Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection.

BACKGROUND: Basiliximab (Simulect), a high-affinity chimeric, monoclonal antibody directed against the alpha chain of human interleukin-2 receptor (CD25), reduces the incidence of acute renal allograft rejection when used in combination with cyclosporine (Neoral) and steroids. This study was designed to compare the safety and efficacy of basiliximab to polyclonal anti-T-cell (ATGAM) therapy for the prevention of acute rejection in de novo renal transplant recipients. METHODS: This 1-year, open-label, randomized trial was conducted in recipients of cadaveric or living-related donor renal transplants. All patients received cyclosporine (Neoral), mycophenolate mofetil (CellCept, MMF), and corticosteroids. Patients who were randomized to basiliximab therapy received a 20 mg i.v. bolus dose on days 0 and 4, and the majority of patients were initiated on cyclosporine within 48 hr of transplantation. Patients who were randomized to antithymocyte globulin therapy (ATGAM, ATG) received 15 mg/day i.v. within 48 hr of transplant and continued treatment for up to 14 days; ATG was stopped once therapeutic cyclosporine blood levels were achieved. The initiation of cyclosporine use was delayed in the ATG group until renal function was established (serum creatinine <3.0 mg/dl or 50% fall from baseline). RESULTS: Of the 138 randomized patients, 135 received at least 1 dose of study medication (70 patients, basiliximab; 65 patients, ATG). Demographic characteristics were similar between the basiliximab and ATG-treatment groups. At 12 months, the rate of biopsy-proven acute rejection was 19% and 20%, respectively, in the basiliximab and ATG groups. Although the overall profile of adverse events was similar between basiliximab- and ATG-treated patients, adverse events considered by the investigators to be associated with the study drug occurred more often among patients receiving ATG (42% vs. 11% with basiliximab). CONCLUSIONS: Basiliximab combined with early initiation of cyclosporine therapy resulted in low acute rejection rates similar to those achieved with ATG combined with delayed cyclosporine. Basiliximab therapy showed an excellent safety profile, with no increases in malignancies, infections, or deaths. Based on its convenient two-dose, body-weight independent regimen and comparable effectiveness to ATG, basiliximab is an attractive choice for the prevention of acute rejection episodes in renal transplant patients.

The use of the T tube after orthotopic liver transplantation.

An end-to-end choledochocholedochostomy (CD) over a T tube or a Roux-en-Y choledochojejunostomy (CDJ) have been the standard method of biliary reconstruction following orthotopic liver transplantation (OLTx). The objective of this study was to assess whether or not use of the T tube leads to increased biliary tract complications. Biliary tract complications were categorized as bile leak, stenosis, or obstruction that required therapeutic intervention. OLTx was performed in 161 patients over an 18-month period. Fifty-one patients were excluded from the study leaving a total of 110 patients for evaluation. Fifty-nine had their bile duct reconstructed over a T tube (CD T tube, group I) while the remaining 51 patients underwent bile duct reconstruction without a T tube (CD, group II). No difference was noted between groups I and II in their survival rate, rate of conversion to Roux-en-Y CDJ, or biliary complication rates. Our results indicate that CD (i.e., without a T tube) is both a safe and effective technique to reconstruct the biliary tract following hepatic transplantation. Routine use of a T tube with a CD anastomosis is unnecessary in most liver transplant patients. In addition, the omission of a T tube has reduced the number of radiological procedures performed at our center.

Fibrosing cholestatic hepatitis in renal transplant recipients.

