Presence of autoantibody against ATTR Val30 Met after sequential liver transplantation

BACKGROUND: Recently, sequential liver transplantation has been performed with an explanted liver from a patient with familial amyloidotic polyneuropathy (FAP) because of the shortage of donors. However, metabolism of amyloidogenic transthyretin (ATTR), the pathogenic protein of FAP, has not been well studied in patients who have undergone sequential liver transplantation. The purpose of this study was to examine the changes in serum ATTR levels and to investigate the presence of an autoantibody in patients who underwent sequential liver transplantation with an explanted organ from a patient with heterozygotic FAP (FAP ATTR Val30Met). METHODS: This was a case study performed at the Kumamoto University School of Medicine, Kumamoto, Japan, and Kyoto University School of Medicine, Kyoto, Japan. Intervention occurred by sequential liver transplantation with an explanted FAP patient's liver. Levels of normal TTR and ATTR in the two patients who received the transplanted liver were analyzed by means of an enzyme-linked immunosorbent assay (ELISA) and a matrix-assisted laser desorption/time-of-flight mass spectrometry. In addition, the presence of an autoantibody against ATTR Val30Met was evaluated via ELISA using purified ATTR Val30Met from homozygotic FAP patients' sera. RESULTS: After the operation, the variant TTR levels were unexpectedly lower than levels of normal TTR in serum samples from patients with a transplanted liver from the FAP patient. An autoantibody against the variant TTR was detected on day 3 after the operation in the serum of those patients and continued to be present for at least 2 months after the operation. CONCLUSIONS: An autoantibody against the variant TTR may reduce the serum levels of variant TTR. Although the antibody may play a beneficial role in reducing the pathogenic protein, the long-term effect of the antibody must be investigated further.     

A different amyloid formation mechanism: de novo oculoleptomeningeal amyloid deposits after liver transplantation

BACKGROUND: Liver transplantation has served as a treatment for patients with familial amyloidotic polyneuropathy (FAP) because variant transthyretin (TTR), the pathogenic protein of FAP, is predominantly produced by the liver. However, the effect on amyloid formation of TTR that is synthesised by the retina and the choroid plexus remains to be elucidated in FAP patients with liver transplants. OBJECTIVE: To investigate changes in ocular tissues and the central nervous system (CNS) of FAP patients after liver transplantation. DESIGN: Clinical study. SETTING: Graduate School of Medical Sciences, Kumamoto University, Japan. INTERVENTION: Transplantation of livers from cadaveric or living donors. MEASUREMENTS: Preoperative measures and postoperative (16-108 months) follow-up of clinical data, including routine ophthalmologic, neurologic, and laboratory evaluations. RESULTS: In 22 patients with FAP related to the amyloidogenic TTR (ATTR) Val30Met and 3 patients with FAP ATTR Tyr114Cys, after liver transplantation, 3 patients began to show evidence of de novo glaucoma, and 1 had vitreous opacity that was caused by the variant TTR. Another three patients showed new amyloid deposits in the pupillary margin, which could lead to glaucoma and vitreous opacity. As for changes in the CNS and levels of total protein and TTR in cerebrospinal fluid (CSF), after liver transplantation, two FAP ATTR Tyr114Cys patients exhibited de novo amyloid deposition in the leptomeninges, and total protein and TTR levels in CSF were significantly increased. CONCLUSIONS: Oculoleptomeningeal involvement in FAP was not prevented by liver transplantation because variant TTR produced by the retina and the choroid plexus forms amyloid fibrils in situ.     

Corino-andrade disease (familial amyloidotic polineuropathy type I) in Spain: Urological and andrological disorders

In our hospital, we have followed a group of patients with familial amyloidotic polyneuropathy (FAP), type I. This disease is characterized by a progressive sensitive-motor and autonomic polyneuropathy. The amyloid fibrils of FAP I contain a mutant transthyretin (TTR) molecule. More than 90% of TTR production occurs in the liver. Thus, therapy with liver transplantation has proved useful. All our patients received this treatment. In this study we describe the urological and andrological disorders caused by FAP type I in 12 patients with low bladder pressure and bladder neck obstruction with micturition disorders. In some males, it was accompanied by impotence and retrograde ejaculation produced by autonomic neuropathy. We believe hepatic transplantation may be the best treatment for this disease.     

