Frequency Of Acute Rejection Research Articles

Impaired kidney graft survival is associated with the TNF-alpha genotype.

The TNF2 allele at position -308 of the tumor necrosis factor (TNF)-alpha gene is associated with high TNF production. The purpose was to study the association of this gene polymorphism with rejection episodes and graft survival after kidney transplantation. A retrospective analysis of transplant outcomes of patients who only had been treated with one single form of immunosuppression consisting of cyclosporine, azathioprine, and prednisolon was performed. We found that 115 (73%) patients had the TNF1/TNF1 genotype, whereas 42 (27%) were TNF2 positive. There was no difference in the overall acute rejection frequency between these two groups (50% in each), but our data showed a non-significant tendency towards a higher frequency of steroid resistant rejections in the TNF2 positive group (57% vs. 40%). There was no significant difference in graft survival between the two genotype groups, although an early tendency towards worse survival was seen in TNF2 recipients. However, the TNF2 positive recipients with rejection episodes had far worse graft survival compared with the TNF1/TNF1 recipients with rejection episodes (P<0.02). No difference was seen between the two genotype groups in patients without rejection episodes. Our data propose that potentially high TNF producers with the TNF2 allele do not have an increased risk for rejection episodes, but if rejection episodes occur, they have a significantly increased risk for early graft loss. TNF production may intensify rejection, but is not a primary factor for the induction of such acute immune activation.

RISK FACTORS PREDICTING SURVIVAL OF LIVER TRANSPLANTS

P578 Aim: In a study population consisting 388 adult liver transplantations with 352 recipients risk factors predicting graft survival of liver transplants were studied. Methods: Predictive models were developed for analysing risk factors of liver transplantation outcome. Univariate testing of examined risk factors was performed using Person Chi-squared test for proportions in the case of nominal covariates and the Cochran-Armitage test for trend in the case of ordinal covariates and for time distribution a linear regression model was used. To study the joint effect of multiple factors on graft survival proportional hazard models were used to assess risk factors related to donor and recipient characteristics and on graft rejection exponential regression models were used. Recipient’s and donor’s age, gender compatibility, blood group and HLA compatibility, presensitisation to HLA antibodies (PRA), pretransplant cytotoxic crossmatch test, recipient’s cytomegalovirus status, cold ischemia and anhepatic time, total bleeding and blood transfusions were assessed related to graft survival time, time to acute rejection, graft loss to chronic rejection or chronic dysfunction. Results: Mean recipient age was 47yr, donor age 40 yr, main indications for liver transplantations were cholestatic liever disease in 146 patients, other cirrhosis 74, acute liver failure 74, tumour 26. PRA was positive in 18%, crossmatch in 19%, mean cold ischaemia time 6.3hr, anhepatic time 59min, mean number of blood transfusion 12 units. Frequency of acute rejection was 44%, within the first three months 38%, 7% had steroid resistant rejection and 10% experienced multiple rejections. In the univariate analysis, the significant predictors of graft survival were male gender, gender incompatibility if male recipient- female donor, blood transfusions over 20 units, long CIT, and liver tumour. Graft loss due to chronic graft dysfunction correlated to BDR mismatches. There was a tendency for more rejections with positive crossmatch (P=0.065) and for steroid resistant rejection with PRA positivity (p=0.055). In the multivariate analysis only gender compatibility, recipient blood group and number of blood transfusions were significant risk factors for graft survival. Risk ratio for male recipient and female donor was 1.68 compared with female recipient and male donor. Risk ratio for graft survival in blood group B was 1.75 and for blood group 0 1.68 comapred with A. In multivariate analysis immunological risk factors were not any more significant. Conclusions: In univarite analysis immunological risk factors were found to be significant but in multivariate analysis only gender mismatch was significant for graft survival but not for rejection.

