Ten-Year Efficacy and Safety of Once-Daily Tacrolimus in Kidney Transplant: A Prospective Cohort Study.

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney transplant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 ± 1.6 mL/min/1.73 m2) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 ± 2.2 mL/min/1.73 m2) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 ± 2.2 vs 48.0 ± 2.7 mL/min/1.73 m2 in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy-proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia. In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in patients with kidney transplantation.

The interaction of alcoholic liver disease and hepatitis C.

The following article reviews available data of the interaction of alcohol related liver disease and hepatitis C viral infection as well as special considerations for the treatment of these patients. Alcohol worsens the degree and accelerates the progression of hepatic injury, enhances the risk of developing hepatocellular carcinoma and decreases response to interferon therapy. Patients with hepatitis C should avoid alcohol ingestion.

A two-dose hepatitis B vaccine regimen: proof of priming and memory responses in young adults.

This study shows that two doses of a recombinant hepatitis B vaccine (10 micrograms or 20 micrograms of HBsAg per dose), administered 6 months apart to young, healthy adults, can induce an antibody (anti-HBs) response similar to that expected with the standard three-dose regimen of this vaccine given at intervals of 0, 1, and 6 months. While only 46-67% of the vaccinees displayed a protective anti-HBs titer of > or = 10 mIU ml-1 prior to the receipt of the second dose at 6 months, virtually all were primed as 97-99% of the subjects developed such a titer when tested a month after the second dose. Among vaccinees given 10 or 20 microgram doses, respectively, the secondary rise in antibody following the second dose yielded geometric mean titers (GMTs) of 1103 and 2538 mIU ml-1, respectively. The study further demonstrated that a two-dose regimen of vaccination induced strong immunologic memory for HBsAg, as a booster dose of vaccine given 2 years later resulted in a rapid and vigorous anamnestic antibody response.

Quantitative liver function tests define the functional severity of liver disease in early-stage cirrhosis.

Some patients with early-stage cirrhosis preserve hepatic function, whereas others have little hepatic reserve and rapidly deteriorate. The aim of this study was to use quantitative tests of liver function (QLFTs) to define the degree of functional hepatic impairment in patients with early-stage cirrhosis (Child-Pugh score 5-7) and to determine whether the tests predicted subsequent hepatic decompensation. We recruited 10 cirrhotic (Cr) patients and 10 healthy controls (NI), who were well matched for race, age, weight, and gender. Clearances of caffeine (CF) and antipyrine (AP) after oral administration were measured from timed samples of saliva. The clearance of cholate (CA) was measured from serum samples obtained after simultaneous oral ([2,2,4,4-2H]CA) and intravenous ([24-13C]CA) administration. CA shunt was calculated as (Cl i.v./Clo x 100%). CF elimination rate (Cr v NI, mean +/- SD: 0.03 +/- 0.02 v 0.075 +/- 0.018 h-1, P < .0005) and AP clearance (24 +/- 16 v 40 +/- 7 mL/minute, P < .02) were reduced in Cr patients. CA shunt was increased in Cr patients (43 +/- 18 v 18 +/- 7%, P < .002). Five Cr patients decompensated during follow-up and had the worst CA shunts (76%, 66%, 51%, 48%, and 45%). Three subsequently received successful orthotopic liver transplantation, 1 died of hepatoma, and 1 is on the waiting list for transplantation. In conclusion, QLFTs define the degree of functional impairment in early cirrhosis and may identify Cr patients at greatest risk of decompensation who may require transplantation for survival.

Comparison of a rapid hepatitis B immunization schedule to the standard schedule for adults.

We report a prospective, randomized, single-blinded trial comparing immunogenicity of rapid (0, 1, and 2 months) versus standard schedule (0, 1, 6 months) hepatitis B vaccinations of healthy adults with recombinant hepatitis B vaccine (Engerix-B, 20 micrograms i.m.) (230 of 234) negative to hepatitis B were randomized and completed the study. Groups were similar in age, weight, race, and obesity rate, but the rapid schedule group had more women. Both groups reached > or = 100 mIU/mL at a similar rate, but a higher seroprotection rate at > or = 500 mIU/mL was reached by the standard schedule. No demographic variables influenced the effect of dose schedule on anti-hepatitis B titer. We conclude that rapid schedule vaccination gives a rate that is quicker than, and identical to, the rate of seroprotection of the standard schedule vaccination.

