Tx Pts Research Articles

CORTICOSTERIOID ELIMINATION IN RENAL TRANSPLANTATION: EXPERIENCE IN HIGH IMMUNOLOGIC RISK RECIPIENTS

P246 Body: Rejection rates with early corticosteroid elimination (ECE) in renal transplantation (Tx) have fallen substantially with the use of new potent immunosuppressive (IS) agents. Although high immunologic risk (HIR) renal Tx patients (pts) have been included in a few recent ECE trials, the risk of acute rejection (AR) in HIR pts remains to be defined under modern IS. The purpose of this study was to compare the risk of AR in HIR and low IR (LIR) pts with modern IS. Methods: 98 male and 66 female renal Tx pts. In IRB approved ECE studies were analyzed. Statistical analysis included chi square test. HIR was defined as current or peak PRA>25% or repeat Tx, and LIR was defined as repeat Tx, or current PRA>25%, or peak PRA>25%. IS included Thymoglobulin (51%), IL-2R MAb (15%), steroids <7d (23%), no steroids (77%), MMF (91%), FK506 (60%), CsA (39%), Rapa (68%). Results: No differences existed between HIR and LIR with other risk factors for AR including African American race, cadaveric donor, and DGF. Conclusion: This experience represents the largest reported experience to date in HIR pts with ECE under modern IS. This experience indicates that: 1) HIR pts have higher AR rates at 1 yr, 2) HIR pts without DGF had lower AR with Thymoglobulin induction, 3) poor HLA DR matching increased AR risk in LIR but not HIR pts.Figure

Outcome of listing for cardiac transplantation (Tx) for failed fontan: a follow-up multi-institutional study

The Fontan procedure is a successful palliation for children with single ventricle physiology. However, many will eventually require heart Tx. In 1999, we reported risk factors while waiting and survival after Tx in 47 Fontan pts. This study extends our previous analysis to a larger cohort with longer follow-up. We reviewed 1746 pts. listed at 21 PHTS centers from 1993-2001, using actuarial, parametric, competing outcomes, and multi-variable risk analysis. 97 Fontan pts. <18y old were listed for Tx at a mean of 9.7y (0.5-17.9y); 35% were <6y; 52% were status 1; 18% required ventilator support. 15 pts. died pre-Tx. Pre-Tx survival was 78% at 6 mos and 74% at 12 mos and was no different from 243 children >1y of age with previous sternotomies (CHD) or 747 children without congenital heart disease (NoCHD). Patients who were younger, status 1, had shorter interval since Fontan, or were on a ventilator were more likely to die while waiting. The probability of receiving a Tx at 6 mos was similar for status 2 (68%) vs. status 1 (65%), however, the probability of death while waiting was 5% for status 2 vs. 22% for status 1. 70 pts. underwent Tx. Survival was 76% at 1y, 70% at 3y and 68% at 5y, similar to CHD and NoCHD pts. There were 23 deaths: infection (30%), early graft failure (17%), rejection (13%), sudden death (13%) and graft CAD (9%). In pts. with protein losing enteropathy, albumin (3.0 ± 0.2 vs. 3.7 ± 0.2,p = 0.02) and total protein (5.6 ± 0.3 vs. 6.6 ± 0.2,p = 0.02) increased post-tx. In conclusion, heart Tx is effective therapy for pts. with failed Fontan. Long-term results are comparable to other groups of pediatric Tx pts. The high risk of death pre-Tx in status 1 pts. emphasizes the importance of early referral before the onset of clinical deterioration. The highest risk pre-transplant was for younger patients, those <6 mos post-Fontan, or those on a ventilator.

