Rescue of a living donor with liver transplantation.

Postoperative liver failure is a rare complication after living donor liver resection. This is a case report of a 22-year-old healthy donor who was rescued with liver transplantation 11 days after right hemihepatectomy. Nine months later the patient is alive, and has fully recovered from his multiple organ failure. According to a review of the literature, there are four additional living liver donors, who received a liver transplant. Our own patient is the only survivor, so far. This case demonstrates that even in supposedly healthy living donors postoperative complications cannot be completely prevented. Although liver failure is rare in these patients, timely transplantation may need to be considered as the only life-saving treatment.

Hepatic artery-portal vein fistula formation after percutaneous liver biopsy in a living liver donor.

Percutaneous liver biopsy is a relatively safe method of assessing liver histology in living subjects. The current report depicts a case of arterioportal fistula in a living liver donor who underwent percutaneous liver biopsy as part of the routine transplant workup at our institution. The experience questions the utility of routine percutaneous liver biopsies as part of the living liver donor screening.

Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.

PURPOSE: Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS: The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS: Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION: In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study.

At the time of surgery, occult metastases (micrometastases) are present in more than 50% of colorectal cancer patients, and the liver is the most frequent site of apparent metastatic disease. Frequently, adjuvant chemotherapy is unable to prevent tumor recurrence. Thus, novel therapeutic strategies are warranted. The aim of this study was to establish a model of human colon cancer metastatic to the liver of nude mice, to assess, in this setting, the therapeutic efficacy of radioimmunotherapy (RAIT) compared to standard chemotherapy and to evaluate, in a Phase I/II trial, the toxicity and therapeutic efficacy of RAIT in colorectal cancer patients with small volume disease metastatic to the liver. Multiple liver metastases of the human colon cancer cell line GW-39 were induced by intrasplenic injection of a 10% tumor cell suspension. Whereas controls were left untreated, therapy was initiated on day 10 or 20 after tumor inoculation with the 131I-labeled, low affinity anticarcinoembryonic antigen (anti-CEA) monoclonal antibody (MAb), F023C5 (Ka = 10(7) liters/mol), or the high-affinity anti-CEA MAb, MN-14 (Ka = 10(9) liters/mol), or chemotherapy (5-fluorouracil/leucovorin (folinic acid) versus irinotecan) at their respective maximum tolerated doses (MTDs). Twelve colorectal cancer patients with small volume disease metastatic to the liver (all lesions < or = 2.5 cm) were entered into a mCi/m2-based Phase I dose escalation study with 131I-labeled humanized version of MN-14, hMN-14. The patients were given single injections, starting at 50 mCi/m2 and escalating in 10-mCi/m2 increments. The MTD was defined as the dose level at which < or = 1 of 6 patients develop grade 4 myelotoxicity. In the mice, untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation. The life span of mice treated with 5-fluorouracil/leucovorin was prolonged for only 1-3 weeks, whereas irinotecan led to a 5-8-week prolongation. In contrast, at their respective MTDs, the 131I-labeled low-affinity anti-CEA MAb, F023C5, led to a 20% permanent cure rate, and the high affinity MAb, MN-14, led to an 80% permanent cure rate, when therapy was initiated at 10 days after tumor inoculation. In the 20-day-old tumor stage, although it prolonged life, 131I-F023C5 was unable to achieve cures, whereas 131I-MN-14 was still successful in 20%. Histologically, no remaining viable tumor cells could be demonstrated in these animals surviving > 6 months. In patients, the MTD was reached at 60 mCi/m2 of hMN-14 (at 70 mCi/m2, two of three grade 4 myelotoxicities). Of 11 assessable patients, 2 had partial remissions (corresponding to an objective response rate of 18%), and 5 (45%) had minor/mixed responses or experienced stabilization of previously rapidly progressing disease. These data suggest that in small volume disease, RAIT may be superior to conventional chemotherapy. Antibodies of higher affinity seem to be clearly superior. The clinical response rates in patients with small volume disease are encouraging, being comparable to the response rates of conventional chemotherapeutic regimens but with fewer side effects. Ongoing studies will show whether treatment at the MTD will further improve therapeutic results.