Variant transthyretin in blood circulation can transverse the blood-cerebrospinal barrier: qualitative analyses of transthyretin metabolism in sequential liver transplantation

BACKGROUND: Although the choroid6 plexus of the brain is one of the most important production sites of transthyretin (TTR), the metabolism of TTR secreted in cerebrospinal fluid (CSF) remains to be elucidated. METHODS: To perform qualitative analysis of variant TTR in CSF of patients who underwent a sequential liver transplantation using an explanted familial amyloidotic polyneuropathy (FAP) ATTR Val30 Met patient's liver, levels and forms of TTR of the two patients were analyzed by means of enzyme linked immunosorbent assay (ELISA) and matrix-assisted laser desorption/time-of-flight mass spectrometer (MALDI/TOF-MS), respectively. RESULTS: After the operation, variant TTR levels in serum increased, and in CSF, a significant peak of free form of ATTR Val30 Met was detected in the transplanted patients whose CSF had shown no variant TTR before the operation. CONCLUSIONS: These findings suggest that the variant TTR can cross-the blood-CSF barrier and migrate into CSF from blood circulation. Because leptomeningeal amyloidosis occurs in FAP ATTR Val30 Met as the progression of the disease, this information suggests that in addition to peripheral neuropathy, disorders of the central nervous system (CNS) should be given an attention in patients who underwent sequential liver transplantation using an explanted FAP ATTR Val30 Met patient's liver.     

Rapamycin Attenuates Liver Graft Injury in Cirrhotic Recipient—The Significance of Down-Regulation of Rho-ROCK-VEGF Pathway

To investigate whether rapamycin could attenuate hepatic I/R injury in a cirrhotic rat liver transplantation model, we applied a rat orthotopic liver transplantation model using 100% or 50% of liver grafts and cirrhotic recipients. Rapamycin was given (0.2 mg/kg, i.v.) at 30 min before graft harvesting in the donor and 24 h before operation, 30 min before total hepatectomy and immediately after reperfusion in the recipient. Rapamycin significantly improved small-for-size graft survival from 8.3% (1/12) to 66.7% (8/12) (p = 0.027). It also increased 7-day survival rates of whole grafts (58.3%[7/12] vs. 83.3%[10/12], p = 0.371). Activation of hepatic stellate cells was mainly found in small-for-size grafts during the first 7 days after liver transplantation. Rapamycin suppressed expression of smooth muscle actin, which is a marker of hepatic stellate cell activation, especially in small-for-size grafts. Intragraft protein expression and mRNA levels of vascular endothelial growth factor (VEGF) were down-regulated by rapamycin at 48 h both in whole and small-for-size grafts. Consistently, mRNA levels and protein expression of Rho and ROCK I were decreased by rapamycin during the 48 h after liver transplantation. In conclusion, rapamycin attenuated graft injury in a cirrhotic rat liver transplantation model by suppression of hepatic stellate cell activation, related to down-regulation of Rho-ROCK-VEGF pathway.     

Interleukin 6 in bile as an indicator of liver function after hepatectomy in patients with biliary tract carcinoma