Accelerated transplant vasculopathy portends proliferative restenosis after percutaneous coronary intervention in cardiac transplant patients

Background: Allograft vasculopathy (AV) after cardiac transplant (TX) causes diffuse concentric narrowing. Percutaneous intervention(PCI) is widely used in treating AV. We evaluated l-year clinical and quantitative angiographic (QCA) results of PCI in TX pts. Methods: 432 pts underwent TX at Brigham &Women’s Hospital from Feb 1984 to Aug 2001. Oi these, 24 (92% male, mean age 55 yrs) underwent PCI of 49 lesions. Core-lab QCA determined % diameter stenosis (LX?), reference (RD) and minimal lumen (MLD) diameters. Results: Procedural success was 98.0%. Of 24 pts, 5 (21%) died within lyear of PCI. QCA of 24 PCI lesions in 14 pts (74%) with l-year follow up revealed preprocedure: (RD 2.61*0.23mm. MLD 0.39*0.28mm, % DS 85.1ill.O) and post procedure: (RD 2.74+0.25mm, MLD 2.27*0.38mm. % DS 17.6+8.9, acute gain 1.88+0.47mm). One year follow up showed(RD 2.59*0.22mm, MLD 1.25*0.80mm. % DS 52.0t29.6) a Late Loss (LL) of 1.02r0.82mm and loss index of 0.55iO.43. Restenosis (DS>50%) occurred in 11(46%) lesions. Seventeen matched AV lesions(DS 28.2y&l1.4) at a nonPCI site had a LL of 0.66+0.38mm. Pts with restenosis also had greater LL at the nonintervened matched site than patients without restenosis(0.94*0.36mm vs 0.40*0.16mm, p=O.O03). Patient-specific LL at PCI and non-PC1 sites correlated significantly (r=O.65, p=O.OOl, figure) Conclusions: PCI in TX pts has high procedural success. Restenosis rates are high in pts with rapid progression of AV suggesting common mechanisms

More favorable improvement of arterial wall characteristics by renal transplantation than by hemodialysis

Background: End stage renal disease is associated with reduced arterial compliance (C) and increased cardiovascular events. We evaluated C following hemodialysis (D) and renal transplantation (TX). Methods:Measurements were done in 32 controls(Ctrl, mean age 43y), 43 hypertensives( HT,5Ey), 16 D(56y) and 16 TX pts matched to D for age and sex. Central pressure was derived by radial applanation tonometry using a transfer function. Aortc(Ao) flow was simultaneously measured with Doppler. C was evaluated by the pulse pressure method, an iterative search of the best fit between measured Ao pulse pressure and pulse pressure predicted by a P-element Windkessel. In D pts recordings were done 1 hr before and 1 hr after dialysis. Results:HT and preD had a significantly (~~0.05) higher mean arterial pressure (MAP) than Ctrl, postD and TX. This led to significantly lower C for HT and preD (1.00*0.36 and 0.94+0.34), YS Ctrl. post D and TX (1.42kO.54, 1.15iO.54, 1.49+0.40 ml/mmHg, respectively). After accounting for differences in MAP, Ctrl. HT. pre and post D values could all (‘, graphic) be predicted by the same Langewouters’ model(line and 95% Cl). However, TX(“) demonstrated supra-normal values of C for a MAP(94111 mmHg) similar to postD but a pulse pressure (49*15 mmHg) similar to Ctrl. Conclusion: Improvement of compliance after dialysis follows the non-linear Langewoutsrs’ pressure-volume relationship. Renal TX improves arterial wall characteristics to a higher degree that may be related to structural changes.

Improvement of acute renal dysfunction (ARD) in heart transplant (TX) patients (PTS) during calcineurin inhibitor (CNI) ‘holiday’ without rejection under anti-CD25 monoclonal antibody (MAB) coverage