What is the best immunosuppression in living donor liver transplantation?

INTRODUCTION: As we have learned, there are no golden rules of immunosuppression in solid organ transplantation, and every transplant program is using its own regimen to prevent or treat rejection. We have retrospectively analyzed the incidence and severity of acute rejection in a consecutive series of living donor liver transplants. The major objective during the whole study period was to ultimately avoid any steroids from the beginning. METHODS: Twenty one adult patients and five children received 23 right, one left, and two left lateral lobe grafts from genetically or emotionally related living donors, including four ABO-incompatible pairs. The majority of patients had triple initial immunosuppression, based on tacrolimus, mycophenolate mofetil or sirolimus, and basiliximab or daclizumab. Except methylprednisolone administered before reperfusion in 13 patients, only seven had prednisolone after transplantation, and 12/26 had a completely steroid-free regimen. RESULTS: The overall incidence of biopsy-proven acute rejection was 4/21 in adults (19%) and 4/5 in children (80%). Rejections were mild in five and moderate in three cases, respectively, and easily reversed with steroids in all patients. Different combinations of immunosuppressive drugs or ABO incompatibility did not seem to have an influence on the risk of rejection. CONCLUSION: Despite the small number of patients in this series, completely steroid-free triple-drug immunosuppression with tacrolimus, mycophenolate mofetil, and basiliximab is safe and efficient to prevent acute rejection in adult recipients of living donor liver transplants. At least short-term administration of prednisolone should be considered in pediatric patients.

Safety and efficacy of living donor liver preservation with HTK solution.

BACKGROUND: In living donor liver transplantation (LDLTx) organ procurement is usually well controlled, and allows to assess liver preservation and graft function under standardized conditions. Because publications on histidine-tryptophan-ketoglutarate (HTK) solution are limited, we prospectively studied its safety and efficacy in a consecutive series of LDLTx. METHODS: Twenty-four patients received 22 right, 1 left, and 1 left lateral lobe graft. Liver preservation was done by gravity perfusion with HTK through portal vein, and hepatic artery, and flushing of bile ducts. Total ischemia time was 191 +/- 68 minutes. RESULTS: There was no primary nonfunction, and all partial liver grafts showed good recovery: peak aspartate aminotransferase 577 U/L, total bilirubin 15.15 mg/dL, and partial thromboplastin time 49.37 seconds. One graft was lost from parenchymal fracture secondary to portal hyperperfusion after 6 days, and the patient was salvaged with retransplantation. Thirty-day mortality, including sudden cardiac death, pancreatitis, and hepatic artery rupture, was not related to graft dysfunction. Eight of 24 recipients developed early biliary leakage. There was no late ischemic type biliary lesion. CONCLUSION: These results confirm that HTK solution is safe and effective when used in LDLTx. Potential advantages of HTK in comparison to other preservation solutions are low potassium concentration, low viscosity, no particles, in situ perfusion, no need to flush before reperfusion, improved biliary protection, better recovery of microcirculatory changes, ready to use, and lower costs. Because the risk-benefit ratio is of particular importance in LDLTx the use of HTK solution should be encouraged.

Effects of cyclosporine on human dendritic cell subsets.

Cyclosporine is widely used as an immunosuppressive agent after solid organ transplantation. Limited data are available on the modulation of human dendritic cells by cyclosporine. We investigated the effects of cyclosporine on the phenotype and function of human dendritic cell (DC) subsets. DCs were isolated from peripheral blood using magnetic bead-conjugated antibodies. Cyclosporine did not alter the ability of myeloid and plasmacytoid dendritic cells to take up antigens. Expression of the co-stimulatory molecule CD80 but not CD86 increased on both DC subsets when stimulated with cyclosporine. The ability of cyclosporine treated myeloid DCs to stimulate proliferation of allogenic PBMC was significantly reduced. Similarly, stimulation of memory CD8+ T cells by dendritic cells was impaired by cyclosporine pretreatment. In conclusion, cyclosporine differentially alters function and phenotype of myeloid dendritic cells leading to a partially impaired capacity to stimulate allogenic and autologous T cells.

