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191 THE CLINICAL ROLE OF GENE EXPRESSION TESTING IN ANTICIPATING THE FUTURE DEVELOPMENT OF ACUTE CARDIAC ALLOGRAFT REJECTION M.R. Mehra,1 J.A. Kobashigawa,2 M.C. Deng,3 F.L. Johnson,1 H.M. Baron,4 P.A. Uber,1 P. Lal,4 T. Klingler,4 S. Rosenberg,4 H.J. Eisen,5 1 Department of Medicine, University of Maryland, Baltimore, MD; 2 University of California at Los Angeles, Los Angeles, CA; 3Columbia University College of Physicians and Surgeons, New York, NY; 4 Research and Development, XDx, Inc., South San Francisco, CA; 5 Drexel University College of Medicine, Philadelphia, PA Purpose: Recently, a 20 gene RT- PCR test (genes involved in B and T cell events, hematopoiesis, platelet activation and steroid responsiveness) has demonstrated a high negative predictive value for current biopsy proven moderate to severe cellular rejection but is associated with significant ”false positives”. We sought to examine whether such ”false positive” signatures represent early signals that anticipate development of cellular rejection. Method: RNA was isolated from PBMC’s of 108 de-novo heart transplant recipients (atleast 1 month post transplant, no rejection 30 days prior and currently quiescent (ISHLT grade 0 or 1A) biopsy). The primary end point of this prospective, blinded analysis was to identify the predictive capacity of the multi-gene molecular test on the occurrence of acute cellular rejection (ISHLT grade ⱖ3A) within 2 -12 weeks of follow-up. Results: 66 patients remained quiescent and 42 developed ISHLT grade ⱖ3A rejection within 2–12 weeks. Higher gene scores were noted for future rejectors compared to those without (29.7 vs. 24.1, p-value ⫽ 0.003). The predictive power was most significant 60–180 days post-transplant (pvalue ⫽ 0.0003). Patients ⬍180 days post-transplant with scores above the median (27.4) were 2.5 times more likely to develop rejection. This was driven by genes reflecting immunity (RHOU), steroid responsiveness (IL1R2), hematopoesis and hematological activation(WDR40A and cMIR).

The Journal of Heart and Lung Transplantation February 2006

Background: A wealth of data exists correlating individual rejection episodes with clinical outcomes following heart transplantation. We have previously noted that heart transplant recipients also develop rejection patterns of clinical importance early after transplantation. The effect these patterns have on outcomes are not universally known or accepted. In this study, we sought to analyze whether repetitive episodes of cellular (CR) or antibody-mediated rejection (AMR) impact cardiovascular (CV) death incrementally in a large cohort of heart transplant recipients followed for up to 20 years. Methods: We queried our prospective database of all adult and pediatric endomyocardial biopsies (EMB) between 1985 and 2005. Histologic and immunofluorescence findings were recorded independently. CR was defined as ISHLT score ⱖ1A, and AMR as the presence of complement and immunoglobulin deposits on frozen sections. Survival curves were plotted (for CR episodes ⱖ1, ⱖ2, ⱖ3, etc..., and AMR episodes ⱖ1, ⱖ2, ⱖ3, etc...) using Cox proportional hazards regression. Patients who received induction with OKT3 were excluded, and those who died from non-CV causes censored from the analysis. Results: 18,442 EMB from 667 heart transplant recipients comprised the study data. Results are shown below in a table form. Episodes (n)

CR (p value)

AMR (p value)

ⱖ ⱖ ⱖ ⱖ ⱖ ⱖ ⱖ ⱖ

1 1 1 0.2 0.35 0.89 0.58 0.29

0.1 0.22 0.06 0.01 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001

1 2 3 4 5 6 7 8

Conclusion: In contrast to CR, a repetitive pattern of AMR is associated with a significant and incremental risk of CV death in heart transplant recipients, that reaches statistical significance with ⬎3 episodes. These findings support the decision of the International Society for Heart and Lung Transplantation to include AMR as a diagnosis in endomyocardial biopsies, and should encourage further preventive and therapeutic strategies to avoid repetitive AMR episodes. 193 CALCINEURIN INHIBITOR “HOLIDAY” WITH ANTI-CD25 MONOCLONAL ANTIBODY COVERAGE RESULTS IN AN IMPROVEMENT OF ACUTE RENAL DYSFUNCTION IN HEART TRANSPLANT PATIENTS WITHOUT INCREASING THE RISK OF ACUTE REJECTION M. Cantarovich, N. Giannetti, G. Fontaine, R. Chartier, E. Cyr, R. Cecere, Medicine, Nursing and Cardiovascular and Thoracic Surgery, McGill University Health Center, Montreal, QC, Canada