Heart transplant Tx pts on CNI can develop ARD, which could be improved by reducing or withholding (‘holiday’) CNI dose. Anti-CD25 (anti-IL-2 receptor) monoclonal antibodies (mAb) (basiliximab and daclizumab) have been successfully used for induction immunosuppression after solid organ Tx. Purpose: To describe the effectiveness of anti-CD25 mAb to prevent acute rejection in heart Tx pts with ARD, after the initial post-operative period, requiring temporary CNI ‘holiday‘. Methods: We studied 9 men (61±6 yr.) presenting with 13 events of ARD after heart Tx (1 pt was a recipient of a simultaneous heart/renal Tx, and 1 pt received a renal Tx 12 years after heart Tx). ARD was diagnosed between 1 and 9 months post-Tx in 4 pts, and between 4 and 14 years post-Tx in 5 pts. ARD was defined as an increase in serum creatinine (Scr) >25% vs. the lowest Scr within the previous month (baseline). ARD was secondary to liver failure (1 pt), and multifactorial, including heart failure and diuretics (5 events in 3 pts), CNI toxicity, tricuspid regurgitation and diuretics (3 events in 1 pt), CNI toxicity and diuretics (4 pts). In heart/renal Tx pts, CNI toxicity was confirmed by renal biopsy. In all pts, CNI ‘holiday’ was implemented until Scr decreased to baseline. All pts were on CsA microemulsion (0.7-3.7 mg/kg/day, 2-hr peak levels 216-764 ng/ml). Endomyocardial biopsies were performed every 2 weeks during CNI ‘holiday’. Anti-CD25 mAb were made available on a compassionate basis. Results: Results are shown in the table and expressed as mean±standard deviation. Three pts required hemodialysis (range 2-30 days). CNI ‘holiday‘ was implemented during 20±23 days (range 6-78). Basiliximab, 20 mg iv. at baseline and on day 4, subsequently q.20 days (as needed) was used in 5 pts (9 events), and daclizumab (1.5 mg/kg/iv. q.7 days) was used in 4 pts (4 events). Anti-CD25 mAb were well tolerated, with no episodes of acute rejection. Conclusion: Our results suggest that CNI ‘holiday’ could be safely implemented in heart Tx pts with ARD, after the initial post-operative period, under anti-CD25 mAb coverage. A prospective randomized study is required to confirm our results.

STERIOD AVOIDANCE IN KIDNEY TRANSPLANTATION

306 Previous studies of steriod withdrawal in kidney tx were associated with the occurrence of some late rejection episodes and graft losses. In the current era, the immunosuppression is so effective at preventing acute rejection, that a re-examination of the need for steriods is timely. We describe our experience with 20 kidney tx pts whose maintenance immunosuppression excluded the use of steriods. 19 pts received living donor kidneys: 12 LRD (3 HLA-ID, 6 one-haplo match, 3 zero-haplo match); and 6 LURD, and one recipient of a zero antigen mismatched cadaveric graft. The control group of 25 pts received identical immunosuppression except that it included prednisone. 21 pts received living donor kidneys: 15 LRD (5 HLA-ID, 7 one-haplo match, 3 zero-haplo match); and 6 LURD, and four recipients of cadaveric grafts. Laparoscopic nephrectomy was used for all but one living donor. There was no morbidity in the living donors. All transplants exhibited immediate renal function. All pts were given induction with three doses of solumedrol [500mg, 250mg and 125mg, on days 1, 2, and 3, respectively]; and also basiliximab (N=32) or daclizumab (N=4) (except recipients of HLA-ID grafts). Maintenance immunosuppression was tacrolimus (TAC) and mycophenolate mofetil (MMF; 3 gm/d). TAC was tolerated in all pts, and one was converted from MMF to azathioprine because of GI symptoms. Pt demographics including mean age, duration of dialysis, peak PRA levels, and proportion of recipients of HLA-ID grafts were the same in the two groups. Follow-up has been a median of 61 days (IQ 7-94d) in the steriod avoidance group, and 134 days (IQ 109-218d) in controls. The actuarial pt and graft survivals, and rejection rates were calculated to 120 days. The incidences of bacterial, viral and fungal infection, and occurence PTLD were also determined. (Table) The pt and graft survivals were all 100%. 4 pts in the steriod avoidance group had rejection episodes (1 HLA-ID, 2 one-haplo LRD, 1 LURD), all reversed (3 OKT3, 1 Steriods). 3 control pts had rejection episodes (1 one-haplo LRD, 2 LURD), all reversed (2 OKT3, 1 Steriods). 16 of the pts in the steriod aviodance group remain off prednisone. One pt in each group had a bacterial infection. There have been 0 cases of CMV, fungal infections or PTLD in either group. Longer follow-up is necessary to fully assess risk of graft loss and rejection. These early results suggest that the inclusion of steriods in maintenance immunotherapy may not be necessary in recipients of immediately functioning living donor or zero antigen mismatched cadaveric grafts.Table

