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HLA Antibody Titer and C1Q Reactivity Reflect Response to Desensitization and Facilitate Donor Selection
S470
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
high CVH scores at listing, 1, 3 and 5 years PT: 73, 74, 87 and 75%, respectively. Figure 1A shows differences in the distribution of CVH metrics between HT pts and the GP. Figure 1B shows the most recent CVH score distribution; there were differences in the distribution of CVH scores in age groups (p=0.02). HT pts with low (vs. high) cumulative CVH scores had a HR of 2.95 (p=0.002) for the composite adverse outcome of chronic kidney disease, coronary allograft vasculopathy, relisting or death. Conclusion: CVH scores in pediatric HT pts were stable over time with younger pts more likely to have high CVH. Compared to the GP, HT pts had lower ideal glucose but higher ideal lipids. Low cumulative CVH scores were associated with »3-fold higher risks of adverse outcome. Future interventions to improve CVH in HT pts, such as targeted counseling, should be considered.
on rejection risk remain unclear. It has been thought that use of basiliximab for induction may avoid the risk of (C4dD) and decrease the risk of rejection. We examined C4dD and incidence of rejection the relationship among children treated with ATG I-I as well as those treated with basiliximab I-I. Methods: A retrospective review of charts of patients with PCT performed at our center between June 2012 and April 2018 was performed. Results of C4d immunohistochemistry were available from all EMB of patients (n=56). Results: The population was predominantly male (70%) with a median age of 10 years (IQR 2.63 -14.46 years). 28 patients received ATG and 28 patients received basiliximab as induction therapy. Sixty percent (60%) of the ATG patients had C4dD on the 1st biopsy posttransplant and 25% of patients had a persistent C4dD on the next 5 EMB. When C4dD was demonstrated in ATG patients, other markers of significant rejection were rare; only 4% had ACR grade 2 or higher by the revised 2004 ISHLT grading system (historically 3A, 3B and 4 rejection) and/or histologic evidence of AMR. Only 3% of patients receiving basiliximab for induction had C4dD on any EMB in the first year post-transplant. When C4dD was demonstrated in basiliximab patients, other markers of significant rejection were found frequently; 57% had ACR grade 2 or higher by the revised 2004 ISHLT grading system and/or histologic evidence of AMR. Conclusion: C4d deposition was more common on EMB up to 1 year postPCT in patients receiving ATG induction, compared to basiliximab. Despite less C4dD in basiliximab EMBs, these patients had more rejection episodes. The presence of C4dD may thus not be an accurate measure of rejection in PCT patients and should be taken into consideration when reviewing and determining treatment options. 1186 HLA Antibody Titer and C1Q Reactivity Reflect Response to Desensitization and Facilitate Donor Selection M. Mangiola,1 M.D. Zinn,2 S. West,2 S.A. Miller,2 K. Rose-Felker,2 B. Feingold,2 and A. Zeevi.1 1Transplant Pathology, Univ of Pittsburgh Med Ctr, Pittsburgh, PA; and the 2Pediatrics, Univ of Pittsburgh Med Ctr, Pittsburgh, PA.
