Roux-en-Y gastric bypass for recurrent nonalcoholic steatohepatitis in liver transplant recipients with morbid obesity.

BACKGROUND: Severe obesity is common before and after liver transplantation and has been associated with significant morbidity and mortality. Furthermore, it may cause graft dysfunction through the development of recurrent nonalcoholic steatohepatitis. METHODS: We performed Roux-en-Y gastric bypass in two morbidly obese patients who had undergone liver transplantation and had graft dysfunction secondary to recurrent nonalcoholic steatohepatitis. RESULTS: Both patients demonstrated dramatic weight loss and had normalization of liver enzymes, lipids, and glucose levels. Repeated liver biopsy showed regression of steatosis. CONCLUSIONS: Roux-en-Y gastric bypass can be successfully performed in liver transplant recipients with morbid obesity and may lead to weight loss, correction of metabolic abnormalities, and regression of hepatic dysfunction secondary to recurrent steatosis.

Increased incidence of rejection in patients with delayed graft function.

Because of the difficulties in diagnosing rejection in patients with delayed graft function, such patients were routinely biopsied 7-10 days after kidney transplantation. We found histologic evidence of rejection in 48% of the cases during the lst month posttransplant, a proportion that was significantly higher than in patients with immediate graft function. Furthermore, the 2-year graft survival in patients with delayed graft function and rejection, but not in those without rejection, was significantly lower than in patients with immediate function. The results suggest that there is an association between delayed graft function and rejection and that rejection is the component responsible for the decreased graft survival previously reported for patients with delayed graft function.

Transplantation of a hepatitis B surface antigen-positive donor liver into a hepatitis B virus-negative recipient.

A critically ill, HBV seronegative girl who received a liver from a HBsAg+ donor is described. Despite HBV Ig prophylaxis, she was seropositive for HBsAg shortly after transplantation. Although the postoperative period was complicated, HBV-related problems were not encountered. Liver dysfunction was noted 7 months after transplantation. At that time, she became anti-HBc IgM-positive, with liver histologic findings suggestive of chronic active hepatitis B. The liver function normalized after a reduction of immunosuppressive therapy and introduction of ciprofloxacin. The patient had low level HBV replication during the entire follow-up period (HBV DNA-positive by PCR only) and sequencing of the virus on 4 occasions revealed only wild-type HBV. She subsequently lost serum HBsAg and HBV DNA (even by PCR) and has remained well 2 years after transplantation.

A preliminary report of diltiazem and ketoconazole. Their cyclosporine-sparing effect and impact on transplant outcome.

A prospective randomized trial was conducted to compare the effect of diltiazem (DILT) with ketoconazole (KETO) on sparing of cyclosporine dose and renal transplant outcome. Renal allograft recipients 18 years old and older were eligible for the study. Triple immunosuppression (TRIPLE) including prednisone, azathioprine, and CsA was administered to all patients. The maintenance CsA dose varied by study group. Patients were randomized to receive one of three treatment strategies: group 1-TRIPLE (CsA 8 mg/kg/day); group 2--TRIPLE (CsA 6 mg/kg/day) + DILT (60 mg b.i.d.); group 3--TRIPLE (CsA 3 mg/kg/day) + KETO (200 mg/day). Modification of the DILT dose was allowed as needed to effect blood pressure control in group 2 patients. Mean 1-month CsA dose reductions were 30% and 60% of controls in group 2 and 3, respectively. A continued effect over time was observed in patients administered KETO but not DILT. At 1 year patients taking KETO required an average of 77% less CsA than the average dose necessary to effect similar parent CsA blood levels when no enzyme inhibitor was used. The use of KETO and DILT for 1 year allowed for 53% and 14% reductions in CsA cost, respectively. These savings include the cost of the KETO or DILT. Serum creatinines, mean arterial pressure (MAP), and incidence of liver function abnormalities were similar throughout treatment groups. The rate of rejection, time to rejection onset, and survival (GS/PS) were not different among the groups. Fungal infections were fewer in patients treated with KETO (12%) than in controls (16%) and patients randomized to DILT (19%). KETO failed to prevent Aspergillus infection in one individual. The investigation failed to identify any harmful result of treating renal allograft recipients with either DILT or KETO for the purpose of reducing CsA expense.