Fibrosing cholestatic hepatitis in a specific histologic manifestation of hepatitis B virus infection consisting of periportal fibrosis, hepatocyte ballooning, cholestasis, a relatively scant inflammatory infiltrate, and marked overexpression of hepatitis B viral antigens in hepatocytes. Until recently, fibrosing cholestatic hepatitis had been reported only in recipients of liver allografts. In this report, we present two patient in whom this lesion developed following renal transplantation. Both patients had previous liver biopsies showing relatively mild histologic changes. In one patient, the lesion developed early after retransplantation, during the period of maximal immunosuppression. However, in the second patient this lesion developed after withdrawal of immunosuppression. In both cases, death occurred within a few months because of progressive liver disease. Since this lesion can develop in "relatively healthy" hepatitis B carriers following transplantation of organs other than liver, these patients should have careful monitoring of their liver disease. Moreover, since the disease may progress despite withdrawal of immunosuppression, these patients would clearly benefit from the development of more effective therapies for posttransplant hepatitis B.

Incidence and significance of Aspergillus cultures following liver and kidney transplantation.

Aspergillus infection is a rare but devastating complication following solid organ transplantation, with mortality rates that approach 100%. Aspergillus species (sp) are also ubiquitous in our environment and may contaminate culture plates. To determine the significance of positive Aspergillus cultures, we analyzed all positive cultures from the liver and kidney transplant services at our center for the treatments used and clinical outcomes. Aspergillus sp. were cultured from 4.5% of liver and 2.2% of kidney transplant recipients. A. fumigatus was the most common isolate, followed by A. niger and A. flavus. The lung was the most common site of positive cultures. Body fluids (ascites, pleural fluid) were common sources of positive cultures but were never associated with clinical disease. Positive brain biopsies occurred in 10% of patients. Analysis of risk factors for significant infection revealed that cultures with >2 colonies or more than one site of infection were predictive of significant infection and portended a poor prognosis even with aggressive therapy. Two or fewer colonies from a single site likely represented contamination and may be followed with repeat cultures. The high mortality rate associated with Aspergillus sp. infections in transplant recipients highlights the need for better anti-fungal prophylaxis and treatment.

A controlled analysis of the transjugular intrahepatic portosystemic shunt in liver transplant recipients. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database.

BACKGROUND: The transjugular intrahepatic portosystemic shunt (TIPS) is an important treatment for complications of portal hypertension. As some authors have suggested that TIPS may facilitate liver transplantation technically, the objective of this study was to determine the impact of TIPS on the liver transplant operation and its outcome. METHODS: The analysis was designed as a retrospective cohort study using a multicenter database. Fifty-five patients with TIPS were matched with 55 controls on the basis of 10 pretransplant laboratory, clinical, and demographic features. TIPS patients and control patients were compared with regard to duration of surgery, intraoperative blood product usage, liver and renal function, volume of ascites, survival, and hospital stay. For confirmatory purposes, a parallel analysis using linear regression methods was performed. RESULTS: By matched analysis, TIPS patients had less ascites at surgery (mean 0.9+/-0.20 vs. 2.2+/-0.37 L, P=0.005) and a slightly shorter time from incision to cross-clamp (mean 2.1+/-0.10 vs. 2.5+/-0.15 hr, P=0.03). However, there were not significant differences for total operative time (mean 6.0+/-0.17 vs. 6.3+/-0.25 hr, P=1.00), blood product usage, or any other outcome variable. Regression analysis confirmed these results. CONCLUSIONS: TIPS does not significantly impact the course of liver transplantation surgery. Therefore, preoperative portal decompression solely to facilitate liver transplantation is not an appropriate indication for TIPS.

Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients.