Prostaglandin E plus famciclovir--a new concept for the treatment of severe hepatitis B after liver transplantation.

New concepts for the treatment of hepatitis B in immunocompromised patients are urgently needed. We describe our first experience with the new antiviral agent famciclovir in combination with a short course of prostaglandin E in a patient with severe hepatitis B after liver transplantation. Initial treatment with prostaglandin E reduced the inflammatory activity, as measured by transaminase activities, but did not affect viral replication. Consecutive long-term treatment with famciclovir further normalized liver function and profoundly suppressed viral replication. HBeAg and HBV-DNA -PCR all became negative and only HBsAg persisted. Histology documented marked reduction of cellular infiltration. The patient completely recovered and is back to regular work as a teacher.

Differentiation of liver graft dysfunction by transplant aspiration cytology.

Episodes of graft dysfunction are frequently observed after liver transplantation and can be due to different causes requiring specific therapy. In this study the usefulness and reliability of liver transplant aspiration cytology (TAC) for differential diagnosis of liver graft dysfunction is assessed. Out of more than 1500 TACs performed, 292 TACs, taken during episodes of liver dysfunction due to retrospectively defined causes, were analyzed. Immune activation and parenchymal damage in the aspirates were determined cytologically. In 63 episodes of acute rejection, marked immune activation was present in aspirate but not in blood, with varying degrees of hepatocyte damage and cholestasis. No or only minimal immune activation was observed in 86 cases of toxic, ischemic, or septic liver damage, but considerable parenchymal damage and cholestasis were observed. In 3 cases of hepatitis slight-to-moderate immune activation with large granular lymphocytes was found in the aspirate, while 17 cases of viral infection presented with slight-to-moderate immune activation in aspirate and blood. After successful treatment the cytologic patterns normalized, except when the cause of liver dysfunction persisted. Moreover, typical patterns of parenchymal changes were found for preservation damage of the liver (n = 108), fatty degeneration (n = 3), obstructive cholestasis (n = 5), and acute arterial ischemia (n = 2). One case of moderate subcapsular hematoma was the only complication observed (less than 0.1%). Thus, liver TAC is an easy, safe, and clinically useful method for differential diagnosis of liver graft dysfunction. In particular, differentiation between acute rejection and nonimmunologic causes of dysfunction is very reliable, but hepatitis and viral infections also present distinctive patterns in liver TAC.

Adenine nucleotide metabolism and its relation to organ viability in human liver transplantation.

The relationship between adenine nucleotide metabolism and ischemic damage was studied in human liver. Thirty transplanted grafts were divided into two groups according to their functional outcome. Cellular adenine nucleotide levels were assayed by high-performance liquid chromatography. During cold ischemia, the adenosine triphosphate (ATP) level was not correlated with graft function, but two grafts with low total adenine nucleotides (TAN) levels showed poor function after transplantation. After recirculation, the ATP level showed good recovery in grafts that functioned satisfactorily (n = 24, 5.47 +/- 1.51 mumol/g dry weight), but remained low in poorly functioning grafts (n = 6, 3.30 +/- 1.68 mumol/g dry weight) (P less than 0.01). The level of recovery of ATP was inversely related to the period of warm ischemia during implantation (P less than 0.01). Bile production, used as a parameter of initial function, was observed shortly after implantation in 17 of 24 grafts that functioned satisfactorily, but in only 1 of 6 poorly functioning grafts. It is concluded that loss of adenine nucleotides and lack of bile production during transplantation are good markers of damaged grafts in human liver transplantation.

Intragraft immune events after human liver transplantation. Correlation with clinical signs of acute rejection and influence of immunosuppression.