The crossmatch in renal transplantation. Evaluation of flow cytometry as a replacement for standard cytotoxicity.

Flow cytometry (FC) is increasingly being used as a crossmatch procedure in addition to the standard complement-dependent cytotoxicity (CDC) test. In fact, FC offers a number of advantages over CDC and has the potential to become the primary crossmatch technique for cadaveric donor renal transplantation. We evaluated this possibility in 230 patients crossmatched by both CDC and FC. The results showed that when the T cell crossmatch was negative by FC it was always negative by CDC, and that when the T cell results were positive by CDC (IgM antibodies excluded) they were also positive by FC. As expected, a number of tests were T cell-positive by FC but negative by CDC. A T cell CDC crossmatch was more likely to be positive when FC was positive for both T and B cells and when FC results were quantitatively higher. However, FC was unable to consistently predict a positive, dithiothreitol-resistant B cell CDC crossmatch. A policy to transplant patients with negative FC results (70% of the patients evaluated) and not to transplant sensitized patients with FC+ T cell results (10%) would allow us to make a final decision with only FC in 80% of the cases. Actual graft survival was similar for nonsensitized first-transplant candidates with positive (83%) or all patients with negative (86%) FC results. We conclude that FC is sufficient to make a final decision in most cases. Wider utilization will require improvements in the ability of FC to measure B cell antibodies and to quantitate antibodies to T cells.

Non-A, non-B hepatitis and elevated serum aminotransferases in renal transplant patients. Correlation with hepatitis C infection.

One hundred renal transplant recipients were studied for antibodies to hepatitis C virus (HCV), and to HCV RNA in serum by reverse transcription+nested polymerase chain reaction (RT-PCR). Presence of antibody to HCV confirmed by recombinant immunoblot assay II was considered evidence of HCV infection, and detection of HCV RNA by RT-PCR was considered evidence for active viremia. On pretransplant sera, 18 patients were RT-PCR positive and an additional 3 had antibody evidence of HCV infection. At 1-year follow-up, all of these patients were RT-PCR positive and an additional 7 patients became RT-PCR positive. Clinical diagnosis of non-A, non-B hepatitis underestimated the prevalence of HCV infection (5/28 cases, 18%). Serum alanine aminotransferase (ALT) elevations were neither sensitive nor specific. An isolated pretransplant ALT elevation predicted a 52% chance of being RT-PCR positive for HCV. An ALT elevation greater than 2 months after transplant predicted a 45% chance of HCV positivity; however, 18% of patients who never had any ALT abnormality were also HCV positive. Sixty-eight patients had an early postoperative rise in ALT, but there was no correlation with HCV status. After an average follow-up of over 4 years, 3/28 HCV-positive patients developed cirrhosis. HCV infection in the renal transplant population is common and underdiagnosed by clinical and biochemical parameters. HCV appears not to cause aggressive liver disease in the early posttransplant period, but longer follow-up is needed to define the natural history of HCV in the renal transplant population.

Kupffer cells can present alloantigen in vitro: an effect abrogated by gadolinium.

