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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. Final allograft recipients 18 years old and older were eligible for the study. Sample 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 b mg/kg/day)+ DILT (60 b.i.d.); group 3-TRIPLE (CsA 3 mg/kg/day)+KETO (200 mg/day)

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.

Background. Invasive aspergillosis is a life-threatening complication in liver transplant recipients, with a reported mortality rate of more than 90%. Treatment is difficult, and no single agent is uniformly effective in treating this patient population. Methods. We retrospectively reviewed all fungal cultures from 200 liver transplant patients between 1996 and 1999 at a single tertiary referral center. Results. A diagnosis of aspergillosis was made its 6 patients. Five patients. had pulmonary involvement; 1 presented with an inguinal mass. Time from transplant to infection ranged from 1 week to 34 months. Treatment included surgical intervention and medical treatment. All patients infected with Aspergillus fumigatus were treated with a sequential protocol of lipid complex amphotericin followed by itraconazole. The major side effect of treatment was worsening renal function. One patient died of intracranial hemorrhage during treatment. Conclusion. Successful treatment of aspergillosis in liver transplant recipients should include early diagnosis, sequential medical treatment with lipid amphotericin B and itraconazole, and surgical intervention for invasive disease.

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). We found no correlation between the presence of hepatitis C virus markers in the pretransplant and posttransplant sera and clinical/biochemical parameters or clinical outcome. Hepatitis C virus infection was clinically silent in most patients. Semiquantitation of serum hepatitis C virus RNA in 25 patients with hepatitis C virus infection showed that the hepatitis C virus RNA titer remained the same (n = 12) or increased at least 10-fold (n = 12), and only 1 patient had a decrease in serum hepatitis C virus RNA level. These data suggest that (a) the prevalence of hepatitis C virus infection is high in kidney transplant recipients, (b) active hepatitis C virus replication may be present in the absence of hepatitis C virus antibody, (c) many of these patients who are second-generation enzyme immunoassay–positive but second-generation recombinant immunoblot assay–indeterminate are hepatitis C virus RNA positive, (d) hepatitis C virus infection is usually clinically silent during the initial follow-up period and (e) antirejection immunosuppression may enhance hepatitis C virus replication. (HEPATOLOGY 1993;18:1027-1031).

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.

These studies address infection risk of allogeneic transfusion in an untraumatized, nonseptic rodent model. A' Segaloff Cancer Institute rats served as blood donors and Lewis rats as recipients. Lewis rats' delayed-type hypersensitivity (DTH) response and their ability to clear subdermal Staphylococcus aureus abscesses and Candida albicans pyelonephritis were measured as tests of the effect of transfusions. The effect of pharmacological immunosuppression with either cortisone acetate or cyclosporine provided a "yardstick" to measure the magnitude of transfusion effects. Repeated transfusions at 1-week intervals diminished DTH response to recall antigens (keyhole limpet hemocyanin), but otherwise they showed no evidence of immunosuppression in these experiments. In contrast, we found that transfusions by themselves produced mild immunostimulation. Subcutaneous Staphylococcus abscesses were smaller in animals receiving transfusions. The magnitude of immunostimulation from one transfusion was sufficient to reverse the immunosuppressive effect of cyclosporine by about 50% in a Candida pyelonephritis infection. These studies suggest that blood transfusions have complex interactions with different components of the immune response. T-cell function is impaired by repeated transfusions (diminished DTH response), but other inflammatory responses are accentuated. This suggests that blood transfusions may harm immune response in traumatized animals by causing excessive complement activation or cytokine release.

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.

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.

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.

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.

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.

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)

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.

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.

Donor-specific transfusion effects were studied in the ACI-to-Lewis rat heterotopic heart allograft model using cyclosporine immunosuppression. Low-dose CsA for 1 week plus a single fresh or stored DST given 1 day before allografting significantly prolonged graft survival over CsA therapy alone (median survival time 23.5 days vs. 10 days, P less than 0.01), but third-party transfusion did not (11.5 vs. 10 days, NS). When CsA was started at the time of DST and continued for 2 weeks, maximal graft enhancement was achieved after just one DST. DST/CsA was equally efficacious if given on any day before transplantation, provided CsA was started on the same day as the transfusion. However, pretransplant DST given without CsA shortened subsequent graft survival of day -1 DST/CsA treatment (14.5 days, n = 6, vs. 60 days for controls, n = 10; P less than 0.01). The addition of methylprednisolone to the DST/CsA protocol had no effect on graft survival (51 vs. 53 days, P = NS), but extending the period of postoperative CsA therapy for 4 weeks at reduced dose (2.5 mg/kg/day) significantly prolonged median survival (111 days, n = 11) and resulted in 45% permanent engraftment (greater than 120 days survival). CsA permits graft enhancement with a single DST as early as 1 day before grafting. This avoids the risk of sensitization from DSTs and can extend DST use to cadaveric graft recipients.

