Kaoru Kumada

Living related liver transplantation in children

We reviewed 37 living related liver transplantations (LRLT) performed by our department during the last 27 months on children with end-stage liver disease. The patients were 15 boys and 22 girls aged 7 months to 15 years with biliary atresia (27), cryptogenic cirrhosis (3), Budd-Chiari syndrome (2), progressive intrahepatic cholestasis (2), protoporphyria (1), Wilsons disease (1), and fulminant hepatitis (1). The donors were 14 fathers and 23 mothers. Grafts were made from the left lateral segment (19), left lateral segment with partial S4 (11), left lobe (6), and right lobe (1). After graft harvesting all donors resumed normal liver function and normal life. The recipient underwent total hepatectomy with preservation of the inferior vena cava. FK506 and low-dose steroids were used for immunosuppression. The survival rate was 90% (27/30) in elective cases and 57% (4/7) in emergency cases. Six recipients had functioning grafts but died of extrahepatic complications. Hepatic vein stenosis occurred in 3 cases at 3 months after LRLT and was successfully treated by balloon dilatation. Portal vein stenosis occurred in 1 case at 8 months after LRLT and was also safely dilated. We incurred no hepatic artery thrombosis after introducing microsurgery techniques. Among 12 viral, 5 bacterial, and 3 fungal postoperative infections, 1 Candida pneumonia and 1 EBV-associated lymphoma were lethal. Three patients with ABO-blood group compatible grafts and one with an incompatible graft developed acute rejection, which was controlled in evey case by steroid bolus and/or increasing the dose of FK506. There were no definite episodes of rejection in ABO-identical cases. Children with moderate growth retardation (> or = -1.5 SD of normal growth) caught up in growth soon after LRLT, but those with severe retardation (<-1.5 SD) were slow to attain age-normal height. Appropriate timing, meticulous surgical procedures, and comprehensive management of complications are crucial for successful outcome with LRLT. LRLT is a promising option for alleviating the shortage of livers for pediatric transplantation and may be regarded as an independent modality to supplement cadaver donation.

Diurnal Fluctuations of Arterial Ketone Body Ratio in Normal Subjects and Patients With Liver Dysfunction

To explore the metabolic aspects of chronic liver disease, diurnal changes of arterial ketone body ratio (acetoacetate/3-hydroxybutyrate), reflecting hepatic mitochondrial redox potential, were investigated in normal subjects, patients with chronic liver disease (Childs class A or B), and patients with hepatic failure (Childs class C). Ketone body ratio in normal subjects increased after breakfast from 0.96 to 2.00, after lunch from 2.17 to 2.38, and after dinner from 1.23 to 2.55 with blood glucose level ranging from 103 to 141 mg/dL (5.7 to 7.8 mmol/L). By contrast, the ketone body ratio in the Child A or B group changed little and remained within a range of 0.70-1.35 despite a large change in blood glucose level from 102 to 176 mg/dL (5.7 to 9.8 mmol/L). Ketone body ratio in Childs class C remained near or below 0.4 with no response to glucose administration, despite a marked elevation in blood glucose level. These results indicate that hepatic mitochondrial redox potential undergoes diurnal changes in sharp response to meals in normal liver function but that these fluctuations are absent in patients with liver damage (Childs class A, B, and C). Furthermore, it remains at low levels in severe liver failure (Childs class C). It is also suggested that hepatic mitochondrial redox potential plays an important role in the regulation of blood glucose levels.

Total Replacement of the Suprarenal Inferior Vena Cava with an Expanded Polytetrafluoroethylene Tube Graft in 2 Patients with Tumor Thrombi from Renal Cell Carcinoma

Total replacement of the suprarenal inferior vena cava using an expanded polytetrafluoroethylene vascular graft was successful in 2 renal cell carcinoma patients with extended tumor thrombi densely adherent to the vena caval wall. Right radical nephrectomy in 1 patient and enucleation of the tumor in the solitary right kidney were performed concomitantly. Both patients are well without tumor recurrence and with good vena caval patency 14 and 6 months postoperatively. This procedure could be a safer mode of operation in cases of extended vena caval involvement by malignant tumors. Total reconstruction of the inferior vena cava enables more radical resection of the tumor.