Evaluation of graft morphology is regarded as a cornerstone for diagnosis of acute liver graft rejection. Here we have studied the clinical relevance of biopsy findings obtained either by aspiration cytology or by histology in the first month after human liver transplantation, and have assessed the influence of immunosuppressive induction treatment on the incidence of morphological and clinical rejection. Results of 865 aspiration biopsies (TAC) and 155 core biopsies in 141 patients were correlated with the retrospective clinical diagnosis concerning the presence or absence of acute rejection. This analysis demonstrated that there are almost no false negative findings either in cytology or in histology (less than 0.1% of negative biopsies). In contrast, with both methods a large number of positive biopsy results were obtained that were without clinical correlate ("false positive" biopsies; 46% and 41% of positive cytologies and histologies, respectively). The rates of clinical and morphological acute rejections were differently influenced by the type of immunosuppressive induction protocol used. The incidence of clinical rejection was particularly low with a quadruple drug regimen when cyclosporine therapy was started immediately after transplantation (29% vs. 62% when introduction of cyclosporine was delayed for 2-5 days). Morphological rejections were similarly frequent with immediate and delayed introduction of cyclosporine at 2 mg/kg during quadruple therapy (65-75%) and were only reduced with initial high dose cyclosporine treatment (5 mg/kg) (35%). Antirejection treatment was not required in patients with morphological evidence of rejection but without clinical symptoms. The study demonstrates that cytology and histology are similarly reliable for exclusion and similarly unreliable for diagnosis of clinical acute rejection. The clinical relevance of positive biopsy findings is strongly influenced by the basic immunosuppressive treatment. Certain types of induction treatment can obviously alter the alloresponse in a way that no graft damage occurs despite the presence of marked intragraft immune activation. "False-positive" biopsy findings, therefore, seem to represent a qualitatively modified and self-limited type of intragraft alloresponse that is without clinical consequences ("incomplete" or "subclinical" rejection).

A novel management strategy of steroid-free immunosuppression after liver transplantation: efficacy and safety of tacrolimus and mycophenolate mofetil.

BACKGROUND: Corticosteroids have been used traditionally for immunosuppression after solid organ transplantation. The variety of modern immunosuppressive agents offers the chance to replace drugs with an unfavorable risk-benefit ratio. The objective of this prospective pilot study was to investigate a novel steroid-free immunosuppressive regimen after clinical liver transplantation. METHODS: 30 adult liver graft recipients were included in an intent-to-treat analysis. Dual induction immunosuppression consisted of tacrolimus and mycophenolate mofetil. Prophylactic steroids were not given. Efficacy and safety parameters analyzed were patient and graft survival, incidence and severity of rejection, and adverse events in correlation to immunosuppressive drug levels. RESULTS: Patient and graft survival at 2 years was 86.7 and 83.9%, respectively. Acute rejection occurred in 26.2%, and was associated with subtherapeutic tacrolimus blood levels and diarrhea. All rejections were completely reversible by temporary addition of steroids. Acute renal failure was seen in 10/30 patients, and was related to high tacrolimus blood levels together with primary liver graft dysfunction. 43% of all patients never received any steroids, and 73% were on a steroid-free maintenance regimen. CONCLUSIONS: These results confirm that corticosteroids can be completely avoided from the beginning after liver transplantation. Double drug immunosuppression with tacrolimus and mycophenolate mofetil is effective and safe in terms of patient and graft survival as well as incidence and severity of rejection. In order to avoid under- or over-immunosuppression, which may be caused by impaired absorption or metabolism, close drug monitoring is advised.

Reduction of severe ischemia/reperfusion injury in rat kidney grafts by a soluble P-selectin glycoprotein ligand.