BACKGROUND: Interleukin (IL) 6 is one of the important components of the early signalling pathways leading to liver regeneration, and has been detected in the bile after liver transplantation. IL-6 concentrations in the bile were studied in an attempt to predict liver function after major hepatectomy for biliary tract carcinoma. METHODS: This study involved 24 patients without cirrhosis who underwent major hepatectomy for biliary tract carcinoma. The bile was sampled regularly through external biliary drainage tubes. IL-6 concentrations in bile and serum were measured using an enzyme-linked immunosorbent assay. RESULTS: Bile IL-6 concentrations increased 37-fold (from mean(s.e.) 56(13) pg/ml before hepatectomy to 2071(398) pg/ml on day 1 after operation) in patients without liver failure after hepatectomy (n = 18) and increased sevenfold (from 71(24) to 530(76) pg/ml) in patients with liver failure after hepatectomy (n = 6). The values were significantly lower in patients with liver failure than in those without liver failure (P < 0.05). The bile IL-6 concentration on day 1 after operation exhibited a significant negative correlation with the maximum serum total bilirubin concentration after hepatectomy. Although serum IL-6 concentrations were also increased in both groups after hepatectomy, there was no significant correlation with postoperative liver function. CONCLUSION: Increased bile IL-6 concentrations after hepatectomy may reflect liver regenerative capacity. Measurement of bile IL-6 concentrations may be clinically useful for the early identification of liver failure after hepatectomy.     

他克莫司对移植肝脏再灌注损伤的影响

目的 探讨他克莫司对移植肝脏再灌注损伤的影响.方法 建立大鼠肝移植模型,实验组(40只)和对照组(40只)分别注射他克莫司和生理盐水,检测再灌注24、48和96 h后TNF-α、IL-1、ALT、AST、LDH、内皮素(endothelin,ET)和丙二醛(malondialdehyde,MDA)水平,观察肝脏超微结构和细胞凋亡情况,RT-PCR法检测Fas、Bcl-2的mRNA水平.依据免疫抑制方案,将112例终末期肝硬化患者分为他克莫司组(63例)和环孢素A组(49例),比较临床肝移植使用环孢素A和他克莫司患者肝酶指标及急性排斥反应的发生.结果 实验组TNF-α、IL-1、ALT、AST、LDH、ET和MDA显著低于对照组(P＜0.05),肝脏超微结构受损和细胞凋亡较轻,Fas mRNA合成减少.患者使用他克莫司后急性排斥反应发生率较环孢素A低(x2=39.0,P＜0.05).结论 他克莫司可通过抑制细胞凋亡来减轻大鼠移植肝脏再灌注损伤,临床使用他克莫司能减少急性排斥反应的发生.     

Clinical use of an immune monitoring panel in liver transplant recipients: A prospective,observational study

Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs.We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (−226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV− patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.     

Assessment of Effect of Intraperitoneal Tacrolimus on Liver Regeneration in Major (70%) Hepatectomy Model After Experimental Pringle Maneuver in Rats

AimSmall-for-size grafts have become more important, especially in living donor liver transplants. The Pringle maneuver, used to reduce blood loss, and the immunosuppressive medications used to prevent graft rejection in liver transplants have different side effects on liver regeneration. We researched the effect of situations where tacrolimus and the Pringle maneuver were applied or not on liver regeneration in rats with partial hepatectomy.Material and MethodsThis study was completed with 35 Wistar Albino rats. The subjects were randomly divided into 5 groups: Group 1 had the abdomen opened and no other procedure was performed; Group 2 underwent a 70% hepatectomy; Group 3 underwent a 15-minute Pringle maneuver + 70% hepatectomy; Group 4 underwent a 70% hepatectomy + 5 days of 1 mg/kg/day intraperitoneal tacrolimus; and Group 5 underwent a 150 minute Pringle maneuver + 0% hepatectomy + 5 days of 1 mg/kg/day intraperitoneal tacrolimus. All rats were sacrificed on the seventh postoperative day, remaining liver tissue was weighed, and weight indices created. The remaining liver tissue was stained with phosphohistone H3 and the mitotic index calculated.ResultsThe groups that underwent the Pringle maneuver, 70% hepatectomy, and tacrolimus administration were compared with the control group in terms of mitotic index and weight index, but no statistically significant differences were identified.ConclusionSuppression of regeneration forms a risk after liver transplantation with small-volume grafts. As a result, research on the effect of tacrolimus combined with the Pringle maneuver is important, especially for transplantations using segmented liver grafts. In our study, we showed that the use of tacrolimus had no negative effect on liver regeneration.     