Conclusion: This investigation suggests that a multi-gene molecular marker test anticipates future occurrence of acute cellular rejection. The predictive power is best within 180 days following engraftment, a period of active allograft adaptation. Disclosure: The author is a consultant for XDx, Inc. and has received a research grant from XDx, Inc. 192 THE IMPACT OF A REPETITIVE CELLULAR OR ANTIBODYMEDIATED REJECTION PATTERN ON CARDIOVASCULAR DEATH IN HEART TRANSPLANT RECIPIENTS A.G. Kfoury, M.E. Hammond, J. Stehlik, G.L. Snow, J.T. Seaman, J.W. Long, E.M. Gilbert, J.C. Stringham, D.G. Renlund, U.T.A.H. Cardiac Transplant Program, Salt Lake City, UT

Purpose: To report our experience on the efficacy of anti-CD25 monoclonal antibodies (mAb) in preventing acute rejection in heart transplant (HTx) pts with acute renal dysfunction (ARD), requiring a temporary CNI interruption (“holiday”). Methods: Between 09/99 and 06/05, 11 men (62⫾6 yrs) presented with 15 events of ARD, diagnosed 81⫾67 months post-HTx (range 5–172). ARD was defined as an increase in serum creatinine (Scr) ⬎25% vs. the previous visit. ARD was secondary to CNI toxicity (5 events), tricuspid regurgitation and diuretics (4 events), sepsis (3 events), and multifactorial (3 events). In all pts, the CNI “holiday” was implemented until Scr had decreased to baseline. All the pts were on cyclosporine (CsA) 2.4⫾1.7 mg/kg/day (C2 534⫾162 ng/ml). Basiliximab, 20 mg iv. at baseline and on day 4, then q.20 days (as needed) was used during 11 events and daclizumab (1.5 mg/kg/iv. q.7 days) was used during 4 events. Eight pts were on prednisone, 5 pts were on mycophenolate mofetil, 1 pt was on azathioprine and 1 pt was on

The Journal of Heart and Lung Transplantation Volume 25, Number 2S

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rapamycine. Endomyocardial biopsies were performed 2– 4 wks after the initiation of the CNI “holiday” and as needed thereafter. Results: The CNI “holiday” was implemented during 22⫾22 days (range 4 –79). Anti-CD25 mAb were well tolerated. The pt on azathioprine experienced a reversible grade 2 acute rejection (ISHLT classification). None of the pts experienced a grade ⱖ3 acute rejection.

Conclusion: Patients with BPAR had significantly lower C2 levels than those without. In the absence of induction mean C2 levels of ⬃1000ng/mL (minimum C2⬃220ng/mL) or greater were required for adequate immunosuppression in the first 30 days after cardiac transplantation. Disclosure: This study was funded by Novartis.

Renal Function Before and After CNI “Holiday”

195

Re-initiation of CNI

Scr (␮mol/L) ⴱ

Baseline

ARD

Day 0ⴱ

1-month

3-months

188 ⫾ 53

247 ⫾ 81

158 ⫾ 59ⴱⴱ

171 ⫾ 43ⴱⴱ

162 ⫾ 46ⴱⴱ

last Scr during CNI holiday,

ⴱⴱ

p ⫽ 0.0007 vs ARD.

Conclusion: Our results suggest that anti-CD25 mAb may allow for a CNI “holiday” resulting in an improvement in renal function without increasing the risk of significant acute rejection in HTx pts with ARD. A prospective, multicentre, randomized trial is required to confirm the benefits of this strategy. Disclosure: The author is a consultant for Astellas, Hoffman LaRoche, Novartis, Wyeth.

