ATG Induction Research Articles

Impact of Steroid Withdrawal on Metabolic Parameters in a Series of 112 Enteric/Systemic-Drained Pancreatic Transplants

Background New immunosuppressive protocols and advanced surgical techniques have brought major improvements in pancreas transplantation outcomes. Steroid withdrawal might have a beneficial long-term effect on metabolic parameters. Methods We retrospectively analyzed 112 enteric-drained pancreas transplants (PTx) performed between March 1997 and October 2001. Prophylactic imunosuppression consisted of ATG induction, tacrolimus, MMF, and steroids. Results Actuarial patient, pancreas, and kidney graft survivals at 1 year were 96.4%, 86.7%, and 95.3%, respectively. The 5-year pancreatic graft survival was 77%. In addition to four patients who died with functioning grafts, eight grafts were lost due to intraabdominal infection; ten due to rejection; and the remaining three, due to other complications. One-year follow-up was available for 89 patients, Including 22 (25%) withdrawn from steroids. Significantly lower median serum cholesterol values were measured among patients off steroids (158 mg/dL [range 135 to 231 mg/dL] versus 188 mg/dL [range 91 to 278 mg/dl]; P = .005). In contrast, the difference in triglycerides did not reach statistical significance; that is, at last follow-up, at a median of 41.3 months posttransplant, 64 patients (70% of the available study population) were off steroids. Cessation of steroids resulted in significantly lower cholesterol (median 176 mg/dL [range 101 to 229 mg/dL] versus 196 mg/dL [range 107 to 339 mg/dL]; P = .047) and triglyceride values (median 74 mg/dL [range 34 to 299 mg/dL] versus 98 mg/dL [range 47 to 565 mg/dL]; P = .008), but had no impact on rejection rate, serum creatinine and urea, HbA 1c, or fasting blood glucose levels. Conclusions Steroid withdrawal after pancreatic transplantation can be performed in the majority of cases without risking an immunologic complication, but it seems to be associated also with the benefit of improved lipid metabolism.

Listeria meningitis in transplant recipients

Meningitis is a rare complication following organ and stem-cell transplantation and can be caused by a variety of microorganisms. To retrospectively review the clinical course and outcome of five cases of listeriosis in four organ recipients and one stem-cell recipient during a seven-year period. Patient records for more than 3500 patients undergoing organ or stem-cell transplantation at the university hospital of Innsbruck during a 27-year period were evaluated. Standard immunosuppression consisted of calcineurin inhibitor-based triple drug therapy with or without ATG or IL2 receptor antagonist induction. The first case affected a 35-year-old woman who received an allogenic bone marrow transplant for advanced breast cancer. Cases two and three related to two male heart recipients. Cases four and five were diagnosed in one male and one female renal recipient. Listeria monocytogenes was isolated from blood in two cases and from cerebrospinal fluid in three. Treatment consisted of ampicillin in all cases with the addition of tobramycin (1), TMPS (1), meropenem (2) or imipenem/cilastatin (1). The deaths of two patients were directly related to L. monocytogenes. Although listeriosis is a rare complication following transplantation, this infection should be ruled out in individuals presenting with neurological symptoms and fever.

Improvement in long-term graft survival in cadaveric renal transplant recipients treated with mycophenolate mofetil

Abstract Though mycophenolate mofetil has markedly reduced the incidence of acute rejection in renal transplantation, a significant improvement in graft survival has been more difficult to demonstrate. This retrospective study compares an historical control group of 210 consecutive renal transplant patients, who had received ATG induction associated with cyclosporin, prednisolone and azathioprine, with 187 patients receiving mycophenolate instead of azathioprine. The incidence of acute rejection was decreased with mycophenolate. In rejection-free patients, the 3-year graft survival rates were equivalent. In contrast, graft survival at 3 years improved significantly for patients who experienced a rejection crisis and remained under the initial triple drug regimen with mycophenolate compared to the patients of the historical group who were kept on azathioprine after a rejection episode. In conclusion, mycophenolate mofetil is not only able to reduce the incidence of acute rejection but could also improve the prognostic significance of acute rejection crises.