Changes in serum LECT 2 levels during the early period of liver regeneration after adult living related donor liver transplantation

We investigated changes in serum leukocyte cell-derived chemotaxin2 (LECT2) levels between donors and recipients in the early period during liver regeneration following adult living related donor liver transplantation (LRDLT). Five recipients (three women, two men; 37.0 +/- 15.8 years old), all of whom had end-stage liver failure, underwent LRDLT from healthy five donors (two women, three men; 41.6 +/- 14.3 years old) between June 2000 and February 2001. FK506 and methylprednisolone were used as immunosuppressants for recipients. Serum LECT2 levels decreased immediately after both the hepatectomy in all donors and the implantation of liver graft in all recipients. Donors showed a nadir at 3 to 12 hours, increasing at 24 to 48 hours. The nadir in recipients occurred several hours after the donors. The serum LECT2 levels of donors were significantly higher than those of recipients on day 5 (9.5 +/- 5.9 ng/mL vs 3.1 +/- 2.2 ng/mL, P = .04) and on day 7 (9.3 +/- 3.8 ng/mL vs 3.5 +/- 1.1 ng/mL, P = .04). Serum GPT and GOT levels were inversely proportionate to the serum LECT2 levels. The present studies suggest that LECT2 participates in liver regeneration and injury following hepatectomy.     

Renal dysfunction following adult intestinal transplant under tacrolimus-based immunosuppression

We analyzed data from the records of 24 adult patients who survived more than 2 years after intestinal transplantation performed between 1995 and 2002 under tacrolimus-based immunosuppression. Ages ranged from 19.3 to 59.2 years old (median 32.1 years). Tacrolimus cumulative level was defined as a sum of weekly average tacrolimus level over time. Kidney function was evaluated by the 6-month average serum creatinine level. Estimated creatinine clearance was calculated with the Cockcroft-Gault formula. Student's t test was used for analysis. Primary diseases were mesenteric thrombosis (n = 7), trauma (n = 4), Crohn's (n = 3), Gardner's (n = 5), and others (n = 7). Procedures were isolated intestinal transplant (n = 10), liver and intestine (n = 1), multivisceral transplant (n = 9), or modified multivisceral transplant (n = 4). Cumulative tacrolimus levels ranged between 1161 and 8623 ng*day/mL (median 4132 ng*day/mL) at 0 to 12 months. Pretransplant kidney function as mean creatinine clearance was 114 mL/min per 1.73 m(2) (n = 24). Creatinine clearance decreased to a mean of 49.6 mL/min per 1.73 m(2) (43.5% of pretransplant) at 2 years (P < .0001). The average creatinine clearance at 18 to 24 months in each patient with a cumulative tacrolimus level <4500 ng*day/mL was 63% +/- 25% of preoperative creatinine clearance. In patients with a cumulative tacrolimus level >4500 ng*day/mL, it was 34% +/- 17%. Cumulative tacrolimus level >4500 ng ng*day/mL was significantly associated with a decreased creatinine clearance at 2 years (P = .006). Renal function decreased significantly after intestinal transplantation in adults. Cumulative tacrolimus level in the first year affected renal function at 2 years.     