A RANDOM TRIAL OF MIZORIBINE VERSUS MYCOPHENOLATE MOFETIL IN TACROLIMUS-BASED RENAL TRANSPLANTATION

A61 Aims: Mycophenolate mofetile (MMF) and Mizoribine (MZ) are immunosuppressive drugs that impair de novo purine synthesis. Some recent papers reported the efficacy and safety of MZ with Cyclosporine (CsA) and those of MMF with Tacrolimus (FK506) in renal transplantation. However, there have been no reports comparing MZ and MMF with the FK506-based immunosuppression for renal transplant recipients. This study was designed to investigate the safety and efficacy of MZ and FK506 compared to MMF and FK506 for renal transplant recipients. Methods: From November 1999 to February 2003, there were 37 recipients (28 male, 9 female) entered into this trial. All patients received donor specific blood transfusion (DST) prior to transplantation, and they were transplanted from living donors. From the day of transplantation, 5mg/kg/day of Deoxyspergualin (DSG) was administered for one week, followed by MZ or MMF. MZ or MMF was administered on 5mg/kg/day, 1g b.i.d., respectively; 18 patients were in the MZ group (14 male, 4 female), and 19 patients were in the MMF group (14 male, and 5 female). Results: Rejection (biopsy proven): CMV Infection: There were four cases of CMV infection (4/18: 22%) in the MZ group; however, the MMF group had seven cases of CMV infection (7/19: 38%). Polyoma Infection: Each group had one case of polyoma infection (the MZ group 1/18: 6%; the MMF group 1/19: 5%). Gastrointestinal disorder: There was more diarrhea in the MMF group (4 cases, 21%) than in the MZ group (1 case, 6%). Crossover: Three cases were forced to change from MZ to MMF due to steroid-resistant acute rejection. Conclusions: 1. Although this was a small-scale study, there were no significant differences between the MZ and MMF groups in the frequency of acute rejection. 2. There was more CMV infection in the MMF group than in the MZ group. 3. Further investigation is required, however, MZ and MMF are both useful immunosuppressive agents.Figure

THE ADDITION OF MYCOPHENOLATE AND/OR BASILIXIMAB TO CALCINEURIN INHIBITOR IMMUNOSUPPRESSION REDUCES THE HIGH RISK OF ACUTE REJECTION IN LIVE DONOR TRANSPLANTS

A236 Aims: Live donor (LD) kidneys transplants, particularly from unrelated donors can be associated with poor HLA-matching and high risk of acute rejection. We examined the effect of the addition of MMF +/- a humanised IL-2 monoclonal antibody (basiliximab) to standard calcineurin inhibitor-based therapy on acute rejection in LDs. Methods: A consecutive series of 93 LD transplants (10 unrelated donors) were treated with standard immunosuppression consisting of a calcineurin inhibitor and prednisolone (CNI+P; n=54) or with tacrolimus and prednisolone in combination with MMF + basiliximab for patients with 1 or more HLADR mismatch (MMF+Il-2; n=41). All episodes of graft dysfunction were investigated by needle-core biopsy. Rejection episodes were classified according to Banff classification. Results: The two study groups were well matched for rejection risk factors including recipient age (32 ± 12 vs 36 ± 11 yrs; NS) and total HLA matching (2.3 ± 1.2 vs 2.2 ± 1.4 mismatches; NS). Overall rejection rates were 30/54 (56%) in the CNI+P group and 12/41 (29%) in the IL-2+MMF group (RR=1.898,P=0.0129 Fisher’s exact). Steroid resistant rejection was higher in the CNI+P group (9/54 vs 3/41;RR = 1.38, NS). For patients with 1 or more HLADR mismatch, rejection rates were higher with CNI+P [25/39 (64%) vs 10/29 (34%) P=0.027]. Conclusions: CNI-based immunosuppression in LD transplantation is associated with high rates of acute rejection. Addition of MMF +/- basiliximab significantly reduces frequency of acute rejection even in poorly matched grafts. This approach may form the basis for a new treatment paradigm in immunosuppression for high-risk LD.

Risk factors for graft loss in patients with recurrent IGA nephropathy after renal transplantation

Background The recurrence rate of IgA nephropathy (IgAN) in transplanted kidneys has been reported to be >50%. Although recurrent IgAN has a benign clinical course, recent data suggest that it leads to graft loss in a substantial number of patients. Methods We performed a retrospective single-center analysis of 34 renal transplant recipients, with biopsy-proven IgAN as the cause of end-stage renal failure. Results Renal allograft biopsies were performed in 30 patients, of whom 24 did and 6 did not have biopsy-confirmed recurrent transplant IgAN. Recurrent transplant IgAN was more often detected in men and at later timepoints after post-transplantation. Four patients with recurrent transplant IgAN progressed to graft failure. Progression to graft failure was associated with worsened renal function, higher systolic blood pressure, and the lack of presenation of angiotensin-converting enzyme inhibitors (ACEs) at the time of allograft biopsy. Immunologic factors such as frequency of acute rejection, HLA typing, and immunosuppression did not show a relation to recurrence or graft loss. Conclusions Recurrent transplant IgAN increased with long-term graft survival and risk factors for graft loss due to recurrent IgAN were similar to those among IgAN in native kidneys.