BACKGROUND: Infection and rejection are two common complications after liver transplants. In a preliminary study, administration of granulocyte colony-stimulating factor (G-CSF) to liver transplant recipients was associated with a decrease in sepsis episodes, sepsis-related deaths, and rejection compared with a historical control group of patients. The purpose of this study was to evaluate further the efficacy of G-CSF in liver transplant patients in a randomized, placebo-controlled, double-blind, multicenter trial. METHODS: Adult patients with a United Network Organ Sharing classification of 1 or 2 were randomized to receive a placebo, 100 microg/day of G-CSF or 300 microg/day of G-CSF. The study drug was started preoperatively and then continued after the transplant for a maximum of 21 days. Patients were evaluated for microbiologically-documented infection, biopsy-proven rejection, number of treatments for rejection, length of stay in the intensive care unit and hospital, graft survival, death, and adverse events. RESULTS: During the first 30 days after the transplant, the median peak white blood cell count was 16.5x10(9)/L, 34.6x10(9)L, and 54.8x10(9)/L for the placebo, low-dose G-CSF, and high-dose G-CSF patients, respectively. The incidence of infection was 30% in G-CSF patients (34 of 114 patients) and 34% in placebo patients (20 of 58 patients). Except for more nosocomial pneumonias in the G-CSF patients (7 in 114 patients vs. 0 in 58 patients, P=0.056), the types of infections and causative organisms were also similar in both treatment groups. Although the number of treatments for clinically suspected or proven rejection was similar in the G-CSF and placebo patients, biopsy-proven rejection occurred more often in G-CSF patients (34 of 114 patients or 30%) than placebo patients (11 of 58 patients or 19%) (P=0.093). There were no cases of graft loss caused by rejection. G-CSF had no effect on length of stay in the intensive-care unit or hospital. There were 22 G-CSF patients (18%) and 10 placebo patients (15%) who died within 120 days after the transplant. No serious adverse events were attributed to G-CSF. CONCLUSION: Despite producing substantial increases in the white blood cell count after the transplant, G-CSF had no beneficial effects on infection, rejection, or survival in this study. Biopsy-proven rejection and nosocomial pneumonias were more common in patients treated with G-CSF compared with those taking the placebo. No serious adverse events were attributed to G-CSF.

Grepafloxacin pharmacokinetics in individuals with hepatic dysfunction.

The pharmacokinetics of grepafloxacin, a new broad spectrum fluoroquinolone antibiotic, were studied in 2 trials involving 14 healthy volunteers, 10 individuals with mild (Child-Pugh Class A) impairment of liver function, and 12 with moderate (Child-Pugh Class B or C) hepatic impairment. All participants received an oral dose of grepafloxacin 400 mg, daily for 7 days, and plasma and urine grepafloxacin concentrations were measured over 7 days. The pooled data from participants with impaired liver function showed that, compared with healthy individuals, peak plasma grepafloxacin concentrations, area under the plasma concentration-time curve and proportion of the dose excreted in the urine were increased. In addition, apparent total clearance was reduced in the presence of hepatic dysfunction. Peak concentrations were increased by 36% and 48% in individuals with Class A and B disease, respectively; the corresponding reductions in clearance were 33% and 55%, respectively. Child-Pugh scores and components of the scores showed no correlation with any pharmacokinetic variables. Based on these findings, we recommend a daily grepafloxacin dose of 400 mg in patients with mild hepatic impairment, irrespective of the severity of infection. Grepafloxacin should not be used in patients with moderate or severe liver disease.

Thoracoscopic esophageal myotomy in the treatment of achalasia.

We treated 24 patients with achalasia using thoracoscopic (22 patients) or laparoscopic (2 patients) esophagomyotomy. The only operative complications were mucosal lacerations, which occurred in 3 patients and required conversion to an open procedure in 2. Twenty-two (91%) patients were eating by the second postoperative day. Analgesics were only required for the management of pain from the chest tube, which remained in place for a median time of 24 hours. The median postoperative hospital stay was 3 days (range, 20 to 14 days). The myotomy proved to be incomplete in the first 3 patients, who required a second myotomy; this was done laparoscopically in 2. One patient had a paraesophageal hernia repaired 6 months after the myotomy, and 1 patient required an esophagectomy 1 year after the myotomy for a large nonfunctioning esophagus. Late follow-up showed that swallowing was excellent in 17 (71%) and fair to good in 4 (17%). Sixteen (66%) of these 24 patients have regained their original weight. Thus, excellent to good results were ultimately obtained in nearly 90% of the patients. These results suggest that esophageal myotomy performed using minimally invasive techniques appears to be the treatment of choice for achalasia.

Effects of oral prostaglandins on indomethacin-induced renal failure in patients with cirrhosis and ascites.