Pediatric liver transplantation with daclizumab induction

BACKGROUND: A new class of monoclonal antibodies (non-T-cell depleting) has gained favor for induction therapy after transplantation. This study evaluated the non-T-cell depleting antibody to the CD25 cell, daclizumab, as a single-dose induction agent immediately after pediatric liver transplantation to spare the use of the calcineurin inhibitor, tacrolimus, for 7 days in respect to both efficacy and renal function. METHODS: From January 1998 to November 2001, 81 pediatric orthotopic liver transplant recipients receiving 89 liver grafts were evaluated. The treatment arm (n=61) received daclizumab 1 mg/kg immediately after liver transplantation along with mycophenolate, steroids, and, on postoperative day 7, tacrolimus. The control group did not receive induction therapy, whereas tacrolimus, mycophenolate, and steroids were started immediately after surgery. RESULTS: The induction group had fewer patients with rejection within the first 30 days after liver transplantation (9 [14.8%] vs. 10 [50%]; P=0.003). The mean time to first rejection was similar between groups (12.1 [+/-7.8] days vs. 18.5 [+/-8.1] days; P=not significant). There was a 3.39 increase in relative risk to develop rejection within the first 30 days after orthotopic liver transplantation if the patient did not receive induction therapy (relative risk=3.39; 95% confidence interval [1.61, 7.14]). Two-year actuarial survival for the induction group was 93.2% compared with 85% in the control; graft survival was also similar between groups (87.8% vs. 72.7%) at 2 years. CONCLUSION: Daclizumab 1 mg/kg given immediately after pediatric liver transplantation and withholding tacrolimus, is safe, efficacious, and reduces rejections within the first 30 days after surgery.     

Changes in renal function in patients with familial amyloid polyneuropathy treated with orthotopic liver transplantation.

BACKGROUND: Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease caused by a point mutation in the gene encoding transthyretin, which is secreted by the liver. Orthotopic liver transplantation (OLT) has been proposed to prevent disease progression. Little is known about long-term changes in renal function and lesions after OLT. METHODS: The renal function of 33 patients with FAP was evaluated (proteinuria, serum creatinine, creatinine clearance) before OLT and over a period of at least 5 years afterwards. A pre-transplantation renal biopsy was performed in 14 patients and a follow-up biopsy in eight patients. RESULTS: Before transplantation, mean serum creatinine concentration was 86 micromol/l (47-126 micromol/l) and creatinine clearance was 71.9+/-31.6 ml/min/1.73 m(2). Proteinuria was detected in 54% of patients (0.3-4 g/day). Pre-transplant renal biopsies (n = 14) revealed glomerular, tubular and vascular amyloid deposits in 90, 58 and 66% of patients, respectively. Eleven patients (33%) died after OLT. Death occurred most frequently in patients having weight losses >7 kg (P<0.05). After transplantation, 25 patients (76%) suffered acute renal failure but only one required dialysis. One month after transplantation, the mean serum creatinine concentration was 134.1+/-73 micromol/l and remained constant during follow-up. Eight patients underwent a second renal biopsy 2 years after transplantation. No significant changes in deposits or renal toxicity due to calcineurin inhibitors were detected. CONCLUSION: Although liver transplantation in FAP does not affect existing renal amyloid deposits, it prevents the progression of renal disease.     

Influence of posttransplant time on dose and concentration of tacrolimus in liver transplant patients

Abstract The dosage of tacrolimus (D), the trough blood concentrations (C) and the evolution of the D/C ratio were followed for 1 year after transplantation in so adult patients (38 males and 12 females) undergoing liver allograft. A total of 1489 samples were analysed by the IMx tacrolimus method. The overall median concentration was 11.27 ng/ml. During the 1st month the median of the tacrolimus levels was 8.4 ng/ml, and 73.1 % of the analysed samples were within the established therapeutic range. The median oral tacrolimus dose was progressively reduced from 0.12 mg/kg per day during the 1st month to 0.06 mg/kg per day at the end of studied period. A significant negative association was observed between the D/C ratio and the posttransplantation period ( r = -0.3892; P < 0.0001). The median D/C ratio ranged from 0.0144 at 1st month to 0.0053 at 1 year. Significant D/C declines were observed after the 1st and 3rd months posttransplant. The decrease in corticosteroid doses and the increase in serum albumin may explain the reduction in clearance with time.     