CAN WE PREVENT CHRONIC GRAFT LOSS? STRATEGIES AND OUTCOME IN 1000 LIVE RELATED RENAL TRANSPLANTS FROM A DEVELOPING COUNTRY

P266 Aims: This study describes strategies to prevent graft loss in a living related programme from a developing country. Methods: One thousand and forty five live related transplants were performed between 1985 and 2001. Analysis of survival was divided into three periods (1986 – 1993) 184 transplants, (1994 – 1997) 350 and (1998 – 2001) 511 transplants. Strategy included young donor selection, matching donor recipient body weight ratio, improvement in histocompatibility by DNA typing and flow cross match. Tailoring immunosuppression by ATG, IL2 induction, switch from Aza to MMF and CyA reduction, HLA match and donor age. Early diagnosis of dysfunction by imaging and frequent biopsy. Molecular diagnosis of TB, CMV and HCV, stringent control of hypertension, treatment of hyperlipidaemia and diet control. Maintenance immunosuppression was by triple drug regimen. Statistical methods used were Kaplan Meier, Log rank and Cox analysis. Results: Analysis of 1 and 5 year graft survival in the three eras showed that it was 80% and 51% in the first (1986-1993), 89% and 69% in second (1994-1997) and 92% and 81% in the third period (1998-2001). Age of donors was < 30 years in 34% in the first era and this increased to 40% in the third era while age > 50 years decreased from 13% to 8%. ATG and IL2 induction allowed use of poorly matched donors. In the first era there were 4% (1-2 antigen matched transplants) and 29% identical. This changed to 12% (1-2 antigen matched) and 18% identical in the third era. Graft loss due to chronic rejection reduced from 60.2% in the first era to 26% in second and 12.9% in the 3rd era. Of the total graft losses of 198, 46% were due to chronic rejection and 27% were due to death with graft function where the main reason was infection in 61%. Conclusions: In a living related programme graft loss equates with end of life. We feel that attempts can be to salvage a good proportion of grafts by early diagnosis and effective therapy of rejection, individualized immunosuppression, prevention of graft threatening infections, hypertension and hyperlipidaemia. Knowing limitations inherent in the available donor strategies can be developed to prolong graft survival.

CMV MISMATCHED HAND-TRANSPLANTATION SHOULD BE AVOIDED

P655 Aims: Since hand-transplantation was launched in 1998, a total of 24 hands/forearms have been transplanted worldwide. Cytomegalovirus (CMV) still represents one of the major problems in solid organ transplantation. We herein describe the management of CMV infection and/or disease in 5 CTA recipients. Methods: Immunosuppression consisted of Tacrolimus based triple drug therapy with ATG or CD25-receptor antagonist induction. Donor/recipient CMV match was negative/negative (n=1), negative/positive (n=1), positive/positive (n=2) and one patient underwent high risk CMV mismatched (positive/negative) transplantation. CMV testing following transplantation was performed using the pp65-antigenemia assay and the Murex Hybrid Capture CMV DNA assay. Patients were given Gancyclovir (GCV) i. v. followed by oral GCV or ValGCV prophylactically. Results: Patient and graft survival after a mean follow up of 29,4 months is 100 %. At least one rejection episode occurred in all cases with a CMV positive donor or recipient. In two of these patients excessive viral loads were observed. Gancyclovir treatment failed to permanently prevent CMV infection since every patient except for one CMV negative/negative matched developed CMV infection or disease. In those patients requiring a more toxic second line therapy (Foscarnet and/or Cidofovir) temporary renal impairment and neutropenia was observed. Conclusions: CMV infection/disease complicated the postoperative course after CTA transplantation in four of five recipients. High virus load and high level immunosuppression are thought to be responsible for this high complication rate. A close time correlation suggests an association between virus replication and rejection. Therefore, CMV mismatched CTA transplantation carries a high infectious as well as immunological risk and should be avoided.

INFECTIOUS COMPLICATIONS LIMIT THE OUTCOME OF LIVER TRANSPLANTATION IN MEDICAL URGENCY CODE 2 (MUC 2).