Enteral nutritional support in acute alcoholic pancreatitis.

BACKGROUND: The experience to date with total enteral nutritional (TEN) support in acute alcoholic pancreatitis patients admitted to the University of Kentucky affiliated hospitals was reviewed. METHODS: Standard enteral formulas sufficient to meet patient's needs were administered into the small bowel via endoscopically placed nasoenteric feeding tubes in five patients. Feedings were administered for a mean of 28.4 days. Pancreatitis was mild to moderate in severity by Ranson's criteria in four patients, and severe in one. RESULTS: Four patients developed complications of pancreatitis before initiation of TEN, representing the most common indication for nutritional support. Nutritional status was maintained by TEN with no significant complications from this nutritional support identified. Diarrhea that did not limit tube feeding developed in a single patient. CONCLUSIONS: This experience further supports the safety of TEN in acute pancreatitis and suggests that adequate nutritional support can be delivered by this route.

Pediatric rectal Dieulafoy's lesion.

Dieulafoy's lesions are an unusual cause of gastrointestinal hemorrhage. The overwhelming majority of lesions are found in the upper gastrointestinal tract, particularly along the lesser curvature of the stomach in the region supplied by the left gastric artery. Rectal Dieulafoy's lesions have never before been reported in the pediatric population, and our case represents only the third reported occurrence of a rectal Dieulafoy's lesion in the English medical literature. Successful treatment was administered, i.e., the combination of sclerotherapy followed by thermocoagulation. We therefore recommend that rectal Dieulafoy's lesion be included in the differential diagnosis of children with severe rectal bleeding and that management follow the same principles used to treat upper gastrointestinal tract Dieulafoy's lesions: injection therapy followed by heater probe coagulation.

Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275.

BACKGROUND: Active nutrition therapy and the anabolic steroid oxandrolone (OX), in selected patients with severe alcoholic hepatitis, significantly improved liver status and survival. We report here on the changes in their nutritional parameters. METHODS: Protein energy malnutrition (PEM) was evaluated and expressed as percent of low normal in 271 patients initially, at 1 month and at 3 months. Active therapy consisted of OX plus a high caloric food supplement vs a matching placebo and a low calorie supplement. RESULTS: PEM was present in every patient; mean PEM score 60% of low normal. Most of the parameters improved significantly from baseline on standard care; the largest improvement seen in visceral proteins, the smallest in fat stores (skinfold thickness). Total PEM score significantly correlated with 6 month mortality (p = .0012). Using logistic regression analysis, creatinine height index, hand grip strength and total peripheral blood lymphocytes were the best risk factors for survival. When CD lymphocyte subsets replaced total lymphocyte counts in the equation, CD8 levels became a significant risk factor (p = .004). Active treatment produced significant risk factor (p = .004). Active treatment produced significant improvements in those parameters related to total body and muscle mass (ie, mid arm muscle area, p = .02; creatinine height index, p = .03; percent ideal body weight, p = .04). CONCLUSION: Deterioration in nutritional parameters is a significant risk factor for survival in severe patients with alcoholic hepatitis. This deterioration is reversible with standard hospital care. Active therapy further improves creatinine height index, mid arm muscle area and total lymphocyte counts. Hence, these later parameters appear to be the best indicators for follow-up assessments.

Helicobacter pylori is a risk factor for hepatic encephalopathy in acute alcoholic hepatitis: the ammonia hypothesis revisited. The Veterans Administration Cooperative Study Group No. 275.