Nonsteroidal antiinflammatory drugs (NSAID), such as indomethacin, reduce production of renal prostaglandins and markedly impair renal function in patients with cirrhosis and ascites. To determine if simultaneous administration of oral prostaglandin analogs minimizes the renal impairment, 10 patients received indomethacin and either misoprostol or placebo in a double-blind, crossover study. Indomethacin reduced urinary sodium from 23 +/- 9 to 8 +/- 4 microEq/min in 4 hours. Misoprostol with indomethacin tended to prevent the fall in urinary sodium (from 35 +/- 15 to 46 +/- 21 microEq/min at 4 hours), but sodium excretion fell to the same level in both groups by 8 hours (6 +/- 3 microEq/min). Indomethacin reduced creatinine clearance in 4 hours by 49%; misoprostol plus indomethacin reduced creatinine clearance by only 34%. Misoprostol tended to minimize or delay the nephrotoxic effects of indomethacin, suggesting that more potent prostaglandin analogs may prevent the renal impairment induced by NSAID.

Hemodynamic consequences of therapeutic portosystemic shunting: recent experience with transjugular intrahepatic portosystemic shunts.

TIPS provides a side-to-side portosystemic shunt without a major abdominal operation. Although TIPS is relatively less invasive, it is associated with similar hemodynamic alterations as surgically created side-to-side shunts. An important difference is that a mild degree of portal hypertension is maintained with TIPS similar to small diameter shunts. TIPS provides effective portal decompression and prevents variceal hemorrhage. However, the risk of encephalopathy is relatively high and stenosis is a long-term concern in many patients. An important advance in the future use of TIPS will be tailoring the diameter of the shunt to optimize regional and systemic hemodynamics in a given individual to minimize the risk of bleeding or to decrease ascites accumulation while limiting the risk of hepatic encephalopathy and liver failure.

Acute tumor lysis syndrome after intrathecal methotrexate administration.

A 44-year-old man had acute tumor lysis syndrome after a single dose of intrathecal methotrexate was administered for lymphomatous meningitis (high-grade, small noncleaved B-cell) in the setting of untreated systemic disease. The metabolic derangements reversed completely with conservative therapy and did not recur with subsequent treatment. Intrathecal methotrexate administration results in potentially toxic systemic methotrexate levels which persist longer than an equivalent systemic dose. Active central nervous system lymphoma may increase the duration of toxic levels in the circulation and contribute to the peripheral effects of the drug. The pathogenesis of tumor lysis syndrome in this patient and the mechanisms of systemic toxicity of intrathecal methotrexate are discussed.

Transjugular intrahepatic portosystemic shunts for refractory ascites: assessment of clinical and hormonal response and renal function.

Cirrhosis is frequently complicated by ascites that may become resistant to diuretic therapy. Transjugular intrahepatic portosystemic shunts (TIPS) represent a new treatment for this debilitating condition. The aim of this study was to ascertain the clinical efficacy of TIPS, as well as its impact on renal function and on hormonal parameters. Five inpatients with refractory ascites were studied prospectively before TIPS, and 3 and 14 days after TIPS. After TIPS, ascites completely resolved or was minimal in all patients. Diuretics were discontinued in three subjects and decreased by at least 50% in two. One patient developed liver failure after TIPS and required liver transplantation; the others remained stable after a mean follow-up of 14 months. Mean urinary sodium excretion increased from 2.1 +/- 0.6 mEq/24 hr before TIPS to 13.0 +/- 4.3 mEq/24 hr 14 days after TIPS. Mean serum creatinine and glomerular filtration rate also tended to improve during the study period. With the exception of the patient who developed liver failure, plasma aldosterone concentration decreased from a mean of 126.0 +/- 29.9 ng/dL to 22.8 +/- 6.8 ng/dL (P = .04), and plasma renin activity decreased from a mean of 9.0 +/- 3.0 micrograms/L/h to 0.9 +/- 0.1 microgram/L/h (P = .08). Additionally, 19 patients who underwent TIPS for refractory ascites outside of this protocol were followed prospectively for a mean of 282 days. Clinical improvement in ascites control was noted in 74%, and the mean dose of diuretics was decreased by more than 50%. Nonresponders more often had underlying renal disease. In conclusion, TIPS is an effective therapy for refractory ascites in most patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction.

