparison of frequency-modulated and amplitude-modulated color Doppler sonography].

PURPOSE: We examined whether amplitude-modulated color Doppler (power Doppler) sonography provides a better anatomic imaging of the vascular course of the hepatic artery after liver transplantation. PATIENTS AND METHODS: 82 patients were examined with Doppler sonography after liver transplantation. The distal section of the hepatic artery was imaged both with frequency-modulated color Doppler (color Doppler) and power Doppler and a Doppler spectrum derived from each mode for determination of the flow velocity. RESULTS: Native imaging of the hepatic artery was possible in 78/82 patients, in 2/82 patients only after administration of Levovist, and in 2/82 patients it could not be seen. In these two patients the diagnosis of hepatic artery occlusion was confirmed by angiography. The anatomic course was demonstrated more longitudinally by power Doppler than by color Doppler (p < 0.001; chi 2 test) which made the angle correction easier. A disadvantage of power Doppler was the lack of image contrast to the portal veins; thus evaluation of the vascular course in this section was better possible with color Doppler by means of a specifically generated aliasing in the flow of the hepatic artery (p < 0.001; chi 2 test). Determination of the flow velocity showed no significant differences between color and power Doppler supported duplex sonography. CONCLUSIONS: The combined use of color Doppler and power Doppler improves visualization of the hepatic artery after liver transplantation. The lack of visualization of the vessel after administration of Levovist is diagnostic for occlusion of the vessel.

Adult↗

PubMed1998

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.

Adult↗

PubMed1998

Biphasic spiral computed tomography versus digital subtraction angiography for evaluation of arterial thrombosis after orthotopic liver transplantation.

RATIONALE AND OBJECTIVES: The authors characterize the spiral computed tomographic (CT) findings in patients with hepatic arterial thrombosis after orthotopic liver transplantation (OLT). METHODS: In nine with and 15 patients without hepatic artery thrombosis (HAT) after OLT, unenhanced and contrast-enhanced biphasic spiral CT was performed during arterial and venous phases, and evaluated by consensus of two blinded readers. Evaluation included signs of parenchymal and vascular changes in the liver. Findings subsequently were correlated with those of digital subtraction angiography (DSA). RESULTS: Among all patients, eight had complete occlusion of the proximal hepatic artery and one patient had partial thrombosis, as revealed by conventional DSA. Characteristic CT findings of HAT included irregularly shaped confluent hypoattenuating liver areas (n = 8), seen both before and after administration of contrast material. Necrotic lesions and changes consistent with ischemic type of biliary lesion were documented in six patients. Biphasic CT allowed detection of HAT in eight patients. Because of inadequate contrast enhancement during the arterial phase, thrombosed intrahepatic arteries were not adequately diagnosed in one patient. Overall CT sensitivity to detect HAT was 89%, specificity was 100%. CONCLUSIONS: Characteristic biphasic spiral CT findings in hepatic artery thrombosis contribute to early detection of arterial thrombosis after OLT and are helpful for planning more invasive diagnostic approaches.

Adolescent↗

PubMed1998

Biphasic spiral computed tomography for detection of hepatocellular carcinoma before resection or orthotopic liver transplantation.

RATIONALE AND OBJECTIVES: The authors correlate computed tomography (CT) findings in biphasic spiral technique with histopathology in patients with hepatocellular carcinoma (HCC) who had undergone liver resection (LR) or orthotopic liver transplantation (OLT). METHODS: Preoperative biphasic spiral CT findings in 33 consecutive patients (23 men, 10 women, aged 43-74 years; LR group: n = 17; OLT group; n = 16) with liver cirrhosis and HCC were reviewed retrospectively by consensus of two radiologists and correlated with pathology from liver specimens. RESULTS: Of the 16 patients in the OLT group with 1 to 5 confirmed HCC lesions (total lesions: 29; mean lesion diameter: 2 cm; range: 0.6-5.0 cm), CT before OLT depicted 22 lesions in 15 patients (sensitivity for lesions with a diameter of 0.5-1.0 cm, 20%; for lesions 1.1-2.0 cm, 82%; and for lesions 2.1-3.0 cm and > 3.0 cm, 86% and 100%, respectively). Among the 17 patients in the LR group (total lesions: 21; mean lesion diameter: 5.4 cm; range: 1.0-11.0 cm), CT detected 18 lesions. Lesion-by-lesion sensitivity, as correlated with pathology, was calculated at 76% and 86% in the OLT and LR groups, respectively (overall sensitivity, 80%). The diameter of CT detected lesions, compared with liver specimens, corresponded in 90% of lesions (maximum deviation, 15%). Characteristic CT findings of HCC included unenhanced hypoattenuating focal liver lesions (32 lesions), with hyperattenuation (38 lesions) in the arterial phase of contrast material administration. CONCLUSIONS: Biphasic spiral CT for preoperative HCC detection correlated with pathology in 80%, thus proving this technique to represent a sensitive imaging modality for pretherapeutic evaluation of HCC.

Adult↗

PubMed1998

[Effect of donor/recipient HLA-B match on transplant survival in patients with liver transplants with HBV cirrhosis].

We retrospectively analysed 87 recipients of orthotopic liver transplants with HBV cirrhosis for the impact of HLA-B matching on postoperative outcome. Our data demonstrate a significantly increased graft survival for patients with 1 or 2 HLA-B matches (p < 0.02).

Adult↗

PubMed1998

Orthotopic liver transplantation for hepatic associated metabolic disorders.