Portal venous (PV) injection of alloantigen can result in tolerance. We have previously reported that this effect is abrogated by pretreatment with gadolinium (Gd), an element known to inhibit Kupffer cell phagocytosis. To further elucidate the role of Kupffer cells (KC) in PV tolerance, the present study examined the ability of KC to present alloantigen in vitro to syngeneic responder lymphocytes after in vivo PV administration of alloantigen with or without pretreatment with Gd. Wistar Furth (WF) rats were pretreated 24 hr prior to KC harvest with a PV injection of 1 x 10(7) allogeneic Lewis (LEW) rat lymphocytes (KC-L) or saline (KC-N). Another group received Gd intravenously 24 h prior to the PV injection of LEW cells (KC-L + Gd). KC were isolated from the WF rats using collagenase digestion and Percoll (90% pure by morphologic criteria and by monoclonal antibodies KU-1 and ED-2). Responder WF lymphocytes were cocultured with media alone, or with KC as prepared above, for 72 hr. KC-L demonstrated significant stimulation of the WF responders (P = 0.02 vs KC-N). Gd abrogated this stimulation (P = 0.04, KC-L vs KC-L + Gd) but not by nonspecific inhibition of the cocultures (KC-N vs KC-L + Gd, P > 0.05, no difference). This study demonstrates that KC can effectively present PV alloantigen for the activation of naive syngeneic T lymphocytes, thereby further supporting the hypothesis that KC play an integral role in the induction of PV tolerance by presentation of antigen to responder T cells.

Hepatitis C virus infection in kidney transplant recipients.

To determine the prevalence and significance of hepatitis C virus infection in kidney transplant recipients, paired serum samples collected from 100 renal allograft recipients on admission for kidney transplantation and 1 yr after transplantation were tested for antibody to hepatitis C virus with second-generation enzyme immunoassay and recombinant immunoblot assay and for hepatitis C virus RNA with reverse transcription-polymerase chain reaction. Before kidney transplantation, hepatitis C virus antibody was detected with second-generation enzyme immunoassay in 18 patients (12 second-generation recombinant immunoblot assay-positive, 6 second-generation recombinant immunoblot assay-indeterminate). Nine of 12 second-generation recombinant immunoblot assay-positive and 2 of 6 second-generation recombinant immunoblot assay-indeterminate samples were hepatitis C virus RNA positive. In addition, 7 of 82 patients who had no detectable antibody on second-generation enzyme immunoassay or second-generation recombinant immunoblot assay were hepatitis C virus RNA positive. After kidney transplantation, hepatitis C virus antibody was detected in 19 patients (12 second-generation recombinant immunoblot assay-positive, 7 second-generation recombinant immunoblot assay-indeterminate, 14 seropositive for hepatitis C virus antibody). Eleven of 12 patients with second-generation recombinant immunoblot assay-positive results and 4 of 7 with second-generation recombinant immunoblot assay-indeterminate results were positive for hepatitis C virus RNA. Hepatitis C virus RNA was present in 28 patients 1 yr after kidney transplantation. Six patients appeared to have acquired active hepatitis C virus infection 1 yr after kidney transplantation (seroconverted to hepatitis C virus RNA positivity).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of the polymerase chain reaction for cytomegalovirus to the development of hepatitis in liver transplant recipients.

In a pilot study, the polymerase chain reaction was found to be more sensitive than standard viral culture methods for the detection of cytomegalovirus, particularly from blood and tissues. We therefore applied this technique to 71 serially collected liver biopsies from 16 orthotopic liver transplant patients. All patients were CMV-seropositive (n = 15) or seroconverted (n = 1). Seven patients (9 biopsies) had histologically proved CMV hepatitis, and all these biopsies were CMV PCR-positive. Six of these 7 patients had a prior liver biopsy that was CMV PCR-positive, but culture and histology-negative, an average of 13.2 +/- 6.9 days before the histologically positive biopsy. The 7th patient was not biopsied prior to the diagnostic biopsy. Three patients had 7 liver biopsies that were CMV PCR-positive, but histologically negative for CMV hepatitis. Two of these three had CMV infection confirmed by viral culture of blood or liver biopsy. The remaining 6 patients had a total of 26 liver biopsies that were negative for CMV by PCR, culture, and histology. Among liver transplant patients, CMV PCR performed on liver biopsy specimens correctly identified all histologically proven cases of CMV hepatitis. CMV PCR positivity in liver tissue did not correlate with latent infection and preceded the development of CMV hepatitis or other meaningful CMV infection in 8 of 10 patients.