Postransplant lymphoproliferative disorder (PTLD) may not be associated with development of bronchiolitis obliterans

Bronchiolitis obliterans and bronchiolitis obliterans syndrome (BOS) secondary to chronic rejection remains a major cause of mortality in lung transplant recipients. Identified risk factors for the development of BOS include the frequency and severity of acute rejections (AR) and CMV infection. Reduction of immunosuppression is a standard treatment of PTLD. We investigated whether PTLD and the relaxation of immunosuppression increases the risk of developing BOS. From a single institution between 1988 and 2003, 24/346 lung transplant recipients (7 %) were diagnosed with PTLD. The median age of recipients with PTLD was 35.5 years (12-55 years). There were 14 heart-lung, 5 single, and 5 double lung recipients. Median time to diagnosis of PTLD was 257 days (48-5221 days). Fifty-eight percent (14/24) were diagnosed with BOS within 180-1837 days (median 524 days). Fifty percent (12/24) are deceased. The median follow-up from time of PTLD diagnosis was 31 mo (1-117 mo) for those with and 9.5 mo (1-115 mo) for those without BOS. Twenty-one percent (3/14) developed BOS prior to the diagnosis of PTLD. Two additional subjects met ISHLT criteria of BOS 0-p prior to diagnosis of PTLD. AR was diagnosed in 11/14 (79%) with PTLD + BOS and 4/10 (40%) with PTLD alone. Median time to first episode of AR was 17 days with only 2 subjects having a first AR after PTLD was diagnosed. Episodes of AR in the PTLD + BOS group were 2.0 episodes /pt vs. 0.8/pt in the PTLD alone group. Grade A1, A2, and A3 AR was diagnosed in those with BOS at rates of 0.28, 0.93, 0.36 vs. 0.1, 0.3, 0.2 episodes/pt, respectively with PTLD alone. CMV infection preceding the development of BOS was detected in 6/14 (43%) of the those with PTLD + BOS and 3/10 (30%) with PTLD alone. All CMV infections preceded the diagnosis of PTLD. In this series, subjects with PTLD + BOS had higher frequency and higher grade of AR and more CMV infection than those who did not develop BOS. Although those without BOS had shorter follow-up time, the diagnosis of PTLD and subsequent reduction of immunosuppression does not necessarily lead to increased rates of BOS.

Increased mononuclear cell activation and apoptosis early after human liver transplantation is associated with a reduced frequency of acute rejection

Experimental models of orthotopic liver transplantation (OLT) have shown that the very early events post-OLT are critical in distinguishing immunogenic and tolerogenic reactions. In rodents, increased leukocyte apoptosis and cytokine expression have been demonstrated in tolerogenic strain combinations. Information from human OLT recipients is less abundant. The aim of this study was to determine the amount of early leukocyte activation and apoptosis following human OLT, and to correlate this with subsequent rejection status. Peripheral blood mononuclear cells (PBMC) were isolated from 76 patients undergoing OLT - on the day prior, 5 hrs after reperfusion (day 0), and 18-24 hrs post-OLT (day 1). The mean level of apoptotic PBMCs on post OLT day 1 was higher than healthy recipients (0.9% +/- 0.2 vs. 0.2% +/- 0.1, p=0.013). Apoptosis was greater in nonrejecting (NR) (1.1% +/- 0.3) compared with acutely-rejecting (R) (0.3% +/- 0.1, p=0.021) patients. On day 1, PBMC from NR patients had increased expression of IFN-gamma (p=0.006), IL-10 (p=0.016), and CD40 ligand (p=0.02) compared with R. Donor cell chimerism on day 1 did not differ between the groups indicating that this was unlikely to account for increased PBMC apoptosis in the NR group. Interestingly, the level of chimerism on day 0 was significantly higher in NR (3.8% +/- 0.6) compared with R (1.2% +/- 0.4, p=0.004) patients and there was a close correlation between chimerism on day 0 and cytokine expression on day 1. These results imply that similar mechanisms are occurring in the human liver to promote graft acceptance as in the experimental models of liver transplantation and suggest that strategies that promote liver transplant acceptance in rodents might be applicable to humans.