P549 Background: Organ shortage has caused a critical increase of the waiting time and occuring deaths on liver transplant waiting lists reflected also by an accumulation of acutely decompensated patients listed MUC 2 while waiting for liver transplantation (LT). Secondary organ impairment represented by renal failure and encephalopathy combined with a breakdown of the host defence puts these patients at high risk for post transplant infectious complications. Many of these patients are even transplanted during ongoing infection. Aims: With particular regard to infectious complications we have analyzed retrospectively a series of MUC 2 listed patients undergoing LT at our center. Methods: Between June 1997 and June 2003 a total of 360 LTs were performed at the Innsbruck University hospital and 22 of these patients (6%) were listed MUC 2. Prophylactic immunosuppression consisted of Calcineurin inhibitor based triple drug therapy using ATG or IL2 receptor antagonist induction in 64%. Results: Nine patients suffered from alcoholic liver disease, eight from viral hepatitis, the remaining five from miscellaneous diseases. In 5 patients additionally a hepatocellular carcinoma was diagnozed. Median hospitalization was 28 (range 12-111) days; median ICU stay was 9 (range 4-88) days. Overall perioperative infection rate was 50% and rejection rate was 23%. Six patients developed surgical complications and 5 got neurological disorders. Fifty nine percent of patients required dialysis or continuous veno-venous hemofiltration for up to 21 days. Specifically in this cohort we observed 7 episodes of oral or genital HSV lesions, 2 patients (both CMV mismatch transplants) developed CMV disease and another 5 patients received Gancyclovir for pre-emptive therapy or prophylaxis. Two patients developed pneumonia, 5 sepsis which originated in 4 cases from a contaminated central venous line and one MRSA endocarditis which resulted in lethal outcome. After a median follow up of 3 years 1 patient was retransplanted and 4 patients died 3 of them from infectious complications. Conclusions: Given that infectious complications can be managed successfully LT of MUC 2 listed patients may result in acceptable results. Infections remain the most common complication in these patients and account for the vast majority of fatal outcomes.

EFFICACY AND SAFETY OF INDUCTION THERAPY WITH ANTITHYMOCYTE GLOBULINS (ATG) IN HEPATITIS C VIRUS (HCV) POSITIVE LIVER TRANSPLANT PATIENTS : COMPARISON WITH ANTI-CD25 INDUCTION THERAPY

A245 Aims: Hepatitis C virus (HCV) reinfection is the rule following orthotopic liver transplantation (OLT) for HCV-related cirrhosis. In this retrospective study we compared the efficacy, the safety and the overt HCV recurrence rate following induction therapy using either ATG or anti-CD25 monoclonal antibodies (basiliximab or dacluzimab) in combination with steroids and tracolimus. Methods: We included 31 consecutive OLT patients; those who died before day 30 were excluded from that study. They were transplanted between 01-99 and 12-02. The patients were follow-up until day 180. Overt HCV recurrence was defined as an increase in liver enzymes with histological evidence of HCV-related lesions, in the absence of acute rejection. Results: There were 20 men, 11 women of a mean age of 57 ± 6 years. All were HCV RNA positive at the time of OLT; genotype 1(1b) was found in 74 % (64.5 %) of patients. The first 16 patients received ATG induction (Group I) (1 mg/kg/d for 3 consecutive days, then adapted to TCD2(+) lymphocyte count [to be less than 50/mm3] and to tacrolimus trough levels). The following 15 patients (group II) received induction therapy with either basiliximab (20 mg twice at day 1 and 4) or dacluzimab (2 mg/kg at day 1 and 1 mg/kg at day 8). Tacrolimus was started on average at day 1. Steroids were started per op. The rate of acute rejection was similar both in group I (37.5 %) and in group II (20%) (p=ns). The rate of bacterial (50% in group I vs. 40% in group II, p=ns), viral, i.e. cytomegalovirus (25% in group I vs. 33% in group II, p=ns), and fungal (18.75 in group I vs. 26.6% in group II, p=ns) infections was similar in both groups. Renal function as well as hematological parameters were similar in both groups during the study period. Liver enzyme levels, i.e. aspartate (AST) and alamine aminotransferase (ALT), gamma glutamyl transpeptidase (γGT) and bilirubin were similar in both groups from day 8 until day 180. Overt HCV recurrence occured in 56.25 % in group I and in 80 % in group II (p = ns). HCV RNA viral load was not statistically different during follow up between the 2 groups; however there was an increase from baseline values. Conclusion: We conclude that induction therapy with ATG in OLT HCV(+)/RNA (+) recipients is efficient, safe as compared to induction with anti-CD25 antibodies, particularly with respect to HCV recurrence and overall infections.