Hepatic associated metabolic disorders represent 5% of the indications for orthotopic liver transplantation (OLTX) according to the European Liver Transplant Registry. We studied the outcome of this group at our institution after OLTX and combined liver/kidney transplantation. Between September 1988 and January 1997, 837 OLTXs were performed in 735 patients. Patient survival and graft function at 1 yr were 91.3 and 86%, respectively. Thirty-nine OLTXs were performed in 38 patients (15 female/23 male, median age +/- SD: 35 +/- 14 yr, range 4-60 yr) due to liver associated metabolic disorders (4.7%). Indications included Wilson's disease (n = 14), alpha-1-anti-trypsin-deficiency (n = 7), hemochromatosis (n = 4), erythropoetic protoporphyria (n = 4), cystic fibrosis (n = 2), Crigler-Najjar syndrome type I (n = 1), glycogenosis type I (n = 1), ornithine-transcarbomylase-deficiency (n = 1). In addition 4 patients suffering from primary hyperoxaluria type I received combined liver/kidney grafts. Survival rate the 1 yr after OLTX and combined OLTX/NTX was 91.8%. Twenty patients received cyclosporin A (55%) and 17 patients tacrolimus (45%) as primary immunosuppression. The mean follow-up was 28.6 months (range 4-73 months). Two patients with hemochromatosis died 1 and 3 months after OLTX, respectively, from Aspergillus sepsis followed by multiorgan-failure. One patient died of malignant lymphoma 5 months after transplantation. One patient required retransplantation 2 months after OLTX following arterial thrombosis and ischemic type biliary lesion. One year after OLTX, all patients demonstrated good graft function, liver grafts (ALT 17.9 +/- 13.6 IU/L, bilirubin 0.8 +/- 0.3.mg/dl, thromboplastin time 94 +/- 15%), and combined liver/kidney grafts (creatinine 2.4 +/- 1.4 mg/dl). OLTX, respectively combined OLTX/NTX, represent a successful therapy for hepatic associated metabolic disorders. Survival rates and graft function are similar to those in liver graft recipients for established indications at our institution. OLTX seems to be an excellent treatment for hepatic based therapy resistant neurological disorders.

Adolescent↗

PubMed1998

A liver with polycystic liver disease as graft for orthotopic liver transplantation.

Donor organ shortage calls for widening of criteria for organ transplantation. In exceptional cases, even livers with macroscopic alterations may be accepted for transplantation. The case of a patient who received a liver graft from a donor with previously unknown adult polycystic degeneration is reported. The liver showed only small bilobar cysts with less than 10% of hepatic replacement and was successfully used for orthotopic liver transplantation. Two years after transplantation the patient is in good clinical condition and has returned to work.

Cysts↗

PubMed1998

A randomized, placebo-controlled trial with anti-interleukin-2 receptor antibody for immunosuppressive induction therapy after liver transplantation.

The introduction of quadruple induction therapy after liver transplantation with the murine anti-interleukin-2 receptor (IL-2R) antibody (BT563) has decreased the incidence of serious side effects, such as tachycardia, hypertension, rash, fever and nausea since it does not lyse its target cell. To investigate the immunosuppressive efficacy of BT563, a placebo-controlled trial was performed and BT563 was added to the standard triple induction after liver transplantation. Forty consecutive recipients of primary orthotopic liver transplants (OLT) (median age 47 yr [range 18-65]) were randomized. All patients received triple immunosuppression with cyclosporine A (CyA), prednisolone (PRED) and azathioprine (AZA). In addition, 19 patients received BT563 (Biotest, Dreieich, Germany) at a dose of 10 mg/d from day 0 until day 12. The remaining 21 patients received a placebo infusion at the same days after transplantation. Minimal follow-up for all patients was 3 yr. Patient survival at 3 yr was 74% in the BT563 group and 90% in placebo group. Similar results were observed for graft survival. Two acute rejection episodes were detected in the BT563 group and 9 acute rejections (5 steroid-resistant) were observed in the placebo group (p < 0.034). The incidences of sepsis, pneumonia, cholangitis, urinary tract infections as well as cytomegalo-virus (CMV) infections were similar in both groups. Side effects of the BT563 therapy and/or post-transplant lymphoproliferative disease (PTLD) were not detected. Quadruple induction therapy with BT563 significantly reduces the incidence of rejection episodes after liver transplantation, while infectious complications and/or PTLD is not increased. Therefore, the anti-IL2 receptor antibody BT563 constitutes a safe and efficient addition to the immunosuppressive induction regimen following OLT.

Acute Disease↗

PubMed1998

Pregnancies following liver transplantation--how safe are they? A report of 19 cases under cyclosporine A and tacrolimus.

The number of pregnancies following liver transplantation is increasing due to better patient and graft survival and quality of life. Out of 156 women of a reproductive age, there were 19 pregnancies in 16 women, 12 on CsA and seven on tacrolimus, which occurred between 7/92 and 1/97. The median age of the women was 27.9 yr, median time after transplantation 33 months. There were four spontaneous and two induced abortions in the first trimenon. Ten women delivered ten healthy babies; three newborns had problems (alcoholic embryopathy due to recurrent alcohol abuse of his mother, pneumonia, weight < 2000 g). In eight women mostly mild complications were observed, such as hypertension (n = 5), nonspecific elevation of liver enzymes (n = 2), infection (n = 3) and premature labor (n = 1). Mean gestational age was 39 wk and mean birth weight 2900 g. One case of prematurity and three cases of growth retardation occurred. Cesarean sections were performed in 7 patients (54%) for maternal hypertension (n = 2), presumed fetal hypoxia (n = 4) and breech position (n = 1). All children are normally developed, the oldest being 5 yr old. Although experience with tacrolimus is limited, pregnancies following liver transplantation carry an acceptable risk if carefully monitored by an experienced team of transplant surgeons and obstetricians.

Adult↗