Induction immunosuppressive therapy stratified according to risk categories in renal transplantation

Background Immunosuppressive therapy is critical during the induction phase for it directly affects graft outcome. Many centers use uniform regimens, although not all patients represent similar risks. The purpose of this study was to evaluate a prospective protocol of immunosuppression according to 2 significant risks in kidney transplant: acute rejection (AR) and delayed graft function (DGF). Methods This study included 35 patients (group I) stratified before starting the immunosuppression as follows: (1) standard risk, (2) increased risk of AR, and (3) augmented risk of DGF. Standard risk patients were treated with Cyclosporine (CsA) and Prednisone (Pred) (n = 18). Patients with increased risk of AR were treated with CsA plus Pred plus Mycophenolate Mofetil (n = 4) or sequential induction with antithymocyte globulin (n = 5). Patients with augmented risk of DGF were started on sequential induction with late inception of CsA (n = 8). Comparisons were made with a series of 20 patients (group II) who received a uniform regimen including CsA plus Pred plus Azathioprine. Results AR and DGF rates were 6% and 16% for group I versus 39% and 39% for group II ( P = .01 and P = .1, respectively). Serum creatinine values at 30 and 360 days were 1.43 ± 0.45 and 1.29 ± 0.40 in group I and 1.99 ± 1.05 and 1.60 ± 0.42 in group II ( P < .05 for each comparison). Adverse effects, graft survival, and average costs were similar in both groups. Conclusion The use of differentiate protocols was associated with better graft function and a reduced frequency of AR and DGF. Although 50% of patients required sequential or triple-drug induction, the adverse events and costs were similar. These results encourage the use of individualized immunosuppression.

Impact of HLA-C on acute rejection in liver transplantation

Although liver transplants show a special tolerogenic behaviour, rejection remains an important problem that involves several immunological mechanisms, some of which are unknown. Our study sought to analyze the influence of HLA-C polymorphism on short-term liver graft acceptance by HLA-C genotyping of 100 orthotopic liver transplant recipient-donor pairs. Recipients were statified according to the occurrence of acute rejection. HLA-Cw*06 allele appeared to be underrepresented among recipients without versus those with acute rejection or those in control groups. With regard to HLA-C allelic compatibility, the frequency of acute rejection or those in episodes decreased with fewer HLA-C mismatches. These findings suggest the participation of HLA-C molecules in liver graft alloresponses, involving HLA-C genotyping, as well as compatibility.

Human leukocyte antigen–C in short- and long-term liver graft acceptance

In liver transplantion, rejection is still an important problem, and the role of human leukocyte antigens (HLA) has not been clearly established. At present, the possible involvement of HLA-C antigen in liver transplantation is still unexplored. The aim of this work was to analyze the influence of HLA-C polymorphism on the outcome of liver transplantation. For this purpose, genotyping of 100 orthotopic liver transplant recipient-donor pairs for HLA-C was performed with polymerase chain reaction–sequence-specific primers (PCR-SSPs). Liver recipients were stratified according to the occurrence of acute rejection. Patients without acute rejection were found to have a lower frequency of the HLA-Cw*06 allele compared with those with acute rejection or the control group. Moreover, when the role of HLA-C dimorphism was analyzed, natural killer (NK)1-alloantigens were found to be predominant in recipients without acute rejection. When the match of HLA-C single alleles and NK-alloantigens between donor and recipient was analyzed, it appeared that the frequency of acute rejection gradually decreased with decrease of the number of allele mismatches. Graft survival was increased when the number of mismatches in both HLA-C or NK-alloantigens was lower. In conclusion, the HLA-C locus may play a role in liver graft alloreactivity or allotolerance and, therefore, may be useful to avoid acute rejection and to achieve graft acceptance, resulting in a better final outcome in liver transplantation. (Liver Transpl 2003;9:218-227.)

Human polyclonal anti-hepatitis B surface antigen immunoglobulin reduces the frequency of acute rejection after liver transplantation for chronic hepatitis B.