Immunosuppression following intestinal transplantation

Acute rejection is still the main risk factor following intestinal transplantation. Potent immunosuppression decreases rejection frequency, but may increase immunosuppression-related complications. Isolated small intestinal transplantation was performed in 14 adult patients with short bowel syndromes. Immunosuppression included tacrolimus and rapamycin in combination with steroids for 6 months after ATG or daclizumab induction therapy. In addition to protocol biopsies, cellular immune status and soluble immune parameters were used to guide immunosuppression. CMV and EBV markers were determined on a routine basis. Ten of 14 patients (71%) survived for 1 to 38 months (median 26 months). Eight patients are at home, in good physical condition, completely on enteral nutrition. Among the 5 patients (36%) who developed acute rejection, 2 patients with early postoperative events underwent graft removal and 1 patient died due to multiple organ failure. Two patients developed severe acute rejection episodes at 10 and 24 months following transplantation. Both patients recovered following OKT3 rescue therapy and increased baseline immunosuppression with repeated methylprednisolone and infliximab treatment. Infections included peritonitis (n = 3), pneumonia (n = 3), central line infection (n = 5), urinary tract (n = 2), CMV (n = 2), and EBV (n = 4). Two patients developed anastomotic leaks at the esophageal and coloanal anastomosis. In conclusion, acute rejection episodes can be controlled by potent immunosuppression using tacrolimus in combination with rapamycin. Immunosuppression-associated complications, including infections, were in an acceptable range. However, even late after transplantation, reduction in immunosuppression may lead to severe rejection without major clinical symptoms.

ATG versus basiliximab induction therapy in renal allograft recipients receiving a dual immunosuppressive regimen: one-year results

ATG versus basiliximab induction therapy in renal allograft recipients receiving a dual immunosuppressive regimen: one-year results

ATG induction therapy effective in renal transplantation

ATG induction therapy effective in renal transplantation

A three arm study comparing immediate tacrolimus therapy with ATG induction therapy followed by either tacrolimus or cyclosporine in adult renal transplant recipients

taken to assess the influence of ATG induction on tacrolimus (Tac)-based and cyclosporine microemulsion (CyA)based triple therapies compared with immediate tacrolimus triple therapy. In the absence of induction, Tac-based therapies have consistently proved superior to CyA-based therapies in reducing the rates of acute rejection after renal transplantation. 2 METHODS The 6-month, open-label, randomised, prospective, parallel-group study was conducted in 30 European centres. Patients were randomly assigned to immediate Tac therapy (Tac triple) (n185) or ATG/Tac (n186) or ATG/CyA (n184). Administration of azathioprine (AZA) and corticosteroids was initiated on the day of transplantation (day 0) in all groups. In the Tac triple group, tac administration commenced at day 0, but in the patients receiving ATG induction, Tac and CyA administration was delayed for 9 days. The initial ATG dose (day 0) was 1.25 mg/kg and subsequent doses were adjusted according to the patients’ conditions. ATG dosing was discontinued on day 11. The initial doses for Tac and CyA were 0.30 mg/kg per day and 8 mg/kg per day, respectively, each given in two divided doses. The target whole blood trough levels up to day 42 and from day 43 to 180 were: Tac 10 to 20 ng/mL and 5 to 15 ng/mL, respectively, and CyA 150 to 300 ng/mL and 100 to 200 ng/mL, respectively. Corticosteroids were administered intravenously to all three groups at 500 mg on day 0 and 125 mg on day 1. The subsequent doses were tapered from 20 mg (day 2) to 10 mg (days 91 to 180). AZA was administered at 2 mg/kg IV on day 0, and 1 to 2 mg/kg PO up to day 90, thereafter dosing could be discontinued. The study was undertaken in accordance with the Declaration of Helsinki and approved by the local ethics committees. Written informed consent was obtained from all participants. RESULTS The baseline characteristics of three treatment groups were well balanced. Of the intent-to-treat population, a total of 22 Tac triple patients, 28 ATG/Tac patients, and 38 ATG/ CyA patients withdrew during the study, mostly because of adverse events. A total of 13 patients (5, 3, and 5, respectively) died either during the study or after withdrawal. Of the intent-to-treat population, 86.5% of the Tac triple patients, 83.3% of the ATG/Tac patients, and 77.7% of the ATG/CyA patients completed the 6-month study. The mean trough blood concentrations for Tac and CyA remained within the recommended ranges throughout. Based on the intent-to-treat population, differences in estimated patient and graft survival rates over 6 months were not significant between the three groups (KaplanMeier method). For the Tac triple, ATG/Tac, and ATG/ CyA groups, patient survival was 97.0%, 98.4%, and 97.0%,

Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney

Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney

ANALYSIS OF REJECTION AND ATN AFTER INDUCTION WITH ATG, BASILIXIMAB AND DACLIZIMAB IN CADAVERIC KIDNEY TRANSPLANT RECIPIENTS