PRETRANSPLANT INITIATION OF ALG INDUCTION THERAPY IMPROVES LONG TERM OUTCOME IN B-CELL FLOW CYTOMETRIC CROSSMATCH POSITIVE RENAL ALLOGRAFT RECIPIENTS

294 Aim: Early immunologic allograft failure is associated with a positive (+) flow cytometric crossmatch (FCXM) in kidney transplantation (KTx). We have previously observed that appropriately timed intense immunosuppression (IS) can improve immediate function and reduce early rejection of renal allografts. We have now extended the observation to 8 years posttransplant. Methods: 61 consecutive cadaveric KTx performed between 1990-92 were analyzed. A negative (−) Amos one-wash T-Cell XM was a prerequisite for Tx. B-Cell FCXM was (−) in 39 recipients (pts) and (+) in 22. IS consisted of Minnesota ALG (ALG) induction: given intraoperatively prior to kidney implantation in 39 pts (preTx ALG group), or postoperatively in recovery room in 22 pts (postTx ALG group), in addition to steroids, cyclosporine and azathioprine. Pts were divided into 4 groups based on timing of ALG initiation and FCXM status. Kaplan-Meier actuarial graft survival was determined and curves were compared by log rank analysis with a p value < 0.05 considered significant. Results: All groups were similar with respect to recipient age, race, PRA, retransplant status, and number of HLA mismatches. Only 3 pts were T FCXM (+) and the groups did not differ in this regard. (Table)TableGraft survival was similar in FCXM (−) pts regardless of the timing of ALG and in FCXM (+) pts receiving PreTx ALG. Survival was diminished in FCXM (+) pts who were given ALG PostTx. In FCXM (−) KTx, timing of ALG therapy had no impact on the Tx outcome, but in FCXM (+) Txs, pregraft initiation of MALG therapy resulted in improved graft survival, equivalent to that of FCXM (−) KTx. This extends our previously reported observations of improved early graft survival in FCXM (+) Tx pts receiving PreTx ALG. Conclusion: We conclude that PreTx initiation of ALG improves the long-term outcome of B-Cell FCXM (+) KTx recipients. We recommend that FCXM be used to identify a high-risk group of pts for whom optimal immunosuppressive management can result in successful engraftment.

USING THE FRAMINGHAM DATABASE TO PREDICT CORONARY HEART DISEASE (CHD) EVENTS IN RENAL TRANSPLANT PATIENTS

853 Cardiovascular disease is the single most significant cause of death in end-stage renal disease (ESRD). The utilization of cardiac risk factors in the general population as predictors for coronary heart disease (CHD) events in a patient undergoing renal transplantation has not been described. Andersen et al. developed a Framingham heart study equation to predict the probability of CHD events using the traditional cardiac risk factors (age, gender, systolic BP (SBP), total cholesterol (Chol), HDL, tobacco use, diabetes [DM], and LVH). Our goal was to examine the applicability of the Framingham CHD risk profile in ESRD patients at the time of renal transplantation. 249 patients (pts) from a single-center renal transplant (Tx) program were analyzed. All pts underwent renal Tx in the calendar year 1995. 214 (86%) underwent 1° renal Tx (49% cadaveric, 26% living-donor, and 22% kidney-pancreas). Average f/u was 3.4 years. The population, with a mean age of 40.7±13 yrs, was 60% male. Average SBP was 139±18.3 mmHg, total Chol 229±55.3 mg/dl, and HDL was 58.4±22.5 mg/dl. 23% of the pts were smokers, 21% had LVH on baseline electrocardiogram and 41% of pts had DM. 10% of the cohort had pre-Tx CHD. 29 pts (11.6%) experienced a post-Tx CHD event defined as angina, CHF, acute MI, cardiac arrest, or sudden death. This was significantly greater than the expected CHD event rate computed for the general population without preexisting heart disease (7.02/249;2.7%), reflecting a 3.8-fold increase in CHD risk in our Tx pt population (p<0.001). The risk of a CHD event was highest in the early post-Tx period. Univariate analyses showed that age (p=0.01), creatinine at discharge (p=0.04), and pretransplant CHD (p=0.004) were associated with post-Tx CHD events. Multivariate analysis demonstrated that pre-Tx CHD (p=0.04) was the only variable predictive of a post-Tx CHD event. Other variables including gender, SBP, diabetes, smoking, LVH, Chol, or HDL were not independently predictive of post-Tx CHD events. Despite underestimating the incidence, the Framingham equation predicted 4-yr risk was highly associated with the hazard of CHD in Tx pts (p=0.0028, Cox prop. hazards). This analysis confirms the increased incidence of CHD events in renal Tx patients. The Framingham risk model appears to be a useful tool in identifying Tx pts at risk for CHD events. For assessing short-term (<5 years) risk however, the calculated result should be multiplied by a factor of 3.8 to obtain a more accurate prediction of a post-Tx CHD event.