Use of polyclonal anti-hepatitis B surface antigen immunoglobulin (HBIg) has been shown to reduce hepatitis B virus (HBV) recurrence after liver transplantation (LT) and to decrease the frequency of acute cellular rejection (ACR). However, the protective role of HBIg against ACR remains controversial, since HBV infection has been also associated with a lower incidence of ACR. To assess the relationship between HBIg immunoprophylaxis and the incidence of rejection after LT. 260 patients (158 males, 43 +/- 14 years old) submitted to LT were retrospectively evaluated and divided into three groups, according to the presence of HBsAg and the use of HBIg. Group I was comprised of HBsAg-positive patients (n = 12) that received HBIg for more than 6 months. Group II was comprised of HBsAg-positive patients that historically have not received HBIg or have been treated irregularly for less than 3 months (n = 10). Group III was composed of 238 HBsAg-negative subjects that have not received HBIg. HBIg-treated patients (group I) had significantly less ACR episodes, when compared to group II and III. No differences between groups II and III were observed. Long-term HBIg administration contributes independently to reduce the number of ACR episodes after LT.

Successful withdrawal of steroid after renal transplantation

STEROIDS have constituted the foundation stone of immunosuppressive therapy in renal transplantation for the last four decades. In spite of the fact that the doses used can be considerably lower when cyclosporine A (CsA) is concurrently administered, steroids continue to cause a plethora of undesirable side effects and complications. Some of those unwanted effects, such as loss of bone mass or factors contributing to the development of increased risk of cardiovascular disease, remain active even at the low doses used in long term immunosuppressive therapy. For this reason, one of the planned aims of immunosuppression therapy today is to further reduce and eventually completely remove steroids. However, the benefits accruing from the cessation of steroids must be weighed against the risk of precipitating acute or chronic rejection of the allograft. The recent use of CsA in the formulation known as Neoral with its well documented pharmacokinetic advantages and, more importantly, with the significant reduction in the frequency of acute rejection in patients on mycophenolate mofetil (MMF) has brought up to the forefront again the idea of removing steroids from the long term immunosuppressive therapy scheme. We report here the results of a prospective controlled trial in which renal transplant recipients receiving Neoral, MMF, and steroids were randomly assigned to a change in their therapy which included either steroid withdrawal or alternate day steroid therapy. MATERIAL AND METHODS

Bronchiolitis obliterans with organizing pneumonia: possible association with human herpes virus-7 infection after lung transplantation

transplant database of the centre was carried out. All single lung (SL), double lung (DL) and heart-lung block (HL) transplant patients who survived over 2 years post transplant were included in the study group. They were grouped as follows: A 5 D-/R(n5102), B 5 D-/R1 (n570), C 5 D1/R(n533) and E 5 D1/R1 (n592). The respective incidence of BOS in the different groups was 43.1%, 45.7%, 51.5% and 47.8% (p50.32). The 3-year BOS free survival was 65%, 56%, 58% and 67% respectively (p.0.05). In group A, the significant risk factors for developing BOS were three or more episodes of acute rejection (p50.02) and non-CMV pulmonary infection (p50.03). The mean number of acute rejection episodes per 100 patients days within the first six months were 1.28 (group A), 1.06 (group B), 0.50 (group C) and 1.11 (group E) [p,0.05]. Conclusion: Although CMV has been shown to be a risk factor for BOS, its absence did not preclude lung transplant patients from developing BOS. Moreover, absence of CMV was associated with an increase in the number of acute rejection episodes within the first transplant year. However, this could be accounted for by changes in frequency of acute rejection over time. Moreover, this may also reflect the non-uniformity of the pathological processes that are grouped as BOS.

Interstitial pneumonitis after lung or heart-lung transplantation in very young recipients

2121672). There were 78 episodes of acute rejection, 29 in 13 DR patients (2.2 episodes/patient), and 49 in 21 NR patients (2.3 episodes/patient). ISHLT grades in 38 biopsies were A1 (9), A2 (19), A3 (8), lymphocytic bronchiolitis (1), acute rejection 1 cytomegalovirus (1). Multiple, often recurrent infections caused by a wide spectrum of organisms occurred in 13 DR patients (81.3%) and in 24 NR patients (82.8%). Nine patients (3 DR, 6 NR) developed obliterative bronchiolitis, causing death in 5 patients (1 DR, 4 NR). Fifteen patients (33.3%) died, 4 (25%) of 16 with DR and 11 (37.9%) of 29 with NR. In 1 DR patient death was due to sarcoidosis in the graft and the native lung. Mean time to death after tx for DR was 1483 days (6423280) and for NR was 1128 days (3222547). Mean time to death after DR was 1227 days (33-3155). Our findings of DR in 16 (35.5%) of 45 patients surviving . 30 days after tx is probably conservative given the limitations of our study. Although the frequency of acute rejection and infections is similar in both groups, DR may confer a slight survival advantage due to better control of subclinical rejection which warrants further study.

