Mathew E. Brunson

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.

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.

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 ketocon-azole (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.

Effect of various prokinetic agents on post Roux-en-Y gastric emptying

The effect of various prokinetic drugs was assessed in animals with Roux-en-Y gastrojejunostomy. The agents tested were (1) bethanechol 2.5 mg subcutaneously at 0 min and 30 min postprandially (pp); (2) metoclopramide 20 mg intravenous bolus at 0 min pp; (3) a combination of 1 and 2; (4) oxytocin 5 mg intramuscularly at 0 min and 240 min pp; (5) motilin at 100 ng/kg/hr; or (6) 300 ng/kg/hr continuous intravenous infusion from 0 to 270 min pp. Only bethanechol administration resulted in significantly less gastric retention (65 ±6% vs 32±5% retention at 5 hr). (P<0.002). The animal results with parenteral bethanechol were confirmed in humans with chronic delayed gastric emptying following Roux-en-Y gastrojejunostomy, with a decrease in gastric retention on radionuclide scan from 78.5±5% to 26±12% at 2 hr pp (P<0.01). Initially all patients responded with symptomatic improvement. However, subsequently 3/6 (50%) of patients required total or near total gastrectomy for recurrent symptoms of gastric stasis. Nevertheless, 2/6 (33%) of patients have no further evidence of gastric stasis, and a trial of bethanechol is recommended prior to considering further gastrectomy in patients with the Roux-stasis syndrome.

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.

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.