BACKGROUND: Inflammatory leukocyte-endothelium interactions, mediated by selectins, contribute to renal ischemia/reperfusion (I/R) injury. We examined the influence of the soluble P-selectin glycoprotein ligand 1 (sPSGL) on early I/R-induced changes in a rat kidney transplantation model with long cold ischemia. METHODS: After 24 hr of cold storage, syngeneic kidneys were grafted into bilaterally nephrectomized rats. Before transplantation, recipients received either 1 mg/kg of sPSGL or vehicle (n=8 per group). Six hours after reperfusion, grafts were removed for light microscopy and immunohistochemistry. Capillary blood flow was measured under a fluorescence microscope by using the concentric-circles method. RESULTS: A greater proportion, 74.7+/-7.2% (sPSGL) vs. 28+/-7.4% (controls), of all dye-labeled outer medullary capillaries appeared in the 12-microm radius (P<0.01), indicating dense blood flow, whereas 7.6+/-2.9% vs. 43.3+/-9.7%, respectively, appeared in the 60-microm radius (P<0.05), indicating rarefied blood flow. In the sPSGL-treated group, the extent of severe tubular damage within the inner stripe of the outer medulla was lower compared with controls (37.5+/-8.3% vs. 78.4+/-3.5%, P<0.01). Outer medullary heat shock protein 72 expression was 14.5+/-1.6% in the sPSGL-treated group compared with 9.6+/-1.4% in controls (P<0.05). The number of infiltrating polymorphonuclear leukocytes was similar in both groups. Treatment with sPSGL had no influence on the serum creatinine level. CONCLUSIONS: Our data suggest that impairment of outer medullary blood flow is crucial in I/R injury of kidney grafts with prolonged cold storage. Reduction of capillary blood flow perturbations by sPSGL protects tubular cells from severe structural damage. Blocking early selectin-mediated leukocyte adhesion may have therapeutic implications in improving the prognosis of renal transplants with severe I/R injury.

Different cellular patterns associated with hepatitis C virus reactivation, cytomegalovirus infection, and acute rejection in liver transplant patients monitored with transplant aspiration cytology.

Fine-needle aspiration biopsy (FNAB) is a routine diagnostic tool used for the monitoring of the graft during the first postoperative weeks after liver transplantation. The cellular pattern of acute liver rejection is typical in transplant aspiration cytology (TAC), documented and published by several authors. The lymphoid response associated with various viral infections may, however, provide differential diagnostic problems in the cytological monitoring. In this study, we have investigated in detail the cellular pattern of lymphoid response associated with hepatitis C virus (HCV) reactivation, and compared it with the pattern of cytomegalovirus (CMV) infection and with the typical diagnostic findings of acute cellular rejection. HCV reactivation was associated with rather mild total inflammation in the graft (4.5 +/- 1.5 CIU at the peak). The inflammatory infiltrate consisted mainly of small lymphocytes (3.1 +/- 0.2 CIU at the peak), with only occasional activated cells and without lymphoid blast response. No lymphoid activation was seen in the blood. CMV infection was associated with a mild immune response (3.9 +/- 0.4 CIU at the peak) recorded as a slight lymphoid activation and occasional blast cells both in blood and in the graft together with lymphocytosis in the graft (2.4 +/- 0.7 CIU at the peak). The typical findings of acute rejection were easily distinguished from the cellular pictures of both viral infections. The rejections were lymphoid blast (3.6 +/- 3.4 CIU at the peak) and activated lymphocyte (3.5 +/- 2.6 at the peak), dominated by a high peak of total inflammation (9.3 +/- 7.0 CIU). No blast cells and only a few activated cells were seen in the blood during rejection episodes. Thus, the cellular patterns of HCV reactivation and CMV infection differed slightly from each other, but significantly from that of acute liver allograft rejection monitored with the FNAB cytology.

Arterial ketone body ratio as a predictor of donor liver viability in human liver transplantation.

The viability of the donor liver was assessed with regard to early postoperative survival in human liver transplantations from 40 brain-dead donors at Hannover Medical College and 13 living donors at Kyoto University by measuring the arterial ketone body ratio (AKBR). Of 40 grafts harvested from brain-dead patients in Hannover, 35 survived the first week after operation, but 5 developed initial nonfunction of the transplanted graft within the first week. The mean AKBR values were 1.11 +/- 0.11 for grafts that survived and 0.44 +/- 0.10 for grafts that failed (P < 0.01). The AKBR values of the 5 initially nonfunctioning cases were all below 0.7. Of 13 grafts harvested from the living donors in Kyoto, all survived the first week. The AKBR values of the donors were all above 1.0, with a mean value of 1.87 +/- 0.23. Among all 53 cases, the survival rate of the grafts with AKBR above 0.7 was significantly higher than that of the grafts with AKBR below 0.7 (100% vs. 62%, P < 0.01). No other donor parameters, including age, dose of dopamine administered, and clinical laboratory findings, were significantly related to differences in graft survival rates. AKBR is a useful index for the evaluation of donor liver viability. Grafts used from donors with AKBR of less than 0.7 have a significantly increased risk of early nonfunction. Grafts from donors with AKBR of greater than 1.0 have, in our experience, always been viable after transplantation.