Psychological adjustment of liver transplant candidates.

The psychological functioning of 20 adult liver transplant candidates was evaluated. Using standardized assessment instruments, we found few personality disturbances and normal levels of anger. However, clinically significant levels of depression and anxiety were reported for 28% and 37% of the sample, respectively. Moreover, patients whose coping strategies were characterized by avoiding the exigencies of their illness reported more depression, more anxiety, and increased psychopathology. Disease severity was also positively correlated with anxiety and avoidant coping strategies. Implications of these findings for the pre-transplant psychological evaluation are discussed.

Laparoscopic cholecystectomy in a high-risk diabetic CAPD patient.

An obese 48-year-old diabetic woman with end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) developed symptomatic cholelithiasis within 2 weeks of initiating CAPD. She was not a good risk for either open cholecystectomy or postoperative hemodialysis, and the relatively noninvasive surgical approach of laparoscopic cholecystectomy was considered to minimize postoperative morbidity and to allow the patient to resume her CAPD treatments after a short postoperative recess from dialysis altogether. The patient tolerated the procedure well with no complications. She resumed routine CAPD on her third postoperative day.

Hyperacute and acute kidney graft rejection due to antibodies against B cells.

Because of the perception of its uncertain clinical significance, the B cell crossmatch is not universally performed before renal transplantation. Even though sporadic cases of hyperacute rejection associated with B cell antibodies have been reported, doubts remain in light of other studies suggesting no effect on graft survival. This report describes 4 cases of graft rejection (3 hyperacute and 1 acute) that occurred in patients with anti-B-cell antibodies specific against donor HLA-DR or DQ antigens. Absence of anti-donor class I antibodies was confirmed in all cases by 2-color flow cytometry. Strong evidence for an antibody-mediated mechanism was found in one patient with anti-class I and anti-class II antibodies in serum transplanted with a class II mismatched kidney. In this case, only anti-class II antibodies were recovered in the eluate of the nephrectomy specimen. These four cases were compiled from three different institutions over a four-year period, which confirms the infrequent occurrence of these events. While anti-class II antibodies may not always be detrimental for graft survival, these results also confirm that they have the potential to cause hyperacute or acute graft loss. We conclude that the information provided by the B cell crossmatch should be available at the time that a decision to proceed with a renal transplant is made.

Immunosuppression without prophylactic antilymphocyte preparations.

1. Triple-drug immunosuppression following third party transfusion can result in graft survival equal to protocols that employ prophylactic antilymphocyte preparations. 2. T1/2 was statistically improved in cadaveric and living-related donor grafts in the CsA era. 3. Patients 65 years and older had an excessive death rate. Younger groups were admixed. Extreme youth was not a risk factor. 4. Black recipients had excessive late graft loss. 5. Diabetic recipients had only a slight decline in graft and patient survival rates. 6. First and multiple graft recipients had similar transplant survival rates. 7. Delayed graft function remains costly in this immunosuppressive scheme.

Depletion of dietary arginine inhibits growth of metastatic tumor.

The effects of dietary arginine on the growth of a murine colon tumor metastatic to the liver were examined in a model of advanced neoplastic disease. Tumor growth was influenced by arginine both in vivo and in vitro. An arginine-supplemented diet stimulated tumor growth by 55% compared with controls. Conversely, an arginine-depleted diet inhibited tumor growth by 78% compared with controls. In vitro culture of both murine and human colon tumor cells confirmed that arginine was necessary for cell growth. Flow-cytometric analysis using propidium iodide and bromodeoxyuridine suggested that colon tumor cells cultured without arginine enter a quiescent S phase and depend on arginine for further growth and cell cycle progression. The potential roles for selective dietary arginine modulation in patients with cancer with advanced disease are discussed.