Pre-Transplant Circulating Antibodies Predict Antibody-Mediated Rejection Using the New ISHLT Grading Scale

Abstracts Conclusions: Virtual crossmatch accurately predicts actual flow crossmatch results in patients undergoing OHT. This technique can be reliably used in sensitized patients without compromising patient safety or clinical outcome. 218 No Harm, No Foul? The Prospective Treatment of Sensitized Heart Transplant Recipients with Plasmapheresis and IVIG-Five Year Follow-Up M.W. Weston,1,4 M. Lopez-Cepero,2 T. Jarmi.3,5 1Cardiology, Tampa General Hospital, Tampa, FL; 2Immunology, Lifelink Immunology Laboratory, Tampa, FL; 3Nephrology, Tampa General Hospital, Tampa, FL; 4Cardiology, University of South Florida College of Medicine, Tampa, FL; 5Nephrology, University of South Florida College of Medicine, Tampa, FL. Purpose: The panel reactive antibody (PRA) screen is used to identify sensitized (SENS) patients awaiting heart transplantation. Patients with elevated PRAs include multiparous women, those who received blood transfusions, and those on mechanical circulatory support. SENS patients have a prolonged waiting time. The increased use of mechanical circulatory support ensures that patients with elevated PRAs and positive crossmatches will be more common. SENS patients were treated with plasmapheresis and IVIG immediately prior to transplantation. We report five year follow-up findings on the effect of the treatment on survival, frequency of rejection, and coronary vasculopathy. Methods and Materials: 26 of 52 patients awaiting heart transplant were found to be sensitized (SENS) using flow cytometry. SENS patients underwent plasmapheresis followed by 20 gm of IVIG immediately prior to heart transplantation. The SENS group was compared to a matching group of patients with PRAs o10% (NONSENS). The patients were followed for at least five years. T-test findings comparing both SENS and NONSENS were evaluated to determine whether a difference in outcome exists. Kaplan-Meier techniques were used to estimate survival. Results: Comparisons of the SENS and NONSENS patients revealed that survival (po0.27) and the incidence of rejection post transplant (po0.96) are not significantly different.There was no difference in the development of coronary vasculopathy (po0.35). There was a trend to a greater number of infections experienced by the SENS patients. SENS patients with flow PRA Class II positive did not have a greater incidence of rejection compared to flow PRA Class II negative (po1.0). Conclusions: Preoperative plasmapheresis and IVIG in SENS patients awaiting heart transplantation is effective with no difference in the incidence of survival, rejection or coronary vasculopathy after five years. SENS patients with PRA Class II positive did not have a greater chance of rejection. 219 Predictive Value of HLA Antibody Characteristics in Progression of Subclinical Antibody Mediated Rejection in Heart Transplant Recipients M. Askar,1 E.R. Rodriguez,1 P. Reville,1 J. Gatto,2 J. Schold,1 J. Daghstani,1 A. Zhang,1 L. Klingman,1 E. Hsich,1 R. Starling,1 N. Smedira,1 N. Moazami,1 D. Taylor,1 C. Tan.1 1Cleveland Clinic, Cleveland, OH; 2The Ohio State University, Columbus, OH. Purpose: Donor specific antibody (DSA) is a risk factor for antibodymediated rejection (AMR). Concomitant detection of C4d & C3d in heart biopsies correlates with DSA and allograft dysfunction. Detection of C4d only in surveillance biopsies may not be associated with allograft dysfunction. However, conversion from C4d only to C4d þ C3d is noted in 20% of cases (C4d converters). We studied DSA patterns in clinical (C4dþC3dþ & C4d converters) & subclinical (C4dþ) AMR. Methods and Materials: Of 1589 transplants, 610 were screened for AMR (last 6 yr). We studied DSA patterns in C4dþ asymptomatic patients, C4dþC3dþ biopsies symptomatic patients & patients who started as C4dþ & converted to C4dþC3dþ. We also compared cPRA & crossmatches.