Backgrounds of early intragraft immune activation and rejection in liver transplant recipients. Impact of graft reperfusion quality.

In solid organ transplantation, acute rejections are most frequent during the first weeks. The aim of this study was to investigate the relationship between graft reperfusion injury and later immune responses against the graft. Intragraft immune activation was routinely monitored by transplant aspiration cytology in 47 recipients of hepatic allografts. As a parameter of reperfusion quality, oxygen saturation of hemoglobin (SO2) in hepatic tissue was determined intraoperatively by a near-infrared spectroscopy. Grafts that presented aspiration cytology scores of 2 or more (i.e., more than 10% of lymphocytes activated) at 1 week after operation (group I, n = 14) were associated with a higher heterogeneity of hepatic tissue SO2 at the end of operation (coefficient of variation in 12 points 18.3 +/- 18.3%, mean +/- SD) than grafts with no or very mild intragraft immune activation (group II, n = 33, 9.2 +/- 4.2%; P < 0.01). Group I was also accompanied by higher postoperative peak glutamic oxalacetic transaminase level (corrected by graft size, P < 0.05) and higher donor age (43.9 +/- 12.9 vs. 32.6 +/- 13.9 years, P < 0.02). Heterogenous reperfusion (P < 0.01), higher peak glutamic oxalacetic transaminase level (P < 0.01), and higher donor age (P < 0.05) were also associated with clinical rejection at 1 week (n = 10), but not with later-onset rejection (n = 11). These data suggest that intragraft immune activation and clinical rejection in the early phase after hepatic engraftment are strongly influenced by graft injury, which can be recognized early after reperfusion.

Persistence of donor lymphocytes in liver allograft recipients.

Occasional cases of graft-versus-host disease after liver transplantation indicate a transfer of donor lymphocytes by human liver grafts. However, little is known about the usual fate and potential function of passenger lymphocytes in clinical liver transplantation. In this study, we have analyzed liver graft recipients for the presence of donor lymphocytes in the early course after transplantation. The presence of such cells in blood, the graft, and, occasionally, the skin was studied by the use of mAb to polymorphic HLA class I determinants and double-staining techniques in flow cytometry and immunocytology. The findings were compared with the clinical courses and with the results of routine graft biopsies. Within the first week after transplantation, in all 16 patients, between 1% and 24% donor lymphocytes (T, NK, and B cells) were detectable in blood, and in 14 of 22 patients (64%), between 2% and 23% donor T cells were found in the graft. After more than 2 weeks, donor cells were still present in blood in 2 of 14 patients at very low numbers. The presence of donor lymphocytes in the graft was associated with intragraft immune activation in 5 of 15 patients, but no clinical rejection occurred in these cases; mild graft-versus-host disease was observed in one patient. These findings demonstrate that donor lymphocytes regularly persist in liver-grafted patients for some time; this transient mixed lymphoid chimerism is only rarely associated with clinical graft-versus-host disease and some evidence even suggests that these donor-derived lymphocytes may exert beneficial immunomodulatory properties.

A new oral formulation of cyclosporine for early oral immunosuppressive therapy in liver transplant recipients.