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.

Enterococcal bacteremia after transjugular intrahepatic portosystemic shunts (TIPS).

The objective of this study was to analyze a series of patients with Enterococcus faecium infection following transjugular intrahepatic portosystemic shunts (TIPS) in order to define the risk factors, outcome, and role of treatment including hepatic transplantation. This study is a case series from a tertiary referral center for liver transplantation. The medical records of four patients referred to one teaching hospital in San Francisco between 1990 and 1995 for evaluation or management of Enterococcal infection following TIPS were reviewed. A review of the microbiology records of all 314 patients who underwent TIPS at that institution and a MEDLINE search were performed to assess whether any other cases existed. The effect of therapy on survival was assessed, in particular, the repeated use of TIPS and prolonged courses of antibiotics. All four patients had thrombosis of their TIPS at the time of diagnosis of enterococcal bacteremia. All were treated with prolonged courses of intravenous antibiotics. One patient had echocardiographic evidence of subacute bacterial endocarditis with chronic aortic insufficiency. In all cases, liver transplantation was contraindicated in the acute setting because of uncontrolled endovascular infection. Two of four patients survived; these were the only two patients who had had a successful repeat TIPS. Enterococcal bacteremia is a rare complication following TIPS but carries a high mortality. It usually occurs in the setting of technically difficult TIPS with shunt thrombosis. Management should be focused on long term antibiotics and attempts at reestablishment of portal decompression with another TIPS. Liver transplantation should not be considered until the infection is cleared. Prophylaxis for Enterococcus species should be considered in technically difficult or unsuccessful TIPS.

Cholestatic hepatitis C in liver allografts.

Some liver allograft recipients with hepatitis C virus (HCV) infection develop hyperbilirubinemia, which might be the result of a cholestatic variant of hepatitis C. We evaluated all liver biopsy samples from 6 liver transplant recipients who had polymerase chain reaction-positive HCV infection and histologic evidence of hepatitis and jaundice and compared them with liver biopsy samples from a control group of transplant recipients with HCV hepatitis without jaundice. Patients with known ductopenic rejection, biliary obstruction, or co-infection with hepatitis A or B were excluded from the study. Measurement of viral titers and genomic typing were performed when possible. Six patients developed hepatitis and jaundice, with maximum bilirubin levels ranging from 5.8 to 47.6 mg/dL. In this group, 5 (83%) had moderate interface hepatitis (control group, 15%), 6 (100%) had confluent necrosis (control group, 12%), 5 (83%) had bridging fibrosis (control group, 18%), 4 (67%) had significant hepatocyte swelling (control group, 9%), 4 (67%) had prominent ductular proliferation (control group, 3%), and 6 (100%) had mild duct damage and inflammation (control group, 53%). All 6 of the patients with cholestasis had allograft failure. Of these, three allografts were available for review, which did not reveal occult obstruction, rejection, or duct loss. All patients in the control group have retained their allografts. In 4 patients with cholestasis, the median HCV RNA titer was 93.97 mEq/mL, with a mean of 54.19 mEq/mL (control mean = 5.2 mEq/mL). Five patients also underwent viral genomic typing: 2 with type 1a, 2 with type 1b, and 1 with mixed type 1a and 1b. Cholestasis in patients with posttransplantation hepatitis C may be caused by an aggressive HCV infection that exhibits histologic features of confluent necrosis, hepatocyte swelling, and/or ductular proliferation. Viral titers are often increased in such patients.

Successful reversal of hepatic encephalopathy with intentional occlusion of transjugular intrahepatic portosystemic shunts.