194 ADEQUATE CYCLOSPORINE (CSA) MICROEMULSION (NEORAL®) C2-LEVELS CRITICAL WITHIN THE FIRST 30 DAYS TO PREVENT REJECTION AFTER CARDIAC TRANSPLANT J. Kobashigawa,1 D.G. Renlund,2 H.B. Lehmkuhl,2 J. Segovia,2 1 UCLA Heart Transplant Program, David Geffen School of Medicine at UCLA, Los Angeles, CA; 2for the International CERL080A2401 Study Group, Salt Lake City, UT A recent study of C2 monitored CsA in cardiac transplantation suggested a target range of 1200 –1400 ng/mL in the first months post-transplant. We analyzed C2 and efficacy data from a multicenter (MC) trial in de novo cardiac transplant recipients randomized to enteric-coated mycophenolate sodium (EC-MPS, myfortic®) or to mycophenolate mofetil (MMF) within a CsA-steroids regimen. Our analysis aims to assess CsA C2 targets during the first 30 days. Methods: In a single-blind, MC trial, 154 de novo heart transplant patients were randomized to EC-MPS 1080mg b.i.d. (n⫽78) or MMF 1500mg b.i.d (n⫽76). CsA was monitored by C0 (Month 1 target, 250 – 400ng/mL). Data on biopsy-proven acute rejection (BPAR) and closest corresponding C2 levels to Day 30 were available for 123 patients. Results: BPAR occurred in 34 patients (27.6%); incidence was similar with induction (17/52, 32.7%) or without (17/71, 23.9%; p⫽n.s.). Efficacy was equivalent in EC-MPS and MMF group (27.4% vs 27.9%; p⫽n.s.) Mean C2 levels were significantly lower in patients with rejection (865.9ng/mL vs 1032.9ng/mL; p⫽0.03) compared to rejection-free patients. Subgroup analysis revealed significantly lower C2 levels in patients with rejection (790.0ng/mL vs 1094.7ng/mL; p⫽0.01) compared to rejection-free patients in the non-induction group. This difference was not significant if induction was used (Table 1). CsA C2 Levels With/Without Rejection Rejection n ⴝ 34 C2-levels (mean ⫾ SD, range) N ⫽ 123

Induction (n ⫽ 52) No induction (n ⫽ 71)

No rejection n ⴝ 89

p

941.8 ⫾ 448.9

937.6 ⫾ 288.04

0.8

[203.0–1870.0] 790.0 ⫾ 401.59

[240.0–1446.5] 1094.7 ⫾ 359.25

0.01

[179.0–1403.0]

[217.0–1927.0]

THE IMPACT OF A NATURAL DISASTER ON LUNG TRANSPLANTION: LESSONS LEARNED V.G. Valentine, L. Seoane, G.A. Lombard, S.G. LaPlace, P.M. McFadden, C.H. Van Meter, D.E. Taylor, Lung Transplantation, Ochsner Clinic Foundation, New Orleans, LA An excerpt from Mark Twain’s Life on the Mississippi published in 1870 describes New Orleans in the following way: “. . .the water is up to the top of the inclosing levee-rim, the flat country behind it lies low— representing the bottom of a dish—and as the boat swims along, high on the flood, one looks down upon the houses and into the upper windows. There is nothing but that frail breastwork of earth between the people and destruction.” Twain further points out that “. . .one does not appreciate the sight of earth until he has traveled through a flood.” His first chapter states that the Mississippi River “...draws its water supply from an area as vast as most of Europe.” This great river as it meanders in a crescent through New Orleans “...empties 406 million tons of mud into the Gulf of Mexico-which brings to mind...the rude name for the Mississippi—the Great Sewer. Personally, I never imagined that such filth and foul would invade my home with nearly four feet of Edgar Allan Poe’s “liquid mass of loathsome and detestable putridity” admixed with centuries of New Orleans’ debris for no less than a week yielding an indescribable odor where rancid would be too kind. All of this because of Hurricane Katrina, which has affected more than 90,000 square miles and altered the lives of over 1 million people, forever. Despite the destruction of New Orleans and the total loss of one our nurse coordinator’s home, all of our patients’ records were recovered which allowed for speedy follow-up and counseling. All listed patients and all but one of our lung recipients are alive with no significant ill effects. Preparation, rescue, reconfiguration and relocation of lung transplantation will be discussed in the context of recovery, reconstruction, and renewal. Paradoxically, New Orleans now has an opportunity to rise to unrivaled beauty, elegance, and tastefulness from this calamity thereby fulfilling Twain’s omen that like Boston and Chicago, New Orleans will have its own “burnt district.” 196 PRE-TRANSPLANT PANEL-REACTIVE ANTIBODY AND THE INFLUENCE ON SURVIVAL IN LUNG TRANSPLANT RECIPIENTS – ANALYSIS OF THE UNOS DATABASE L.U. Nwakanma,1 C.E. Simpkins,2 J.A. Williams,1 D.C. Chang,2 M.C. Borja,1 A.S. Shah,1 J.V. Conte,1 1Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, MD; 2Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD Background: The role of panel-reactive antibody (PRA) in lung transplant recipients has not been clearly defined in a large population. We sought to determine how PRA level affects survival in lung transplant recipients. Methods: Retrospective cohort study of the national data in the UNOS Standard Transplant Analysis and Research (STAR) files from October 1, 1987 to September 15, 2005 was performed. Demographic data, pre-transplant PRA, relevant clinical parameters, and survival of all lung transplant recipients were analyzed. Results: Of the12,751 first lung transplant recipients during this period, pre-transplant PRA was reported on 10,237 (80%) patients.