DACLIZUMAB (ZENAPAX) IN PEDIATRIC RENAL ALLOGRAFTS: FINAL DATA

469 According to NAPRTCS data, acute rejection episodes(ARE) occur in 41% to 58% of pediatric (ped) renal transplant (Tx) patients(pt) by 6 months after Tx. ARE jeopardize graft outcome but the toxicity associated with agents that dramatically reduce AREs may make such agents impractical in ped Tx. We conducted an open label single-arm multicenter study of the safety and pharmacokinetics (PK) of adding daclizumab, a humanized monoclonal antibody with specificity for the α subunit of the IL-2 receptor (IL-2R) on activated T cells, to center-specific maintenance immunosuppression. Patients and Methods: In addition to center-specific immunosuppression, pts received daclizumab, 1 mg./kg IV prior to Tx and bi-weekly for a total of 5 doses. Clinical results are available for 54 pts. The median age of the pts was 10 yrs; 16 were <1-5 yrs., 13 were 6-12 yrs., and 25 were 13-17yrs. 36 received living donor Txs. 18 (33%) were CMV seronegative and received Txs from CMV seropositive donors. 44% have been followed for ≥1 yr. and 87% have been followed for ≥6 months. 74% received cyclosporine, 26% received tacrolimus and 87% received mycophenolate mofetil. Serum daclizumab levels and CD25 expression on pts' T cells were followed monthly for the first 4 post-Tx months and again at 6 months post-Tx. Results: No Tx was lost to rejection; 2 grafts were lost- one to vascular thrombosis and one to recurrent focal sclerosis. Only 3pt (5%) experienced AREs at a mean of Day 22. The AREs were mild and resolved with anti-rejection treatment. No symptoms of cytokine release or anaphylaxis were observed. Infectious serious adverse events were uncommon: 11% developed urinary tract infections, 6% developed bacteremia, and only 7% had CMV viremia. One pt developed atypical lymphoid hyperplasia, but none developed lymphoproliferative syndrome. PK studies of daclizumab serum levels showed that predose levels ranged from 2-6 μg/ml and were not significantly different than in adult Tx pts. At the time of Tx, levels of CD25+ T cells were lower than those observed in adults. Daclizumab levels were sufficient to block the IL-2R α subunit without significantly modulating CD25 from the T cell surface. Saturation of the relevant CD25 epitope was present after the first daclizumab dose and remained complete for ≥ 1 month after the last dose. Compared to pts who did not experience ARE, pts with ARE had no difference in CD25 saturation, pretreatment levels of CD25+ T cells, or trough serum levels of daclizumab. Conclusions: The addition of daclizumab to current protocols can reduce ARE in Ped Tx pts without a significant increase in adverse events or infections. The results of this trial suggest that the serum levels of daclizumab achieved with the current regimen are sufficient to achieve the desired immunological effect without additional toxicity.