Functional deterioration of the liver by elevated inferior vena cava pressure: A proposed upper safety limit of pressure for maintaining liver viability in dogs

ObjectiveAbnormally elevated central venous pressure is considered to be an etiological factor in the onset of acute hepatic failure following modified Fontan operation. This paper hypothesises that an increase in inferior vena cava pressure (IVCP) after such an operation has adverse effects on hepatic energy status.DesignVarious degrees of venous hypertension were produced in 10 mongrel dogs by clamping the thoracic IVC with an active veno-venous shunt and varying its flow rate from 60–2.5 ml/min/kg. Arterial ketone body ratio (KBR), reflecting the hepatic mitochondrial redox state, was measured as an index of hepatic energy status.Measurements and results: The lower the flow rates of the shunt, the higher the pressures of IVC and portal vein, while systolic blood pressure was maintained above 100 mmHg. CO significantly decreased when the pump speed was less than 30 ml/min/kg. KBR showed a negative correlation to IVCP as well as a positive correlation to portal blood flow (p<0.05).ConclusionFrom the simple regression line obtained between IVCP and KBR, it was determined that an upper safety limit of IVCP may lie at about 27 cmH2O (20.5 mmHg), and that a IVCP of 35 cmH2O (26.6 mmHg) seems to be the critical level for maintaining liver viability.

Hemodynamics and Hepatic Energy Metabolism in Canine Model of Acute Hepatic Venous Occlusion with Mesocaval Shunt

The relationship between portal hemodynamics and the energy metabolism of the liver with acute hepatic venous occlusion (HVO) was investigated by assessing the changes in the hepatic blood flow, arterial blood ketone body ratio (AKBR) and adenylate energy charge potential (ECP) of the liver tissue in canine model. Acute HVO was induced by the ligation of both the supra- and infrahepatic inferior vena cava (IVC) over the protruding ends of a heparin-coated polyethylene cannula inserted into the IVC. All dogs with only HVO (n = 5) died within 30 min. HVO dogs with additional mesocaval (MC) shunt (n = 10) survived longer than 7 days, during which time their AKBR were maintained in the normal range (over 1.0). ECP was also maintained above the normal level (over 0.850) during the 28-day period. Along with increasing portal pressure caused by the narrowing of the shunt anastomosis, the hepatic blood flow decrease gradually, resulting in a sudden decrease in AKBR and ECP when the portal pressure increased over 11 mm Hg. It is suggested that the normalization of portal pressure is one of the most important factors for maintaining the hepatic energy metabolism and that MC shunt is an effective therapy for maintaining the function of the liver with HVO, as long as portal pressure can be kept within normal range.

Clinical application of arterialization of portal vein in living related donor partial liver transplantation

Arterialization of the portal vein was employed during hepatic arterial reconstruction in our first few clinical experiences of partial liver transplantation using liver grafts obtained from living related donors. This procedure reduced the time required for revascularization of the grafts to about 25 min, and could in fact reduce the ischemic phase of the grafts. Repeated practice of the clinical transplantation technique has shortened the time needed to complete vascular reconstruction, eliminating the need for this procedure in most of our subsequent cases. In many clinical cases, however, there may be emergency situations which require vascular reconstruction, resulting in a prolongation of ischemic phase and the deterioration of the cellular viability of the graft. In such situations, arterialization of the portal vein can be a useful way to prevent the prolongation of the ischemic phase and to rescue the graft.