OBJECTIVE: To determine whether infection with Helicobacter pylori is a risk factor for portosystemic encephalopathy in patients with acute, moderate or severe alcoholic hepatitis. DESIGN: Prospective, multicenter cohort study. SETTING: Eight Veterans Affairs Hospitals. PATIENTS: A cohort of 273 male patients enrolled in a Department of Veterans Affairs Cooperative Study performed to evaluate the efficacy of oxandrolone in combination with nutritional supplementation in moderate or severe alcoholic hepatitis. MEASUREMENTS: Admission serum IgG antibody titers against H. pylori by a specific and sensitive ELISA, demographic characteristics of patients, degree of protein calorie malnutrition, presence of ascites, bilirubin level, and known risk factors for hepatic encephalopathy (gastrointestinal bleeding, azotemia, hepatorenal syndrome, infection, and severity of disease); outcome was the presence of portosystemic encephalopathy. RESULTS: Of 188 patients with decompensated alcoholic hepatitis available for analysis, 117 (62.2%) had encephalopathy. Ninety-two (78.6%) of these were infected with H. pylori, compared with 62% of patients without encephalopathy (p = 0.013). In a step-wise regression model, H. pylori was an independent risk factor (relative risk: 2.4, 95% CI: 1.2-4.8) adjusting for ascites and protein-calorie malnutrition. CONCLUSIONS: Patients with acute, moderate or severe alcoholic hepatitis have a high H. pylori infection rate (as determined by serology), and those infected are at higher risk for portosystemic encephalopathy.

Changes in partition of extracellular fluid volumes in anemic dialyzed uremic patients after partial correction of the anemia with recombinant human erythropoietin treatment.

The purpose of this work was to study the effects of correcting anemia on the distribution and partition of body fluids in dialyzed uremic subjects. We studied nine (7 m, 2 f) patients before and three months after the start of i.v. treatment with rHu-EPO, measuring total body water (TBW) with 3H2O, extracellular fluid volume (ECFV) with 35SO4 and plasma volume (PV) with 125I-SA. The intracellular water (ICW) and the interstitial fluid volumes (IFV) were derived by calculation from those measurements. The total blood volume (TBV) was calculated from the PV and the packed cell volume (PCV). Mean TBW, 482 +/- 45 (M +/- SD) ml/kg/bw and ECFV, 168 +/- 27.5 ml were significantly lower in patients than in nine matched normal controls, while the mean ICW (315 +/- 43 ml/kg) was similar. PCV before the start of rHu-EPO was 17.2 +/- 2.9% and had risen significantly to 31.3 +/- 4.8% (p = 0.000) after three months of therapy. Body weight (58 +/- 13 kg), TBW, ECFV and ICW did not change. TBV before rHU-EPO was 68.7 +/- 7.5 ml/kg and remained nearly unchanged, while PV fell significantly from 57 +/- 9 to 48 +/- 8 ml/kg (p < 0.025), with the calculated IFV rising from 111 +/- 25 to 127 +/- 27 (p = 0.000). The PV/IFV ratio decreased from 0.53 +/- 0.12 to 0.38 +/- 0.09 (p = 0.001). The decrease in PV/IFV ratio was paralleled by simultaneous increase in PCV in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased plasma interleukin-8 concentrations in alcoholic hepatitis.

Patients with alcoholic hepatitis often have hepatic polymorphonuclear leukocyte infiltration and neutrophilia. Interleukin-8 is a cytokine that stimulates neutrophil chemotaxis and release of lysosomal enzymes. It is made by several types of cells, including fibroblasts, Kupffer cells and hepatocytes. In this study, serial plasma interleukin-8 concentrations were measured with enzyme-linked immunosorbent assay in 40 consecutive patients with moderate-to-severe alcoholic hepatitis over a 6-mo period. Two control groups included 10 patients without clinically important liver disease admitted for treatment of alcohol dependence and 12 healthy male volunteers. The mean plasma interleukin-8 level on admission was markedly increased: 695 +/- 146 pg/ml in the alcoholic hepatitis patients. The alcohol-dependent control group and the normal volunteer controls had mean interleukin-8 concentrations of 106 +/- 28 pg/ml and 10 +/- 5 pg/ml, respectively. Initially increased interleukin-8 levels in alcoholic hepatitis patients decreased to a mean of 182 +/- 42 pg/ml over the first month; levels had decreased further to 124 +/- 79 pg/ml after 6 mo. Increased interleukin-8 concentrations in patients with alcoholic hepatitis suggest a role for interleukin-8 in the neutrophilia and hepatic polymorphonuclear leukocyte infiltration of alcoholic hepatitis.