THE LONG-TERM USE OF MYCOPHENOLATE MOFETIL IN PEDIATRIC RENAL TRANSPLANTATION. A REPORT OF THE PEDIATRIC MYCOPHENOLATE MOFETIL STUDY GROUP (PMMSG)

471 In an open-label, single arm, multicenter mycophenolate mofetil (MMF) dose escalation trial, the PMMSG has previously reported that, in pediatric (ped) renal transplant (Tx) patients (pts), MMF, in conjunction with cyclosporine (CsA) and prednisone (Pred), was well tolerated and resulted in a 35% rate of acute rejection episodes (ARE) at 6 months after Tx. While MMF appears to be safe and effective in preventing AREs in the short term, there are no data about its long term safety or efficacy in ped Tx pts. In 1998, NAPRTCS reported that at 3 years, ped pts with cadaver donor (CAD) Txs have a 69% incidence of ARE and a graft survival rate of 72%, while pts with Txs from living donors (LD) have a 55% ARE rate and a graft survival rate of 85%. The PMMSG has now followed, for a minimum of 3 years, 40 ped pts who received initial maintenance immunosuppression with MMF, CsA and Pred. All pts who were initially enrolled in the study were followed for patient survival, graft survival, and malignancy status even though some pts were prematurely withdrawn. The mean age of the pts. at Tx was 10.2 ± 4.8 years. Eight pts were <6 years old, 15 were 6-11 years, and 17 were 12-18 years of age. 52% were Caucasian, 38% were Hispanic, 8% were African-American, and 2% were Asian. Seventeen (43%) received Txs from CAD and 23 (57%) Txs were from LD. Thirty-four (85%) were primary Txs. Results: There were no pt. deaths, and 38 of the 40 grafts (98%) were functioning 3 years after Tx. One graft was lost to recurrent focal glomerulosclerosis on Day 53, and a second was lost to vascular thrombosis on Day 48. At 3 years, 47% of pts on study had been treated for an ARE. All ARE were successfully reversed: 47% of the ARE required corticosteroids only, 21% were treated with either OKT3 or an anti-lymphocyte antibody, and 32% were treated with both corticosteroids and either OKT3 or an anti-lymphocyte preparation. Twenty-seven pts (68%) received MMF for ≥ 3 years. MMF was discontinued prior to 3 years in 13 pts at a mean of 571 ± 265 days after beginning MMF. In 3 pts (8%), MMF was withdrawn because of an unsatisfactory therapeutic response, and in 2 other pts, the study was terminated because the pt was converted from CsA to tacrolimus. In 4 pts (10%), MMF was discontinued because of an adverse event that required the medication be discontinued for >2 weeks. Two pts were lost to follow up; one was discontinued from the study for noncompliance, and another for continuing growth retardation. Opportunistic infections developed in 15 pts (37%): Oral thrush 6 (15%), Candida UTI 1 (2%), Herpes Zoster 6 (15%), Herpes Simplex 5 (12%), tissue invasive CMV 2 (5%), CMV viremia syndrome 1 (2%). One pt (2%) developed a B cell lymphoma at 39 months that responded to discontinuation of all immunosuppression and chemotherapy. Conclusions: In ped renal Tx pts, MMF in combination with CsA and Pred provides effective maintenance immunosuppression for 3 years. At 3 years, graft survival is excellent and the rate of additional ARE after the first 6 months is low. Long term therapy with MMF is well tolerated in ped pts.

Is The Therapeutic Efficacy of Mycophenolate Mofetil In The Treatment Of Cardiac Allograft Rejection Related To Blood Level?

74 Mycophenolate Mofetil (MMF) is a unique immunosupressive agent that has shown to be efficacious in the treatment of cardiac allograft rejection (REJ). Prior reports suggest that MMF efficacy in Tacrolimus based patients is related to MMF blood level. The objective of this study is to evaluate the incidence of REJ in relation to the blood level. Between November 1997 and October 1998, we retrospectively analyzed the clinical outcome of 133 MMF treated patients post cardiac transplant (TX) who had regular MMF blood level monitoring at the time of heart biopsy. Mean follow up period was 6.5 mos. Demographics were as follows: 82% male, mean age 51.2 yrs; 19% were on mechanical support. 94% of pts were on cyclosporine (CSA), 6% Tacrolimus; prednisone was initiated at 20 mg daily on all pts. Samples were divided into 3 groups, according to the 12 hr trough blood level (group I: <2, group II: 2-4, group III: >4 mg/l, see Table). REJ was defined as ISHLT grade 3A or greater. The mean blood level of the REJ and REJ free group was 2.37±1.86 and 2.44±1.86 mg/l (P=0.26). No significant renal, hematologic, or hepatic side effects were noted.Table: Therapeutic Efficacy of MMF in Relation to Blood Level Conclusions: MMF therapeutic efficacy as an immunosuppressive agent in the treatment of cardiac allograft REJ may be independent of its blood level. Further analysis in cardiac TX pts immunosupressed with CSA and prednisone is required. Monitoring blood level may not be cost-effective.