A comparison of daclizumab to ATGAM induction in simultaneous pancreas-kidney transplant recipients on triple maintenance immunosuppression

Daclizumab (DAC) is a molecularly engineered humanized IgGa monoclonal Ab directed against the alpha chain of the interleukin-2 receptor (IL2R). Inhibiting the amplification of the immune response by blocking IL2R can reduce the frequency of acute rejection without the attendant risk of infection. The purpose of this retrospective study was to compare DAC to antithymocyte (ATGAM) induction in 24 simultaneous pancreas-kidney (SPK) transplants performed between September 1995 and September 1998. The primary endpoints were the incidence within 6 months posttransplant of: 1) biopsy-proven acute rejection; and 2) infection. The two groups (DAC, n = 12; ATGAM, n = 12) were matched on age, race, ESRD, number of HLA mismatches, PRA level, and cold ischemia time. DAC (1 mg/kg) was given on the day of transplant, then every other week (a total of five doses); ATGAM (15 mg/kg) was given on post-transplant day 1, then daily for 7-10 d. Immunosuppressive therapy consisted of cyclosporine (Neoral 8-10 mg/kg/d) or Prograf (0.16-0.2 mg/kg/d), mycophenolate mofetil (Cell- 2-3 g/d) and steroids. Of the 12 DAC patients, 3 patients (25%) had biopsy-proven acute rejection versus 8/12 (67%) of the ATGAM patients. The time to acute rejection was significantly different by group (DAC = 110 d; AT-GAM = 26 d). There was a reduction in the number of patients receiving antilymphocyte drugs for moderate to severe rejection (DAC = 2/12; ATGAM = 4/12), with 2 of the 4 ATGAM patients experiencing more than two episodes of biopsy-proven rejection. There was an increase in infection by group (DAC = 4/12; ATGAM = 7/12): total of three septic infections occurred in the ATGAM group opposed to none in the DAC group. Patient, pancreas, kidney 6-month survival rates were 100% for both groups. We conclude that DAC induction coupled with triple immunosuppressive therapy reduces the incidence of rejection in SPK transplant patients. The time to acute rejection was prolonged in the DAC group compared with the ATGAM group without the attendant risks of rejection.

Successful management of pulmonary tuberculosis in renal allograft recipients in a single center

Pulmonary infections, especially tuberculosis, are responsible for significant mortality and morbidity among renal transplant recipients in developing countries. Conventional diagnostic modalities are associated with a low yield, delaying specific therapy. All patients transplanted within a 1.5-year period were prospectively followed-up for one year. Patients were on a cyclosporine-based triple immunosuppressive regimen. None received isoniazid prophylaxis, and those transplanted in the last seven months of the study period received daily cotrimoxazole. Patients exhibiting unequivocal evidence of pulmonary infections underwent further evaluation. Search for offending organisms was made by sputum examination and bronchoalveolar lavage (BAL). . Thirty-nine infection episodes were recorded in 34 patients. M. tuberculosis was isolated during 10 episodes, pyogenic bacteria and Pneumocystis carinii in 6 each, candida in 4, aspergillus in 3, cytomegalovirus (CMV) in 3, and nocardia and mucor in one episode each. More than one organism was isolated during five episodes. Bacterial pneumonia and tuberculosis were diagnosed in another seven and two patients, respectively, on the basis of a therapeutic response to specific chemotherapy. Over two thirds of the organisms were identified by examination of BAL fluid. BAL was useful in the diagnosis of tuberculosis and P. carinii pneumonia but was relatively insensitive for CMV and bacterial infections. An increased frequency of acute rejection and higher serum creatinine were factors that predisposed to infections. All patients with pulmonary tuberculosis made a full recovery. Tuberculosis and P. carinii are the most common nonpyogenic infections in the first year after transplantation in developing countries. An aggressive search for tubercle bacilli should be made using bronchoscopy and examination of BAL fluid in patients not responding to a short trial of antibiotics. A four-drug regime without rifampicin given for 18 months is effective for pulmonary tuberculosis in patients on cyclosporine. We recommend routine prophylactic use of one single-strength tablet of cotrimoxazole daily for at least six months after transplantation.