Bilateral photon deficient area along lateral abdominal wall in a Tc-99m DTPA renogram. A sign of massive ascites.

A patient with congestive heart failure and hepatic and renal dysfunction underwent Tc-99m DTPA renal scintigraphic studies in which persistent cardiac blood pool activity, hepatic arterialization, and a longitudinal photon deficient area in each side of the abdominal wall were observed. The increase in hepatic artery inflow was believed to be due to a decrease in portal inflow of the liver. The elevation of portal pressure secondary to heart failure is attributable to the decrease in portal inflow of the liver; this phenomenon could account for the hepatic arterialization. Progressive renal dysfunction with high body background resulted in demonstrable ascites as photon deficient areas. Scintigraphic findings of hepatic arterialization plus an abdominal photon deficient area reflect severe heart failure and renal dysfunction.

A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study.

A Veterans Affairs cooperative study involving 273 male patients was performed to evaluate efficacy of oxandrolone in combination with an enteral food supplement in severe alcoholic hepatitis. All patients had some degree of protein calorie malnutrition. On an intention-to-treat basis, only minimal changes in mortality were observed. However, in patients with moderate malnutrition mortality on active treatment at 1 mo was 9.4% compared with 20.9% in patients receiving placebo. This beneficial effect was maintained so that after 6 mo on active treatment 79.7% of patients were still alive, compared with 62.7% of placebo-treated patients (p = 0.037). Improvements in both the severity of the liver injury (p = 0.03) and malnutrition (p = 0.05) also occurred. No significant improvement was observed with severe malnutrition. To better determine the effect on therapeutic efficacy, we compared results with those from a nearly identical population (cooperative study 119) treated with oxandrolone but not given the food supplement. Patients were stratified according to their caloric intake (greater than 2,500 kcal/day was considered adequate to supply energy needs and promote anabolism). For patients with moderate malnutrition and adequate caloric intake, oxandrolone treatment reduced 6-mo mortality (4% active treatment vs. 28% placebo [p = 0.002]). For patients with moderate malnutrition and inadequate calorie intake, oxandrolone had no effect on mortality (30% active treatment vs. 33% placebo). In cases of severe malnutrition, oxandrolone had no effect on survival. However, adequate caloric intake was associated with 19% mortality, whereas patients with inadequate intake exhibited 51% mortality (p = 0.0001). These results indicate that nutritional status should be evaluated in patients with alcoholic hepatitis. When malnutrition is present, vigorous nutrition therapy should be provided, and in patients with moderate malnutrition oxandrolone should be added to the regimen.

Effects of subcutaneous calcitriol administration on plasma calcium and parathyroid hormone concentrations in continuous ambulatory peritoneal dialysis uremic patients.

OBJECTIVE: To ascertain whether the parathyroid hormone (PTH) secretion of continuous ambulatory peritoneal dialysis (CAPD) uremic patients could be suppressed by repeated subcutaneous injections of calcitriol (CLT). DESIGN: Nonrandomized prospective study with weekly evaluation. SETTING: Hospital CAPD clinic. PATIENTS: Seven uremic CAPD patients with signs of severe hyperparathyroidism. INTERVENTIONS: Patients were treated with CLT (2 micrograms), injected subcutaneously three times a week, on alternate days over a period of 8 weeks. MEASUREMENTS: Plasma PTH, ionized calcium (Ca), serum phosphate (Pi), and alkaline phosphatase (AP) were assayed before the start of CLT therapy and weekly thereafter. RESULTS: The average basal PTH was 349 +/- 26 pg/mL (mean +/- SD). It fell significantly by the fifth week to 158 +/- 20, then leveled off. Analysis of the individual data, however, revealed that only 5 of 7 patients had a significant decrease in plasma PTH. Basal Ca was +/- .02 mmol/L; it increased continuously throughout the study, significantly by the fourth week, reaching a level of 1.33 +/- 0.3 mmol/L at the sixth week, then declined slightly. In those patients with significantly decreased PTH, there was an inverse correlation between PTH and the corresponding Ca levels. CONCLUSIONS: In some CAPD patients subcutaneous administration of CLT significantly suppresses PTH. This effect is mainly mediated via an increase in ionized calcium, but a direct inhibitory effect of the vitamin on parathyroid glands cannot be excluded.