HUMANIZED MONOCLONAL ANTI INTERLEUKIN-2 RECEPTOR (IL-2R) ANTIBODY DACLIZUMAB (ZENAPAX??) IN PEDIATRIC (Ped) RENAL TRANSPLANTATION (Tx)

53 Although U.S. Ped renal Tx graft survival rates continue to improve yearly, Ped. patients (pts) continue to represent a high risk group for acute rejection episodes (ARE). In adult renal Tx, Declizumab (Zenapax), a humanized monoclonal antibody with specificity for the α subunit of the IL-2R on activated T cells, has been shown to decrease significantly the rate of AREs without an increase in toxicity or adverse side effects. We are conducting an open label multicenter study of the safety and pharmacokinetics(PK) of adding Zenapax to center-specific standard maintenance immunosuppression. Pts received Zenapax, 1mg./kg IV immediately prior to Tx and bi-weekly for a total of 5 doses. Results are available for 25 pts. The median age of the pts was 12 yr.; 7 were <1-5 yrs., 6 were 6-12 yrs., and 12 were 13-17 yrs. Sixteen pts received living related donor Txs; none of the donors were HLA identical. The Tx of one pt was lost immediately post-Tx because of a technical failure (vascular thrombosis) and she received only 1 dose of Zenapax. At the time of evaluation, 18 of the remaining 24 pts had received ≥ 4 doses of Zenapax. For maintenance immunosuppression, 90% received cyclosporine, 10% received tacrolimus and 95% received mycophenolate mofetil. All 24 Txs are functioning, with a mean serum creatinine of 0.8 mg/dl at day 56; only 1pt (4%) experienced an ARE, which was mild and resolved with anti-rejection treatment. No symptoms of cytokine release or anaphylaxis were observed with Zenapax. Serious adverse events were uncommon in the first 3 months: 4 pts developed urinary tract infections, and 1 pt each developed bacteremia, gastroenteritis, and fever. No pt developed CMV or EBV infection, or lymphoproliferative syndrome. Preliminary PK Zenapax serum concentrations for 3 months were available for 6 pts. Zenapax levels were lower than in adult Tx pts. receiving the same dose. However, in the 6 Ped pts, the Zenapax levels were sufficient to completely saturate the α subunit of the IL-2Rs immediately after the first dose. Saturation remained complete for ≥ 1 month after the last dose. Because the initial pre-Tx percentages of IL-2R+ T cells in these Ped pts were markedly lower than those in adults, it is possible that saturation can be maintained with the lower serum levels of Zenapax. The favorable clinical response and the adequacy ofα subunit saturation suggests that the relatively low serum levels of Zenapax may be sufficient to achieve the desired effect. We conclude that the addition of Zenapax to current maintenance immunosuppression may reduce ARE in Ped Tx pts without an increase in serious adverse events or opportunistic infections.

CLINICAL BENEFIT OF NEORAL DOSE MONITORING WITH CYCLOSPORINE 2-HOUR PEAK LEVELS COMPARED TO TROUGH LEVELS IN STABLE LIVER TRANSPLANT PATIENTS