1185 Antithymocyte Globulin Induction is Associated with Complement Deposition in Pediatric Cardiac Transplant Biopsies S. Ghaleb,1 H. Martinez,1 S. Wittekind,1 D. Witte,2 T. Hengehold,3 and C. Chin.1 1Pediatric Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and the 3University of Cincinnati College of Medicine, Cincinnati, OH. Purpose: Antithymocyte globulin (ATG) has been increasingly used as a means of induction immunosuppression (I-I) in pediatric cardiac transplantation (PCT). ATG contains polyclonal antibodies directed primarily against human T-lymphocytes and may also contain other antibodies with affinity for endothelial surface antigens and other tissues in the transplanted organ, resulting in complement (C4d) deposition (C4dD). This phenomenon has been demonstrated in endomyocardial biopsies (EMB) of adult cardiac transplants though the effects of C4dD
Purpose: Recent reports indicate that >50% of pediatric heart transplant (HT) candidates are HLA-sensitized at time of HT. Clinicians have a difficult choice: wait for an ideal organ offer without HLA antibody (Ab) or take the first acceptable offer. Desensitization can be useful to facilitate HT by decreasing or abrogating HLA Ab. We have evolved to use desensitization to evaluate which HLA Ab may be safely crossed and which to avoid. To illustrate our approach, we present: a non-responder, a partialresponder, and a total-responder. Methods: HLA Ab analysis was done by LuminexÒ single antigen bead assay (SAB), with serial dilutions and C1q-fixing assay. Ab ≥2000 MFI by IgG-SAB and ≥500 MFI by C1q-SAB were used to determine the calculated PRA (cPRA). One desensitization cycle consisted of rituximab (x1), bortezomib (BTZ) (x4), and plasmapheresis (x5). Cycles are repeated leaving 2 weeks between last and first doses of each cycle. Results: Non-responder(Fig 1A): Bw4/Aw4 sensitized patient did not respond to desensitization. Ab reassessment showed rebound, and after the 3rdcycle the titer increased and Ab was C1q+. The patient received HT with a Bw6/Bw6 donor without Aw4 antigens; no donor specific Ab (DSA) is detected 1 year post-HT. Partial-responder(Fig 1B): selective response for 1 HLA Ab group. Both anti-DR53 and DQ7/DQ8/DQ9 Abs were C1q+. However, DQ7/DQ8/DQ9 Ab had lower baseline titer. After 2 cycles, DR53 Ab did not change while DQ7/DQ8/DQ9 Ab was reduced in titer and became C1q-. HT proceeded with a DQ7+ donor and DSA remains negative 2.5 years post-HT. Total responder(Fig 1C): Ab to all but self HLA. A complete response was seen; by the end of 3rdcycle, most Ab was reduced to low titer and C1q-. HT was done crossing 2 C1q- Abs. No DSA detected 118 days post-HT. Conclusion: Multi-dimensional testing of HLA Ab titer and C1q binding and serial monitoring pre- and post-desensitization helps to determine if more treatment is needed and allows for safe HT risk assessment when crossing HLA Abs.
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
high CVH scores at listing, 1, 3 and 5 years PT: 73, 74, 87 and 75%, respectively. Figure 1A shows differences in the distribution of CVH metrics between HT pts and the GP. Figure 1B shows the most recent CVH score distribution; there were differences in the distribution of CVH scores in age groups (p=0.02). HT pts with low (vs. high) cumulative CVH scores had a HR of 2.95 (p=0.002) for the composite adverse outcome of chronic kidney disease, coronary allograft vasculopathy, relisting or death. Conclusion: CVH scores in pediatric HT pts were stable over time with younger pts more likely to have high CVH. Compared to the GP, HT pts had lower ideal glucose but higher ideal lipids. Low cumulative CVH scores were associated with »3-fold higher risks of adverse outcome. Future interventions to improve CVH in HT pts, such as targeted counseling, should be considered.
on rejection risk remain unclear. It has been thought that use of basiliximab for induction may avoid the risk of (C4dD) and decrease the risk of rejection. We examined C4dD and incidence of rejection the relationship among children treated with ATG I-I as well as those treated with basiliximab I-I. Methods: A retrospective review of charts of patients with PCT performed at our center between June 2012 and April 2018 was performed. Results of C4d immunohistochemistry were available from all EMB of patients (n=56). Results: The population was predominantly male (70%) with a median age of 10 years (IQR 2.63 -14.46 years). 28 patients received ATG and 28 patients received basiliximab as induction therapy. Sixty percent (60%) of the ATG patients had C4dD on the 1st biopsy posttransplant and 25% of patients had a persistent C4dD on the next 5 EMB. When C4dD was demonstrated in ATG patients, other markers of significant rejection were rare; only 4% had ACR grade 2 or higher by the revised 2004 ISHLT grading system (historically 3A, 3B and 4 rejection) and/or histologic evidence of AMR. Only 3% of patients receiving basiliximab for induction had C4dD on any EMB in the first year post-transplant. When C4dD was demonstrated in basiliximab patients, other markers of significant rejection were found frequently; 57% had ACR grade 2 or higher by the revised 2004 ISHLT grading system and/or histologic evidence of AMR. Conclusion: C4d deposition was more common on EMB up to 1 year postPCT in patients receiving ATG induction, compared to basiliximab. Despite less C4dD in basiliximab EMBs, these patients had more rejection episodes. The presence of C4dD may thus not be an accurate measure of rejection in PCT patients and should be taken into consideration when reviewing and determining treatment options. 1186 HLA Antibody Titer and C1Q Reactivity Reflect Response to Desensitization and Facilitate Donor Selection M. Mangiola,1 M.D. Zinn,2 S. West,2 S.A. Miller,2 K. Rose-Felker,2 B. Feingold,2 and A. Zeevi.1 1Transplant Pathology, Univ of Pittsburgh Med Ctr, Pittsburgh, PA; and the 2Pediatrics, Univ of Pittsburgh Med Ctr, Pittsburgh, PA.