CsA-ME is a new oral microemulsion formulation of CsA. Studies in stable liver grafted patients with cholestasis and subsequent poor absorption of the conventional cyclosporine formulation showed a substantial increase in CsA absorption after conversion to CsA-ME. To investigate its use in patients during the early course after liver transplantation we recruited 50 liver transplant recipients in two centers. During the first study phase A CsA-ME was administered to 20 patients in incremental doses after a short initial course of intravenous cyclosporine. During the second study phase B (30 patients) CsA-ME was administered from the time of transplantation. One year actual patient and graft survival of patients included in phase A and B of the trial was between 90% and 93.3%; 50% and 60% of the patients enrolled in phase A and phase B of the trial were free from rejection at month 3, respectively. Chronic rejection was diagnosed in one patient. No increase in the incidence of CsA related side effects was observed. The optimum CsA-ME starting dose was found to be 10 mg/kgbw/day for patients without external biliary diversion and 15 mg/kgbw/day for patients with a T tube in situ. Using these starting doses, 26 consecutive patients with external bile diversion via T tube were treated with CsA-ME from the day of transplantation. Intravenous CsA was necessary only in three patients. When CsA-ME absorption in patients with stable liver function was compared with that in patients with early liver dysfunction, no difference in the pharmacokinetic profiles was observed between the groups. Our results indicate that CsA-ME therapy is effective and well tolerated in liver graft recipients, even in patients with external biliary diversion during the early posttransplant phase. Thus, CsA-ME is a useful alternative to intravenous CsA treatment in these patients.

Liver transplantation in children with chronic end stage liver disease: factors influencing survival after transplantation.

To identify pretransplant factors that are influencing survival after orthotopic liver transplantation a Cox proportional hazards regression model was applied to 118 children with chronic terminal liver failure transplanted at Medical School Hannover during the period of 1978 to 1994. The response variable was survival, as covariates a total of 19 pretransplant variables were entered--i.e. age, diagnosis (biliary cirrhosis, metabolic cirrhosis, postnecrotic cirrhosis, cryptogenetic cirrhosis) sex, laparotomy prior to OLT, height, weight, standard deviation scores for height and weight, date of first OLT, serum alanine aminotransferase, asparagine aminotransferase, albumin, total bilirubin, cholinesterase activity, glomerular filtration rate, and prothrombin time. Significant independent predictors of survival after OLT were bilirubin (P=0.0024), SDS for weight (P=0.034), and albumin (P=0.039). In a subsequent discriminant analysis cut off points for these variables could be identified--i.e., bilirubin >340 micromol/L, SDS for weight <-2.2 and albumin < 33 g/L. Patients with one or more of these risk factors were grouped as urgent indication group (n=76) and those with no risk factor as elective indication group (n=42). Comparing the posttransplantation survival in these groups there is a statistically significant difference at 1 year (57% vs. 90.5%) and 4 years (49% vs. 90.5%) after OLT (P=0.0001, log rank test). It is concluded that the risk of OLT is much higher if liver function is very poor. Optimal nutritional support prior to transplantation is mandatory to optimise the clinical status of the children and to improve the results of OLT.

Rescue hepatectomy for initial graft non-function after liver transplantation.

BACKGROUND: Early retransplantation is the therapy of choice in patients with initial graft nonfunction (INF). In rare cases the patients' conditions deteriorate dramatically with severe cardiovascular and/or pulmonary insufficiency while on the waiting list for retransplantation. In this life-threatening situation removal of the graft and temporary portocaval shunt before allocation of a new liver proved to be effective. Our experience with this two-stage hepatectomy and subsequent liver transplantation in patients with complicated INF is reported. METHODS: Hepatectomy was performed in 20 patients with INF associated with severe cardiovascular and pulmonary insufficiency while on the waiting list for emergency liver retransplantation. The mean age was 41.75+/-16.64 years. The time period between primary transplantation and hepatectomy was 2.80+/-2.84 days with a range from 1 to 9 days. RESULTS: Hepatectomy reduced the need for vasopressive agents and improved pulmonary function in the majority of patients. Four patients died before a liver was available due to brain death in one patient and multiorgan failure in three patients. In the remaining 16 patients liver transplantation could be performed after 19.82+/-15.34 hr (range 6.58 to 72.50 hr). Two of the 16 transplanted patients died on the first postoperative day due to multiorgan failure and pneumonia. The remaining 14 of 16 patients survived retransplantation, but 7 died between days 13 and 105 mostly due to sepsis. Seven patients were discharged from the hospital in good condition and show long-term survival. CONCLUSION: Hepatectomy was able to stabilize the cardiovascular and pulmonary function. This study confirms the beneficial effects of hepatectomy and subsequent liver transplantation as a life-saving procedure in patients with INF complicated by cardiovascular and/or pulmonary instability.