As the number of successful liver transplants has increased, the demand for donors has outpaced the supply. Approximately 25% of patients die awaiting an appropriate donor. Current criteria for assessing potential donors need to be closely examined. Fifty-six potential donors were evaluated by our transplant team by utilizing standard liver function tests (LFT's)-SGOT, SGPT, bilirubin. Additionally, a lidocaine metabolism test was performed by giving a 1 mg/kg IV dose of lidocaine over 1 minute and measuring the accumulation of the major metabolite monoethylglycinxylidide (MEGX) at 15 minutes by fluorescent polarization immunoassay (Abbott Diagnostics, Abbott Park, IL). Previous work has suggested that a MEGX less than 50 ng/mL is associated with initial non-function. Thirty-four donors were transplanted (group I) and all had initial function (all MEGX values were greater than 50). Twenty-two donors (39%) were judged unacceptable (group II) by our transplant team and by outside centers based upon one of the following criteria: II A) elevated LFT's--8, 11 B) donor age--5, II C) donor instability--4, II D) no available recipient--3, II E) miscellaneous--2. Standard LFT's were not statistically different in the donors used and in those not used when excluding category II A. Six of seven donors excluded in group I had acceptable MEGX values indicating they may have been transplantable. Ten of 12 patients excluded in groups II B-D had normal LFT's and nine of 12 had acceptable MEGX values indicating they may have been transplantable also. In this era of organ shortage, a reevaluation of donor selection criteria utilizing new tests like MEGX may be necessary to meet the increased need.

Rapid and precise cyclosporine measurements are necessary to maximize immunosuppression and minimize toxicity. The new cyclosporine and metabolites TDx fluorescent polarization immunoassay was studied to determine its precision, sensitivity, and stability. Further, it was compared with the existing radioimmunoassay and high-performance liquid chromatography assays for clinical utility. The TDx procedure utilizes 50 microliter of serum or blood. The range of the assay is 0-1000 ng/ml for serum and 0-2000 ng/ml for whole blood. Precision studies of three control levels provided coefficients of variation of 2.1-5.8% for both assays. The sensitivities of the assays were less than 25 ng/ml for serum and less than 50 ng/ml for whole blood. In order to compare the TDx with the currently used RIA and HPLC methods, 362 simultaneous whole blood and serum samples were obtained from 122 renal transplant recipients over a 4-month period. The serum and whole blood TDx assays excluded fewer patients than either the RIA or HPLC assays with regard to sensitivity. The mean serum cyclosporine concentration for samples above the sensitivity was as follows: TDx 120 +/- 5 ng/ml, RIA 116 +/- 4 ng/ml, and HPLC 100 +/- 5 ng/ml. The mean whole-blood cyclosporine concentration for samples above the sensitivity was as follows: TDx 585 +/- 19 ng/ml, RIA 543 +/- 14 ng/ml, and HPLC 178 +/- 5 ng/ml. Serum and blood TDx levels correlated well with RIA levels, with regression coefficients of r = 0.813 and r = 0.897, respectively. Serum and blood TDx levels did not correlate strongly with HPLC levels, with regression coefficients of 0.332 and 0.781, respectively. Seventeen patients were diagnosed as having acute cyclosporine nephrotoxicity. The serum and whole-blood cyclosporine concentrations in these patients were at the upper end of the therapeutic range for all analytical methods. Five patients had acute cellular rejection; serum and whole-blood cyclosporine levels in these patients did not differ significantly from the stable patients when measured by each of the analytical methods. In conclusion, the TDx cyclosporine and metabolites assay provides reliable blood and serum concentrations that correlate well with RIA measurements in renal transplant recipients. This assay offers rapid sample turn-around times making possible same-day results for all patients without putting great demands upon the laboratory.

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 less than 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 less than 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.