- Email: [email protected]
A sensitive approach
1042
The Journal of Heart and Lung Transplantation, Vol 31, No 9, September 2012
References 1. Mahle WT, Tresler MA, Edens RE, et al. Allosensitization and outcomes in pediatric heart transplantation. J Heart Lung Transplant 2011. 2. Balfour IC, Fiore A, Graff RJ, et al. Use of rituximab to decrease panel-reactive antibodies. J Heart Lung Transplant 2005;24:628-30. 3. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev 2010;24(suppl 1): S7-27. 4. Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010;47: 115-23. 5. Liossis SNC, Sfikakis PP. Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells. Clin Immunol 2008;127:280-5.
A sensitive approach Figure 1 Percentage of the overall population of potential donors who would be an acceptable donor for each study subject preand post-treatment.
Sharon Chih, MBBS,a Heather J. Ross, MD,a Kathryn Tinckam, MD,b Michael A. McDonald, MD,a and Debra L. Isaac, MDc a
nomodulator, it has limited efficacy as desensitizing monotherapy, perhaps due to its lack of effect on plasma cells.3 Although circulating antibody may decrease after IVIg, differentiated plasma cells retain their ability to produce new antibody, which often is eliminated only with plasmapheresis. The addition of rituximab may decrease the need for plasmapheresis; after binding to the CD20 receptor on the B-cell surface, rituximab causes direct signalinginduced apoptosis as well as activation of complement- and antibody-directed cytotoxic pathways.4 This reduces the number of circulating B-cells, differentiating B-cells and subsequent antibody production. Rituximab also appears to decrease some T-cell subsets and inhibit T-cell antigenpresenting activity leading to additional reductions in antibody production.5 High MFI antibodies demonstrate a significantly better response to therapy compared with moderate (3,000 to 7,000) MFI antibodies. We hypothesize that high MFI antibodies most often occur as a result of continued B-cell differentiation in response to the presence of allograft used in reconstructive surgery for congenital heart disease. By blocking new differentiation of B-cells, the strength of antibody is limited to previously differentiated plasma cells and remains at lower MFI levels. We have described the use of IVIg and rituximab as a non–pheresis-based desensitization strategy for pre-transplant pediatric patients. If effective, this therapy can increase the donor pool for broadly allosensitized patients whose transplant risk might otherwise be prohibitively high. These pilot data should provide a foundation for larger studies designed to explore optimal treatment for this growing issue in pediatrics.
Disclosure statement We thank Debra Schauss, Meg Zamberlan and Cynthia Schall for their valuable contributions. The authors have no conflicts of interest to disclose.
Department of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada, bHistocompatibility Laboratory, Univerisity Health Neetwork, Toronto General Hospital, Toronto, Ontario, Canada, and cCardiac Transplant, Foothills Medical Centre, Calgary, Alberta, Canada
We appreciate the opportunity to comment on the recent editorial on prioritizing sensitized heart transplant candidates.1,2 As in the United States, equitable access to organ transplantation in Canada is determined by medical professionals and reviewed every 6 months by the Canadian Cardiac Transplant Network (CCTN). In response to concerns that sensitized patients faced prohibitive wait times for a negative crossmatch, and a lack of strong evidence for desensitization strategies, the CCTN revised the allocation system to incorporate Status 4S. There are limitations to the study that are well outlined in both the article and editorial. However, the editorial raised 3 key points that require further clarification. First, the authors identified concerns regarding failure to report/use a universal mean fluorescent intensity (MFI) antibody titer threshold. The National HLA Advisory Committee of the Canadian Blood Services conducts ongoing proficiency testing in all Canadian HLA laboratories to ensure precision in antibody identification. Using MFI thresholds alone to determine antibody presence results in significant inter-center variability, whereas consideration of laboratory-specific test performance results in much greater standardization.3 Furthermore, the classification of an antigen as unacceptable for inclusion in calculated panel-reactive antibody (cPRA) must involve both the laboratory assessment and the program’s clinical consideration in a given patient. Conversely, if a program wishes to cross an antibody in a patient, then that specific antibody will not be included in the cPRA calculation contributing to priority status. Second, the authors raised concerns about the potential for disadvantaging critically ill patients in favor of “stable” highly sensitized Status 4S patients. The CCTN has mandated discussion prior to allocation of donor hearts out of the procurement region. Hence, if a patient is perceived to
Comments and Opinions
1043
be at higher risk than a “stable” 4S patient, the heart would be allocated to the high-risk patient. The prospect of disadvantaging a sicker patient in favor of a stable 4S patient is discouraged. In addition, it is statistically improbable that a patient with a cPRA of ⬎80% will receive a heart ahead of a more critically ill non-sensitized patient for a given donor heart offer. We agree that ongoing discussion regarding the allocation system to identify and minimize disadvantaged groups is important. The 4S is an improvement on the previous system and a good example of collaboration between centers and Organ Procurement Organizations for broadening organ availability. The CCTN in changing the allocation system has a mandate to re-evaluate prioritization, wait times by diagnosis, blood group and by status (4 and 4S), and to review the allocation of organs and ensure ongoing equity and access for all potential recipients. Each allocation algorithm decision is revisited every 6 months. Third, the authors suggest that all eligible highly sensitized patients be desensitized prior to listing 4S. Given the costs, potential toxicity and absence of large multicenter and/or randomized, controlled data for desensitization, the CCTN considered the 4S strategy to be the more reasonable approach. However, individual centers may undertake desensitization in lieu of 4S listing. Importantly, the long-term results of sensitized patients transplanted with a negative virtual crossmatch are comparable to those of patients with no antibody.4
We agree that robust research is needed to clarify what constitutes a “bad” antibody. Moreover, the community needs to determine the best approach for each patient depending on their mortality risk while waiting, their candidacy for a ventricular assist device (which can extend their ability to wait for a negative crossmatch5), and the breadth and depth of sensitization.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Kfoury AG, Kobashigawa JA. Prioritizing sensitized heart transplant candidates: a sensitive affair. J Heart Lung Transplant 2012;3:677-8. 2. Chih S, Ross HJ, McDonald MA, Isaac DL. Highly sensitized patients in cardiac transplantation: early outcomes from the Canadian prioritized organ sharing program. J Heart Lung Transplant 2012;31:780-2. 3. Tinckam K, Campbell P, Eckels D, et al. Canadian proficiency testing III—standardizing Luminex Ab data is possible. Hum Immunol 2009; 70(suppl 1):S44. 4. Amico P, Hirt-Minkowski P, Hönger G, et al. Risk stratification by the virtual crossmatch: a prospective study in 233 renal transplantations. Transpl Int 2011;24:560-9. 5. Ross H, Tinckam K, Rao V, et al. In praise of ventricular assist devices—mechanical bridge to virtual crossmatch for the sensitized patient. J Heart Lung Transplant 2010;29:728-30.