Effects of calmodulin antagonists and calmodulin on phospholipid base-exchange activities in rabbit platelets

Effects of various calmodulin antagonists and calmodulin on the incorporation of serine, ethanolamine and choline into the corresponding phospholipids, such as phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine by Ca2+-stimulated base-exchange reactions in rabbit platelet membranes were studied. Under a Ca2+-EGTA buffer system, the incorporation of three bases were stimulated by Ca2+ in a biphasic manner. Minimum requirement of free Ca2+ for the reactions was found to be around 0.5 microM and maximal incorporation took place at high Ca2+ concentrations (3-5 mM). Various calmodulin antagonists such as chlorpromazine, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, not only activated the three reactions but also greatly enhanced their sensitivity to Ca2+ (K0.5, 0.1-0.3 microM). In the absence of Ca2+, however, the drugs did not show any effect on the reactions. The concentrations of the drugs required for half maximal stimulation were approx. 30-40 microM. Although platelet membranes contained endogenous calmodulin (0.3-0.6 microgram/mg of membrane protein), the addition of exogenous calmodulin inhibited choline exchange activity but had no or little effect on serine or ethanolamine exchange activity. The results suggest that in the presence of low Ca2+ concentrations, these drugs markedly stimulate base-exchange activities, and choline exchange activity may be regulated by calmodulin.

Enzymatic properties of phospholipid methylation in rabbit platelets

The enzymatic properties of phospholipid methylation in rabbit platelets were examined using S-adenosyl-L-[methyl-3H]methionine as a substrate. pH optimum for the methylation was around 10.5 under Tris-HCl and glycine-NaOH buffer systems. When Tris-HCl buffer was replaced by phosphate buffer, pH optimum shifted to around 8.0 and the methylation was increased approximately threefold, compared with that in the case of Tris-HCl buffer at pH 8.0. The formation of the 3H-methylated phospholipids was increased by addition of exogenous phosphatidyl-N-monomethylethanolamine or phosphatidyl-N,N-dimethylethanolamine, intermediates of the biosynthesis of phosphatidylcholine from phosphatidylethanolamine. However, the increase in product formations by addition of exogenous intermediates was all but equal under Tris-HCl and phosphate buffer systems at pH 8.0. These results suggest that phosphate ion stimulates the first step of the successive methylation to form phosphatidyl-N-monomethylethanolamine from phosphatidylethanolamine. The methylation in platelets was inhibited to 30% of the basal value with Ca2+ (0.2 mM). However, Ca2+ showed different effects on the methylation in various tissues (activation to 150% of the basal value in the adrenal gland and slight inhibition to 82-88% of corresponding basal values in the liver, lung, kidney and brain).

Evaluation of temporary portal vein arterialization: the minimum arterialized blood flow for maintaining liver viability

Abstract. The effect of temporary portal vein arterialization (PVA) on hepatic energy metabolism was investigated by changes in the arterial blood ketone body ratio (KBR) and hepatic energy charge (EC) level in 17 dogs. The KBR decreased markedly after clamping the hepatic hilar vessels combining mesocaval shunt and remained at a low level throughout hepatic ischemia. After PVA, the KBR was rapidly restored and maintained at sufficient levels. EC at 60 min after arterialization also recovered to the preclamping level. By reducing the arterial shunt flow, the critical point of arterialized blood flow for maintaining the KBR at high levels was assessed to be about 10% of the total hepatic blood flow (THBF). These findings demonstrate that temporary PVA is an effective method for maintaining the functional capacity of the liver, and that the minimum arterialized blood flow needed to preserve liver viability is only about 10% of the total hepatic blood flow.

Positive imaging of venous thrombi and thromboemboli with Ga-67 DFO-DAS-fibrinogen

A newly developed thrombus imaging agent, 67Ga-DFO-DAS-fibrinogen (67Ga-fibrinogen), was used for 22 studies in 20 cases of suspected deep venous thrombosis. Increased accumulation of 67Ga-fibrinogen in venous thrombi was depicted at 48 h after injection in 10 of the 15 cases (10 of 17 studies) who showed abnormal findings in radionuclide venography. A hot spot in the lung emboli was visualized in two cases. Seven of the eight cases having anticoagulant therapy showed increased 67Ga-fibrinogen uptake, while follow-up 67Ga-fibrinogen scintigraphy after the administration of heparin and urokinase did not reveal an abnormal hot spot in one case. 67Ga-fibrinogen can be made available simply by adding 67Ga solution to a vial containing fibrinogen-DAS-DFO conjugate. In conclusion, 67Ga-fibrinogen is considered to be a promising agent for detecting active venous thrombi and to assess the effect of anticoagulant therapy.