Study of early corticosteroid withdrawal in cardiac transplantation

Managing immunosuppression is a significant aspect of posttransplantation patient care. Previously, our institution reported that prednisone could be withdrawn in cardiac allograft recipients without jeopardizing midterm survival. We returned to this group of patients to investigate the long-term effects of our steroid taper protocol.We reviewed the records of 162 consecutive cardiac transplant recipients from our institution. Patients who underwent transplantation between 1988 and 1990 were treated with traditional triple-therapy immunosuppression (cyclosporine, azathioprine, and prednisone). Beginning June 1990, we instituted a protocol of early steroid taper with discontinuation by 6 months after transplant. The two groups were comparable with respect to age, sex, ethnicity, cause of heart failure, ischemic time, body mass index, and creatinine at the time of transplantation.Fifty-seven percent of the patients in the early steroid taper group were successfully withdrawn from steroids at 6 months after transplantation. This group had a decreased freedom from and increased frequency of acute rejection (p < 0.01 for each) when compared with the traditional therapy group. There was, however, no difference in freedom from posttransplant coronary artery disease (p = 0.53). The early steroid taper group enjoyed an increased freedom from malignancy (p = 0.01) and trended toward a decreased frequency of infection (p = 0.10) and improved survival (p = 0.06).Steroid withdrawal is possible in 57% of patients at 6 months after transplantation. The institution of an early steroid taper protocol improves the overall freedom from malignancies and may decrease the frequency of infection and prolong overall survival without increasing the risk of posttransplant coronary artery disease.

DACLIZUMAB PROVIDES SUPERIOR IMMUNOSUPPRESSION FOR PEDIATRIC RENAL TRANSPLANTS

170 Background-Renal transplantation in children has a higher incidence of rejection than in adults. Daclizumab is a humanized mAb that binds to the high-affinity IL-2 receptor expressed on alloantigen-reactive T lymphocytes. It has been shown to reduce the frequency of acute rejection in adult recipients of primary kidney transplants. In this study the results of the use of daclizumab induction in pediatric primary renal transplants at a single institution is presented. Methods-A retrospective review of 27 consecutive pediatric renal transplant patients (mean age 10 yrs, range 4 to 18) who received daclizumab induction therapy was performed. Daclizumab (1 mg/kg, IV) was administered pre-operatively and every two weeks post-operatively for a total of 5 doses. Patients also received maintenance immunosuppression consisting of cyclosporine or tacrolimus, mycophenolate mofetil or azathioprine, and corticosteroids. The median duration of follow-up was 11 months (range 1 to 21). The primary endpoint was the incidence of biopsy proven acute rejection at 6 months and overall graft survival. Values are reported as median or mean ± SD. Results-Donors were living related in 14 of the 27 patients (52%), cadaveric in 10 (37%), and living unrelated in 3 (11%). All patients in whom rejection was suspected underwent biopsy and three of these had biopsy proven rejection by 6 months (13%). One of these had a reduction in immunosuppression because of a polyoma virus infection of the kidney. The mean time to rejection was 60 ± 19 days. Two of the three patients with acute rejection were treated with steroid pulse only. One patient was treated with a 10 day course of OKT3 and steroids. The median time to initiation of calcineurin inhibitors was 0 days (range 1 to 11). The mean serum creatinine was 0.9 ± 0.6, 0.8 ± 0.4, 0.9 ± 0.5, and 1.0 ± 0.5 at 3, 6, 9 and 12 months, respectively. Near complete binding of the IL-2Rα was demonstrated beyond 3 months by FACS. Delayed graft function occurred in one patient. There was one case of polyoma virus infection in the transplanted kidney diagnosed at 2 months. There was one case of systemic sepsis, which occurred one month following transplantation. There were no cases of lymphoproliferative disease. Overall graft survival was 100%. Conclusions-Induction therapy with daclizumab followed by maintenance triple immunosuppression markedly decreases the incidence of acute rejection at 6 months in pediatric renal transplant patients when compared to NAPRTCS data. This data suggests that dacluzimab may be an effective induction immunosuppressive agent for pediatric renal transplant.

POLYOMA VIRUS AND ITS EFFECTS ON RENAL FUNCTION AND REJECTION PATTERNS IN KIDNEY TRANSPLANT RECIPIENTS.