术后应用肠外营养对肝细胞癌合并肝硬化病人的影响

目的探讨肝细胞癌合并肝硬化病人术后的营养支持。方法24例行根治性切除的肝癌病人随机分为PN组（n=12）和rhGH＋PN组（n=12）。术前、术后1d和术后6d测肝功能、血糖、AFP、血清前白蛋白、转铁蛋白及血清GH、IGF-1、IGFBP-3，用RT—PCR法检测肝组织（包括癌组织，癌旁组织和术后6d肝穿刺组织）ALBmRNA、IGF-1mRNA、IGFBP-3mRNA的表达，肝组织行Ki67免疫组织化染色。同时选12例因胆石症或肝血管瘤行手术的病人作为正常对照。结果肝细胞癌合并肝硬化病人血清前白蛋白，转铁蛋白低于正常对照组，血清GH水平高于正常对照组，而血清IGF-1、IGFBP-3水平低于正常对照组；术后6d，rhGH＋PN组血糖、血清前白蛋白、转铁蛋白、血清GH、IGF-1、IGFBP-3水平、肝ALBmRNA、IGF—1mRNA、IGFBP-3mRNA表达水平、肝Ki67指数均高于PN组。血清GH水平与血糖呈正相关，血清IGF1、IGFBP-3水平与血清AST、ALT、TBIL呈负相关，与血清ALB、前白蛋白，转铁蛋白呈正相关。结论rhGH＋PN有利于肝细胞癌合并肝硬化病人术后生长激素／胰岛素样生长因子-1轴的恢复，检测血清IGF-1、IGFBP-3水平有助于了解短期营养支持的效果和选择营养素。     

Increased intraabdominal pressure impairs liver regeneration after partial hepatectomy in rats

BACKGROUND: There are many experimental studies showing that increased intraabdominal pressure (IAP) reduces liver blood flow, leading to ischemia and portal venous congestion. But, there is no study evaluating the effect of increased IAP on liver regeneration. It is well known that acute liver ischemia and portal venous congestion impair liver regeneration. We, therefore, aimed to determine the effect of increased IAP on liver regeneration in this study. METHODS: Sprague-Dawley rats underwent partial hepatectomy with or without IAP of 12-14 mm Hg for 24 h or sham operation. Rats were randomly divided into six groups: two sham-operated groups, two hepatectomy groups, and two hepatectomy with increased IAP groups. Mitotic index, proliferating cell nuclear antigen (PCNA)-labeling index, and liver regeneration rate as liver regeneration parameters were studied on day 1 or on day 4 after operation. Additionally, serum aspartate transaminase (AST) level and histopathological changes in intestinal mucosa were studied. RESULTS: Hepatectomy with/without increased IAP groups had significantly higher serum AST levels than the sham-operated group on day 1. Serum AST level was found to be significantly higher in the hepatectomy with increased IAP group than in the other groups on day 4. Intestinal mucosal injury was found in the hepatectomy with increased IAP groups on days 1 and 4. Mitotic index and PCNA-labeling index were markedly higher in all hepatectomy with/without increased IAP groups than in the sham-operated groups. However, together with liver regeneration rate, both indices were significantly less in the hepatectomy with increased IAP groups than in the hepatectomy groups both on day 1 and on day 4. CONCLUSION: Maintenance of IAP between 12 and 14 mm Hg for 24 h impaired liver regeneration after partial hepatectomy in rats.     

Stability and repeat regeneration potential of the engineered liver tissues under the kidney capsule in mice