14 Basiliximab (Simulect) and daclizumab (Zenapax) are monoclonal antibody therapies directed against the alpha subunit of the IL-2 receptor. Although basiliximab and daclizumab have similar mechanisms of action, daclizumab requires 5 doses compared to 2 doses of basiliximab. The cost per dose of basiliximab and daclizumab are comparable ($1224 and $1254 respectively). We examined the recent use of basiliximab and daclizumab in our center and compared the results to ATG (ATGAM) induction in cadaveric renal allografts. 106 patients were treated with ATG from 1/92 to 3/98. 69 patients were induced with basiliximab from 12/97 to 12/98. 37 recipients were induced with daclizumab from 7/97 to 7/98. Maintenance immunosuppression consisting of prednisone, mycophenolate mofetil or azathioprine and cyclosporine or FK506 was used in all patients. Demographics such as recipient age, sex and race were comparable in each treatment group. Rejection and ATN rates are depicted below. (Table)TableExamination of early allograft rejection (1 - 2 months post-transplant) showed the highest rate of rejection among those patients treated with daclizumab while similar early rejection rates were seen in those patients treated with basiliximab and ATG. Late allograft rejection rates (3-4 months post-transplant) were not significantly different in patients treated with basiliximab and daclizumab (p=0.65) and higher than ATG recipients. Rates of post-transplant ATN (as defined by the need for hemodialysis post-transplant) were not statistically different between treatment groups. However, when rejection rates in recipients with post-transplant ATN were examined, recipients induced with ATG had less rejection than those treated with either basiliximab or daclizumab (p=0.06). Lack of a statistically significant difference in rejection with ATN could be attributed to the small number in each treatment group. The total cost of treatment with Zenapax ($6270) was greater than that of a course of Simulect ($2448). Given the similar rejection rates for Simulect and Zenapax at 120 days post-transplant, Simulect appears to be the more economic choice. While ATG is more expensive than both Simulect and Zenapax, patients with post-transplant ATN induced with ATG had a lower incidence of rejection.

Immediate and long-term results of ATG induction therapy for delayed graft function compared to conventional therapy for immediate graft function

The use of polyclonal antibodies for delayed graft function (DGF) was tested in 83 renal allograft recipients. Conventional immunosuppression (CI) was given to 52 patients with immediate graft function (IGF) while 31 patients with DGF received the polyclonal antibody ATG. Administration of OKT3 was restricted to steroid-resistant acute rejections in both groups. The incidence and severity of acute rejections, graft survival rate, CMV infections, and lymphocyte subsets were examined. ATG patients experienced a total of 0.6 acute rejections per patient, whereas CI patients had 0.9 on the average (P < 0.05). Second and third acute rejections occurred less frequently and later in the ATG group than in the CI group (P < 0.01). Steroid-resistant acute rejections occurred in 20 of the CI patients (38%) but in only 7 of ATG patients (23 %). One-year graft survival in the CI and ATG groups was 98.1 % and 93.2%, respectively. A decreased CD4 + to CD8 + T-lymphocyte ratio of about 0.5 was still detectable 5 years after the initial ATG administration. Hence, patients with DGF appear to benefit from induction therapy with ATG.

ATG Induction Therapy and the Incidence of Bronchiolitis Obliterans After Lung Transplantation: Does It Make a Difference?

ATG Induction Therapy and the Incidence of Bronchiolitis Obliterans After Lung Transplantation: Does It Make a Difference?

Reduction of early rejection in adult liver transplantation with ATG induction therapy

Reduction of early rejection in adult liver transplantation with ATG induction therapy

Release of Interleukin-1 and Interleukin-6 From Human Monocytes by Antithymocyte Globulin: Requirement for De Novo Synthesis

AbstractAntithymocyte globulin (ATG) is an effective treatment in patients with severe aplastic anemia (SAA). Its mechanism of action remains unclear, although it has been assumed to be immunosuppressive. However, ATG has also been shown by several laboratories to be immunostimulatory. Recently, interleukin-1 (IL-1) production has been found to be decreased in lipopolysaccharide-stimulated peripheral blood monocytes obtained from SAA patients. We have investigated the ability of ATG to function as an immunostimulatory agent via the production of IL-1 and IL-6 by normal human monocytes in vitro. Supernatants from ATG- stimulated monocytes were assayed for biologically active and immunoreactive IL-1 and IL-6. We have found that ATG, via its F(ab')2 fragment is a powerful inducer of IL-1 and IL-6 production. Furthermore, ATG induction of both cytokines from normal monocytes required de novo synthesis, as determined by 35S-methionine incorporation. Because these two cytokines synergize with other cytokines at both the stem cell and progenitor levels, these stimulatory properties of ATG may be relevant to the treatment of SAA. This would favor the hypothesis of a bimodal mechanism for ATG as an inducer of hematopoietic growth factors and as an immunosuppressive agent.