PURPOSE: To establish a safe and effective method for occluding a transjugular intrahepatic portosystemic shunt (TIPS) in patients who develop uncontrollable, disabling encephalopathy. PATIENTS AND METHODS: The study population consisted of five patients who developed refractory encephalopathy following TIPS. The indication for TIPS was bleeding in four patients and ascites in one. Wallstents that were 10 mm in diameter and 68 mm long were used to bridge the hepatic parenchyma in all patients. The onset of encephalopathy from the time of the TIPS procedure ranged from 24 hours to 210 days. Because encephalopathy was not responsive to conventional medical management, shunt thrombosis was induced by means of temporary inflation of an 11.5-mm-diameter latex occlusion balloon within the midportion of the stent. RESULTS: All shunts were successfully thrombosed when the balloon was inflated for 12 hours or more. Encephalopathy resolved in four patients and improved in the remaining patient. One patient experienced recurrent bleeding within 24 hours of the TIPS occlusion that was controlled medically. CONCLUSION: Temporary occlusion of a TIPS with latex balloons successfully induces shunt thrombosis and improves encephalopathy. However, the patient is again exposed to risks related to complications of portal hypertension.

Creation of transjugular intrahepatic portosystemic shunts with the wallstent endoprosthesis: results in 100 patients.

One hundred patients underwent transjugular intrahepatic portosystemic shunt (TIPS) creation for variceal bleeding (n = 94), intractable ascites (n = 3), hepatorenal syndrome (n = 2), and preoperative portal decompression (n = 1). Shunts were completed in 96 patients. Portal vein pressure was reduced from 34.5 mm Hg +/- 7.6 (standard deviation) to 24.5 mm Hg +/- 6.2; the residual portal vein-hepatic vein gradient was 10.4 mm Hg +/- 0.9. Acute variceal bleeding was controlled in 29 of 30 patients. Of the 96 patients who underwent successful TIPS creation, 26 have died and 22 have undergone liver transplantation; the remaining 48 patients have survived an average of 7.6 months. Variceal bleeding recurred in 10 patients. Fifteen patients developed shunt stenosis (n = 6) or occlusion (n = 9). Patency was reestablished in eight of the nine occluded shunts. Seventeen patients developed new or worsened encephalopathy. The authors conclude that TIPS creation is an effective and reliable means of lowering portal pressure and controlling variceal bleeding, particularly in patients with acute variceal bleeding unresponsive to sclerotherapy and patients with chronic variceal bleeding before liver transplantation.

Hepatic encephalopathy after transjugular intrahepatic portosystemic shunts: incidence and risk factors.

OBJECTIVES: The aim of this study was to determine the incidence of new or worsened hepatic encephalopathy after transjugular intrahepatic portosystemic shunts (TIPS) and to ascertain which clinical characteristics are associated with this complication. METHODS: At the University of California, San Francisco, over 22 months, TIPS were placed successfully in 108 adults. Seventy-seven patients in whom it was possible to assess the development of encephalopathy comprised the study population. Clinically significant encephalopathy was assessed at protocol clinic follow-up and, in some cases, by phone contact with the patient and the referring physician. Post-TIPS encephalopathy was defined as new onset of clinical encephalopathy requiring treatment or worsening of preexisting encephalopathy within 1 yr of TIPS. RESULTS: The overall incidence of new or worsened encephalopathy was 23% (18/77). Post-TIPS encephalopathy was well controlled with lactulose in 78% of cases and was progressive in 22%. Multivariate analysis showed that an increased risk of encephalopathy was associated with an etiology of liver disease other than alcohol [relative risk (RR) 9.2, p = 0.0052], female gender (RR 3.0, p = 0.029), and hypoalbuminemia (RR 2.2 for each 1 g/dl decrease, p = 0.044). CONCLUSIONS: Hepatic encephalopathy is a common complication of TIPS that can be controlled medically in most patients. The identification of clinical variables associated with an increased risk of encephalopathy may be useful in the selection of appropriate candidates for this procedure.