S87 Table 1

C4dþ: n¼34 C4dþC3dþ: n¼30 C4d conv: n¼11 p

Any DSA DSA Cl I DSA Cl II

DSA Cl I þII

mean ⫾ SE cPRA

mean ⫾ SE MFI

19, 56%

9, 26%

12, 35%

2, 6%

28, 93%

20, 67%

26, 87%

18, 60%

11, 100% .0003

4, 36%

10, 91%

3, 27%

.005

o0.0001

o0.0001

44.8 ⫾ 5.1 87.4 ⫾ 5.4 81.1 ⫾ 8.9 o0.0001

7398.5 ⫾ 1525.1 12633.0 ⫾ 1222.8 8378.2 ⫾ 1950.9 .022

Any DSA DSA Cl I DSA Cl II

DR DSA

DQ DSA

cPRAZ50

19, 56%

9, 26%

12, 35%

3, 9%

11, 32%

16, 47%

11, 100% .008 .38 1

4, 36%

10, 91%

6, 55%

9, 82%

10, 91%

.70 .30 .78

.002 .46 .96

.003 .67 .86

.004 .45 .92

.014 .39 .95

Table 2

C4dþ: n¼34 C4d conv: n¼11 p PPV NPV

Results: Significant differences in DSA incidence, mean cPRA, & DSA mean MFI were noted across all groups with C4dþ patients having the lowest values (table 1). DSA mean MFI was significantly higher in patients with clinical AMR (table 1). C4d converters had significantly higher mean cPRA & DSA, driven by higher DQ DSA but not class I DSA compared to patients who remained C4dþ (Table 2). Having any DSA, DQ DSA or cPRAZ50% at time of biopsy was associated with C4d conversion with high -ve predictive value (NPV) but low þve predictive value (PPV). Conclusions: Our data suggest that HLA antibody characteristics may be relevant in determining which subclinical C4dþ may not progress to clinical AMR & warrants investigation in larger cohorts. 220 Pre-Transplant Circulating Antibodies Predict Antibody-Mediated Rejection Using the New ISHLT Grading Scale M. Kittleson, J. Patel, M. Rafiei, A. Osborne, D. Chang, D. Ramzy, L. Czer, N. Reinsmoen, J. Kobashigawa. Cedars-Sinai Heart Institute, Los Angeles, CA. Purpose: The presence of pre-transplant circulating anti-HLA antibodies (PRA) portend worse survival and increase the risk of antibody-mediated rejection (AMR) after transplantation. The diagnosis of AMR is now standardized with the new ISHLT grading scale. The purpose of the current study was to determine whether the presence of pre-transplant PRA is associated with an increased incidence of AMR according to the new ISHLT AMR grading scale.

pAMR0 pAMR1 pAMR2 pAMR3 Total pAMR Treated AMR Median AMR episodes per patient

Peak PRA 0% (66 pts; 701 biopsies)

Peak PRA 26Peak PRA 1-25% (10 pts; 100% (30 pts; 338 biopsies) 113 biopsies)

98% (701) 2% (12/701) 0 0.1% (1/701) 2% (13/701) 0 1

88% (100/113) 10% (11/113) 2% (2/113) 0 12% (13/113) 10% (1/10) 1.5

85% (286/338) 11( (37/338) 4% (15/338) 0 15% (52/338) 17% (5/30) 3

S88

The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013

Methods and Materials: 106 heart transplant recipients transplanted January 2010 to July 2011 were divided into groups based on the peak pre-transplant PRA: 0%, 1-25%, and 26-100%. 1152 biopsies from the 106 patients were examined. Endpoints were total number of pAMR episodes, highest grade of pAMR on biopsy, and incidence of treated AMR. Results: Of the 106 patients, 66 had PRA 0%, 10 had PRA 1-25%, and 30 had PRA 26-100%. Patients with elevated PRA were younger, more often female, and more likely to have a ventricular assist device. Patients with elevated pre-transplant PRA had a higher incidence of pAMR on biopsy, a higher incidence of higher grade pAMR, were more likely to have AMR requiring treatment, and had a higher median number of pAMR episodes (Table). Conclusions: Pre-transplant circulating anti-HLA antibodies are associated with more frequent pAMR on biopsy, higher grade of pAMR on biopsy, a higher incidence of treated AMR. This suggests that patients with elevated pre-transplant PRA should be considered for augmentation of immuonosuppression. 221 To Induce or Not To Induce: A 21st Century Evaluation of Lung Transplant Immunosuppression B.A. Whitson,1 A. Lehman,1 A. Wehr,1 D. Hayes Jr.,2 S. Kirkby,1,2 A. Pope-Harman,1 A. Kilic,1 R.S.D. Higgins.1 1The Ohio State University Wexner Medical Center, Columbus, OH; 2Nationwide Children’s Hospital, Columbus, OH. Purpose: The impact of induction immunosuppression on lung transplant (LTX) recipients survival is unclear. We sought to evaluate the effect of contemporary induction agents in LTX recipients with the primary endpoint of survival and a secondary endpoint of treated rejection in the first year post-transplant (TR1Y). Methods and Materials: We queried the UNOS registry for LTX from 1987-2012. We restricted our analysis to adults (4¼18 years),

Hazard Ratios for INDUCED vs. NONE

CF COPD IPF Other

HR

95% CI

p

0.69 0.88 0.94 0.77

0.58-0.82 0.8-0.97 0.85-1.04 0.68-0.86

o.001 0.008 0.25 o.001

cadaveric LTX performed from 2001-2012 who received either: no antibody based induction (NONE) or the contemporary agents of either basiliximab, alemtuzumab, thymoglobulin, ALG or ATG (INDUCED). Kaplan-Meier estimates of the survival function as well as Cox proportional hazards models compared survival. Results: Of LTX recipients, 12958 meet the inclusion criteria & 5747 (44%) were INDUCED. Of INDUCED agents, 62% were basiliximab, 14% alemtuzumab, and 23% ALG/ATG/Thymo. Being INDUCED increased survival (po0.001). Median INDUCED survival was 73.4 months (95%CI: 61.8–79 months) and 63.9 months (95%CI: 60.6–66.7 months) for NONE. Basiliximab had survival superior to ALG/ATG/ Thymo (p¼0.03). In multivariable analysis, INDUCED had a protective effect for all diagnoses except IPF. Of INDUCED patients, 34% were TR1Y & 38% with NONE (po0.001; note 31% of TR1Y data were uncoded; multiple imputation to assess the impact). There was no effect on dialysis rate (INDUCED, 5%; NONE 6%,p¼0.9). Conclusions: In a contemporary analysis of LTX recipients, induction immunosuppression has a significantly increased survival. Being INDUCED has less incidence of rejection with no effect on the need for dialysis. 222 A Prospective Pilot-Study of Azithromycin for Lymphocytic Airway Inflammation after Lung Transplantation R. Vos,1 S.E. Verleden,1 D. Ruttens,1 A. Vaneylen,1 E. Vandermeulen,1 D.E. Van Raemdonck,1 J. Yserbyt,1 L.J. Dupont,1 E.K. Verbeken,2 G.M. Verleden,1 B.M. Vanaudenaerde.1 1Lung Transplant Unit, KU/