1185 Antithymocyte Globulin Induction is Associated with Complement Deposition in Pediatric Cardiac Transplant Biopsies S. Ghaleb,1 H. Martinez,1 S. Wittekind,1 D. Witte,2 T. Hengehold,3 and C. Chin.1 1Pediatric Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and the 3University of Cincinnati College of Medicine, Cincinnati, OH. Purpose: Antithymocyte globulin (ATG) has been increasingly used as a means of induction immunosuppression (I-I) in pediatric cardiac transplantation (PCT). ATG contains polyclonal antibodies directed primarily against human T-lymphocytes and may also contain other antibodies with affinity for endothelial surface antigens and other tissues in the transplanted organ, resulting in complement (C4d) deposition (C4dD). This phenomenon has been demonstrated in endomyocardial biopsies (EMB) of adult cardiac transplants though the effects of C4dD
Purpose: Recent reports indicate that >50% of pediatric heart transplant (HT) candidates are HLA-sensitized at time of HT. Clinicians have a difficult choice: wait for an ideal organ offer without HLA antibody (Ab) or take the first acceptable offer. Desensitization can be useful to facilitate HT by decreasing or abrogating HLA Ab. We have evolved to use desensitization to evaluate which HLA Ab may be safely crossed and which to avoid. To illustrate our approach, we present: a non-responder, a partialresponder, and a total-responder. Methods: HLA Ab analysis was done by LuminexÒ single antigen bead assay (SAB), with serial dilutions and C1q-fixing assay. Ab ≥2000 MFI by IgG-SAB and ≥500 MFI by C1q-SAB were used to determine the calculated PRA (cPRA). One desensitization cycle consisted of rituximab (x1), bortezomib (BTZ) (x4), and plasmapheresis (x5). Cycles are repeated leaving 2 weeks between last and first doses of each cycle. Results: Non-responder(Fig 1A): Bw4/Aw4 sensitized patient did not respond to desensitization. Ab reassessment showed rebound, and after the 3rdcycle the titer increased and Ab was C1q+. The patient received HT with a Bw6/Bw6 donor without Aw4 antigens; no donor specific Ab (DSA) is detected 1 year post-HT. Partial-responder(Fig 1B): selective response for 1 HLA Ab group. Both anti-DR53 and DQ7/DQ8/DQ9 Abs were C1q+. However, DQ7/DQ8/DQ9 Ab had lower baseline titer. After 2 cycles, DR53 Ab did not change while DQ7/DQ8/DQ9 Ab was reduced in titer and became C1q-. HT proceeded with a DQ7+ donor and DSA remains negative 2.5 years post-HT. Total responder(Fig 1C): Ab to all but self HLA. A complete response was seen; by the end of 3rdcycle, most Ab was reduced to low titer and C1q-. HT was done crossing 2 C1q- Abs. No DSA detected 118 days post-HT. Conclusion: Multi-dimensional testing of HLA Ab titer and C1q binding and serial monitoring pre- and post-desensitization helps to determine if more treatment is needed and allows for safe HT risk assessment when crossing HLA Abs.