Tumor necrosis factor in alcohol enhanced endotoxin liver injury.

Endotoxin administration causes liver injury. Patients with alcoholic liver disease frequently have portal vein and systemic endotoxemia, and some investigators have suggested that endotoxin plays an etiologic role in alcoholic liver injury. Many of the metabolic effects of endotoxin are mediated by the cytokine tumor necrosis factor (TNF). It was the purpose of this study to determine whether TNF plays a role in ethanol-enhanced endotoxin liver injury. Rats were fed either a diet in which 36% of the calories were from ethanol or an isocaloric control diet. After 6 weeks, groups of 10 rats were intravenously injected with either saline, 1 mg/kg endotoxin, or 30 micrograms/kg of a prostaglandin E1 (PGE1) analogue + 1 mg/kg endotoxin 24 hr prior to sacrifice. Ethanol/endotoxin-treated rats had significantly higher liver enzyme levels (ALT: 1064 +/- 355 IU/liter, AST: 2024 +/- 515 IU/liter) compared with isocaloric/endotoxin controls (ALT: 237 +/- 54 IU/liter, AST: 602 +/- 80 IU/liter). Ethanol/endotoxin rats also had significantly higher peak serum TNF concentrations (992 +/- 200 units/ml) compared with isocaloric/endotoxin controls (344 +/- 96 units/ml). Pretreatment of ethanol/endotoxin rats with PGE1 caused significant attenuation of liver injury (ALT: 267 +/- 64 IU/liter, AST: 612 +/- 77 IU/liter) and a diminished serum TNF response. In contrast to chronic ethanol administration, acute gavage with 2 mg/kg ethanol (30% w/v) followed by intravenous injection of 2 mg/kg endotoxin produced significantly lower peak serum TNF concentrations (401 +/- 76 units/ml) than gavage with distilled water (1152 +/- 208 units/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased plasma interleukin-6 concentrations in alcoholic hepatitis.

Interleukin-6 (hepatocyte stimulating factor) is a 26 kd cytokine that plays a major role in the acute phase response, especially the hepatic aspects of the acute phase response. Patients with alcoholic hepatitis manifest many aspects of the acute phase response. In this 6-month study we evaluated serial plasma interleukin-6 levels in 30 consecutive patients with moderate to severe alcoholic hepatitis. Mean admission plasma interleukin-6 activity was markedly increased (49.8 +/- 8.5 U/ml, normal less than 5 U/ml) in patients with alcoholic hepatitis, and levels decreased with clinical improvement to 15.6 +/- 6.1 U/ml at 6 months. Admission interleukin-6 activity correlated significantly (r = 0.82) with the severity of liver disease as assessed by the discriminant function of Maddrey. Also measured were selected assays postulated to be regulated by interleukin-6, including serum albumin (2.3 +/- 0.1 gm/dl), which was significantly depressed; alpha 1-acid glycoprotein (52 +/- 5 mg/dl), which was within normal limits; and IgA (827 +/- 70 mg/dl) and C-reactive protein (3.03 +/- 0.51 mg/dl), which were significantly elevated. Interleukin-6 activity fell over time in a pattern similar to that of bilirubin and C-reactive protein. We suggest that plasma interleukin-6 may not only regulate many aspects of the acute phase response but also may be a marker of inflammation and severity of disease in alcoholic hepatitis.

Cholescintigraphic demonstration of transient and functional common bile duct obstruction in a patient with acute pancreatitis.

Cholescintigraphy has proven useful in diagnosis of acute and chronic cholecystitis and evaluation of common bile duct obstruction. Common bile duct obstruction may be due to mechanical obstruction such as impact stone in the common duct or functional obstruction due to sepsis with intra-hepatic cholestasis or acute viral hepatitis. We present a cholescintigram of a patient with acute pancreatitis showing complete common bile duct obstruction.