911 Background: BK and JC polyoma viruses (PV) are known to remain latent in renal tubules and reactivation of infection occurs in immunosuppressed patients. The subsequent effects on kidney graft function are controversial. We set out to determine if PV virus infection in kidney transplant patients affects graft survival or frequency of acute rejection. Twenty-one PV positive patients were identified by cytological evaluation of urine samples; the number of infected cells was quantitated on Pap stain. The patients were divided in 2 groups. Low (<5 infected cells/sample - A) and high (too numerous to count - B). Concurrent biopsy samples were available in thirteen patients; these were evaluated with routine stains and with immunoperoxidase stain for PV. There were two control groups. The first consisted of twelve patients with stable graft function, defined as having no greater than a 25% change in creatinine from baseline one month post transplant (C1). These patients had never been biopsied. A second control group included thirteen patients with known chronic rejection based on biopsy (C2). All control group patients were negative for PV in urine. Average follow up was 10 months to four years post transplant. Age range was 22 to 75, and transplant types included CRT, LRT or LNRT. Groups were compared using calculation of the least means square slope of 1/creatinine vs. time in months. Data was analyzed using the Kruskal-Wallis test. In addition, the high PV (B) and chronic rejection groups (C2) were compared with regard to occurrence of acute rejection. The following mean slopes were calculated +/-SEM: group A .0041 +/- .0024; group B .0046 +/- .011; group C1 .025 +/- .02; group C2 .00025 +/- .0025. RESULTS: There were no statistical differences found between the low PV and all control groups. There was a significantly greater decay in renal function in the high PV group (B) vs. the control group without chronic rejection (C1) (p = .013). Four out of five in the high PV group (B) vs. two out of sixteen in the chronic rejection group (C2) had at least one episode of acute rejection verified on biopsy (p = .010). Conclusion: Presence of high titer PV viral infection may be a risk factor for acute rejection and negatively affects graft survival.

ANTI-CD25 TREATED CARDIAC ALLOGRAFT RECIPIENTS ACUTELY REJECT THEIR GRAFT VIA THE IL-15 ROUTE

62 Targeting the IL-2/IL-2Receptor signaling pathway with anti-CD25 (IL-2R, α-chain) mAb induction therapy clearly reduced the frequency of acute rejection after clinical organ transplantation. Nevertheless, a substantial number of our cardiac allograft recipients still reject their allograft, even in the presence of anti-CD25 mAb (29%). Recently, we have shown that macrophages secreting the T-cell growth factor IL-15 are abundantly present in these rejecting hearts, thereby suggesting that IL-15 can be the alternate for IL-2 in anti-CD25 mAb blocked rejections. To assess the ability of IL-2 and IL-15 to induce T-cell proliferation of anti-CD25 blocked T-cells, we measured by limiting dilution analysis, the frequency of IL-2 and IL-15 responsive T-cells in peripheral blood obtained from anti-CD25 treated patients during cardiac rejection (n=12) and from healthy controls (n=7) in the absence and presence of the mouse anti-CD25 mAb BT563. In the absence of anti-CD25 mAb the frequencies of T-cells responding to IL-2 (10 ng/ml) and IL-15 (10 ng/ml) in peripheral blood from patients were significantly lower than those measured in samples of healthy controls: median of IL-2 responding T-cells 78/106 (range 2-210/106) vs 154/106 (122-484/106, p=0.0008) and median of IL-15 responding T-cells 67/106 (range 1-207/106) vs 129/106 (range 79-192/106, p=0.02), respectively. A completely different picture emerged when proliferative responses on IL-2 and IL-15 of T-cells were analyzed in the presence of anti-CD25 mAb. Blockade of the IL-2R markedly influenced the prolifer ative capacity of T-cells to respond to IL-2 but not to IL-15. In the presence of anti-CD25 mAb the frequencies of IL-2 responding T-cells from allograft recipients decreased with 83% (median inhibition, range 46-100%), whereas the frequencies of IL-15 responding were not affected (median inhibition 6%, range 0-50%, p<0.001). In summary, limiting dilution analysis revealed that the frequency of T-cells responding to IL-2 and IL-15 of immunosuppressed allograft recipients was significantly lower than those measured in healthy controls. The residual responsiveness of T-cells to IL-2 was completely blocked by anti-CD25 mAb, while the responsiveness to IL-15 proved to be resistant to this IL-2R blockade. We conclude that IL-15 might be a substitute for IL-2 in the rejection process of anti-CD25 treated cardiac allograft recipients.