42 We have previously reported that cyclosporine (CsA) 2-hour peak levels(C2) correlate better with the area-under-the-curve than trough levels (C0) in heart Tx pts receiving Neoral. Moreover, Neoral dose adjustment according to a target CsA C2 blood level of 300-600 ng/ml(EMIT) resulted in 30% dose reduction and initial lower serum creatinine(Scr), without increasing the risk of acute rejection. It has also been reported that C2 levels correlate well with acute rejection after liver Tx. Purpose: to determine the clinical benefit of Neoral dose monitoring with conventional CsA C0 levels compared to 2 different ranges of C2 levels in stable liver Tx pts.Methods: clinical benefit was defined as the absence of acute rejection and no change in Scr at a mean follow-up period of 7 months. We enrolled 35 stable pts one year or more after Tx. There was no difference in primary liver disease, or any of the following baseline values: liver function tests, Scr, Neoral dose and number of pts on Neoral monotherapy. Pts were randomized into 3 groups (Gr) for Neoral dose monitoring: Gr 1(C0 target range 100-200 ng/ml): 7F/4M, 59±13 yr., 39±15 months post-Tx; Gr. 2 ("high" C2, target range 700-1000 ng/ml): 5F/8M, 58±11 yr., 35±17 months post-Tx, and Gr. 3 ("low" C2, target range 300-600 ng/ml): 3F/8M, 56±9 yr., 37±19 months post-Tx. Neoral dose was increased or decreased by 0.5-1 mg/kg/day if measured levels were outside of the target range. A liver biopsy was done if liver function tests increased >50% from baseline.Results: one pt in Gr. 1 and one pt in Gr. 3 presented with a reversible acute rejection episode within 1 month after enrollment; the CsA level of each of these had been below target. Neoral dose (Mg/kg/day), Scr levels, and mean percentage change are shown below.Table Conclusion: Neoral dose monitoring according to a CsA C2 range of 300-600 ng/ml resulted in a lower dose of Neoral and greater clinical benefit (stable Scr without a higher incidence of acute rejection) compared to conventional C0 levels or a higher C2 range in stable liver Tx pts.This research was funded by Novartis Pharma Canada inc.

NEUROTOXICITY IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS TREATED WITH FK506(TACROLIMUS). 2177

Severe neurotoxicity (SN) has been reported in adult liver transplant (tx) pts treated with FK506. Adult renal tx pts may have less SN, but the presence of SN and mild neurotoxicity (MN) in pediatric renal tx pts is not well described. We evaluated SN and MN in pediatric renal tx recipients on FK506.

936-88 Relationship of Donor Age and Pre-existing Coronary Disease by Angiography and Intracoronary Ultrasound to Later Development of Cardiac Allograft Coronary Artery Disease

The increasing demand for cardiac donors has led to a tendency to liberalize age and other criteria for donor acceptability. Since cardiac allograft coronary artery disease (TxCAD) is the major complication limiting longterm post-transplant survival, we analyzed a series of 242 consecutive cardiac transplant patients (Tx pts) who had baseline early post-op coronary angios and a subset of 41 pts with baseline intracoronary ultrasound (ICUS) to determine whether either older donor age or pre-existing CAD at the time of transplant influenced the later occurrence of TxCAD. Fourteen pts had angiographic evidence of some pre-existing CAD (donor CAD group); the other 228 did not (no donor CAD group). New disease was defined as either development of new obstructive lesions or progression of old lesions on serial annual angios. Freedom from new disease was 86%, 71%, and 30% at 1, 2, and 3 years post-op in the donor CAD group and 97%, 89%, and 77% in the no donor CAD group (p = 0.003). No donor CAD pts were subdivided into older (≥40) and younger (&lt;40) groups. Freedom from TxCAD was 92%, 52%, and 43% at 1, 3, and 5 years post-op in the older group (n = 31, mean age 49) vs. 97%, 82%, and 53% in the younger group (n = 184, mean age 24) p = 0.03 (Mantel-Haenszel). Baseline ICUS imaging revealed baseline class 3 or 4 lesions in 7 of 9 older donor hearts, and in only 7 of 32 younger hearts (p = 0.006). Three of these 14 ICUS class 3/4 pts later developed TxCAD vs. only 3 of 27 class 1/2 pts at baseline (p = NS). Older donor age, no calcium blocker use and pre-existing CAD were significant predictors for development of TxCAD (p = 0.0006, 0.0003, and 0.003 respectively, Cox regression analysis). (1) Older donors or pre-existing CAD have a greater tendency to develop TxCAD, (2) ICUS reveals moderate to severe intimal thickening not angiographically detectable and there is a trend toward such disease leading to later TxCAD.