Liver tissue engineering using hepatocyte transplantation has been proposed as a therapeutic alternative to liver transplantation toward several liver diseases. We have previously reported that stable liver tissue with the potential for liver regeneration can be engineered at extrahepatic sites by transplanting mature hepatocytes into an extracellular matrix. The present study was aimed at assessing the liver tissue persistence after induced regeneration by hepatectomy and repeat regeneration potential induced by repeat hepatectomy. Mouse isolated hepatocytes mixed in EHS extracellular matrix gel were transplanted under both kidney capsules of isogenic mice. The hepatocyte survival persisted for over 25 weeks. In some of the mice, we confirmed that the grafted hepatocytes developed a thin layer of liver tissues under the kidney capsule, determined by specific characteristics of differentiated hepatocytes in cord structures between the capillaries. We then assessed the regenerative potential and persistence of the exogenous liver tissue. To induce liver regeneration, we performed a two-thirds hepatectomy at 70 days after hepatocyte transplantation. Three weeks after this procedure, the engineered liver tissues showed active regeneration, reaching serum marker protein levels of 261 +/- 42% of the prehepatectomy level. We found that the regenerated liver tissue was stably maintained for 100 days (length of the experiment). Repeat regeneration potential was established by performing a repeat hepatectomy (that had been two-thirds hepatectomized at day 70) 60 days after the initial hepatectomy. Again, the regenerated engineered liver tissues showed active regeneration as there was an approximately twofold increase in the serum marker protein levels. The present studies demonstrate that liver tissue, which was recognized as a part of the host naive liver in terms of the regeneration profile, could be engineered at a heterologous site that does not have access to the portal circulation.     

A Randomized, Double-Blind, Pharmacokinetic Study of Oral Maribavir with Tacrolimus in Stable Renal Transplant Recipients

Maribavir is being developed as a novel agent for the prevention or treatment of cytomegalovirus infections after stem cell and organ transplantation. This was a randomized, double-blind, placebo-controlled study designed to evaluate the potential pharmacokinetic interaction of concomitant administration of maribavir and tacrolimus. Twenty-five adult renal transplant recipients with stable renal function and stable dosing regimens of tacrolimus were randomized (20 maribavir 400 mg p.o. q12 h: 5 placebo). Tacrolimus whole blood concentration profiles were determined before and after 7 days of co-administration with maribavir. When co-administered with maribavir, tacrolimus mean C_max increased 38%, tacrolimus trough concentrations (12 h post-dose) increased 57% and tacrolimus AUC_(0-τ) increased 51%. Apparent oral clearance of tacrolimus decreased 34% and T_max was delayed by 0.5 h. There were no serious adverse events and no subject prematurely discontinued treatment. Because of the limited 7-day dosing course, the adverse event profile could not be adequately assessed. However, as seen with other maribavir studies, dysgeusia was common (90% of maribavir subjects and 20% of placebo subjects). In conclusion, co-administration of maribavir 400 mg twice daily increases exposure to tacrolimus. Routine therapeutic drug monitoring of tacrolimus blood concentrations should be included both at initiation and completion of maribavir treatment.     

Manifestations of transthyretin-related familial amyloidotic polyneuropathy: Long-term follow-up of Japanese patients after liver transplantation

Purpose

To observe which symptoms of transthyretinrelated familial amyloidotic polyneuropathy (FAP) progressed in the long term after liver transplantation (LT), focusing on cardiac, kidney, and ocular symptoms.

Methods

We reviewed the medical records of 34 Japanese patients with FAP, who underwent LT between 1994 and 2006. The mean follow-up period (±SD) after LT was 9.6 ± 3.4 years. Of the 34 patients, 30 had FAP amyloidogenic transthyretin (ATTR) Val30Met, 1 had FAP ATTR Ser50Ile, and 3 had FAP ATTR Tyr114Cys.

Results

The 10-year survival rates from the onset of FAP and from the time of LT were 100% and 91.4%, respectively. Progression of ocular amyloidosis was seen in 17 (50%) patients, 13 of whom had de novo amyloid deposits in the vitreous body; progression of cardiac amyloidosis was seen in 10 (29%) patients, 4 of whom had newly granular sparkling echo on echocardiography, and 9 of whom had newly implanted pacemakers or implantable cardioverter-defibrillators. Although the mean serum creatinine levels did not increase significantly after LT in any of the patients, the estimated glomerular filtration rate had decreased significantly by 7 years after LT.

Conclusion

Although LT is life-saving for patients with FAP, we observed progression of the ocular and cardiac symptoms of FAP in a significant number of these patients over the long term after LT.