ERRATUM Drazner MH, Brown RN, Kaiser PA, Cabuay B, Lewis NP, Semigran MJ, Torre-Amione G, Naftel DC, Kirklin JK. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multiinstitutional analysis. J Heart Lung Transplant. 2012 Jan;31(1):67-72. In the published version of the above article, there was a typographical error in the word “Conclusions” in the abstract. The correct heading appears below:
CONCLUSIONS: RAP and PCWP remain concordant in most heart failure patients, supporting the ongoing use of JVP to estimate PCWP. Easily identifiable patient characteristics were associated with an increased RAP/PCWP ratio, and their presence should alert clinicians that PCWP may be overestimated by JVP assessment. A higher RAP/PCWP ratio was an adverse risk factor for post-cardiac transplant survival.
The Journal of Heart and Lung Transplantation, Vol 31, No 9, September 2012
References 1. Mahle WT, Tresler MA, Edens RE, et al. Allosensitization and outcomes in pediatric heart transplantation. J Heart Lung Transplant 2011. 2. Balfour IC, Fiore A, Graff RJ, et al. Use of rituximab to decrease panel-reactive antibodies. J Heart Lung Transplant 2005;24:628-30. 3. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev 2010;24(suppl 1): S7-27. 4. Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010;47: 115-23. 5. Liossis SNC, Sfikakis PP. Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells. Clin Immunol 2008;127:280-5.
A sensitive approach Figure 1 Percentage of the overall population of potential donors who would be an acceptable donor for each study subject preand post-treatment.
Sharon Chih, MBBS,a Heather J. Ross, MD,a Kathryn Tinckam, MD,b Michael A. McDonald, MD,a and Debra L. Isaac, MDc a
nomodulator, it has limited efficacy as desensitizing monotherapy, perhaps due to its lack of effect on plasma cells.3 Although circulating antibody may decrease after IVIg, differentiated plasma cells retain their ability to produce new antibody, which often is eliminated only with plasmapheresis. The addition of rituximab may decrease the need for plasmapheresis; after binding to the CD20 receptor on the B-cell surface, rituximab causes direct signalinginduced apoptosis as well as activation of complement- and antibody-directed cytotoxic pathways.4 This reduces the number of circulating B-cells, differentiating B-cells and subsequent antibody production. Rituximab also appears to decrease some T-cell subsets and inhibit T-cell antigenpresenting activity leading to additional reductions in antibody production.5 High MFI antibodies demonstrate a significantly better response to therapy compared with moderate (3,000 to 7,000) MFI antibodies. We hypothesize that high MFI antibodies most often occur as a result of continued B-cell differentiation in response to the presence of allograft used in reconstructive surgery for congenital heart disease. By blocking new differentiation of B-cells, the strength of antibody is limited to previously differentiated plasma cells and remains at lower MFI levels. We have described the use of IVIg and rituximab as a non–pheresis-based desensitization strategy for pre-transplant pediatric patients. If effective, this therapy can increase the donor pool for broadly allosensitized patients whose transplant risk might otherwise be prohibitively high. These pilot data should provide a foundation for larger studies designed to explore optimal treatment for this growing issue in pediatrics.
Disclosure statement We thank Debra Schauss, Meg Zamberlan and Cynthia Schall for their valuable contributions. The authors have no conflicts of interest to disclose.
Department of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada, bHistocompatibility Laboratory, Univerisity Health Neetwork, Toronto General Hospital, Toronto, Ontario, Canada, and cCardiac Transplant, Foothills Medical Centre, Calgary, Alberta, Canada
We appreciate the opportunity to comment on the recent editorial on prioritizing sensitized heart transplant candidates.1,2 As in the United States, equitable access to organ transplantation in Canada is determined by medical professionals and reviewed every 6 months by the Canadian Cardiac Transplant Network (CCTN). In response to concerns that sensitized patients faced prohibitive wait times for a negative crossmatch, and a lack of strong evidence for desensitization strategies, the CCTN revised the allocation system to incorporate Status 4S. There are limitations to the study that are well outlined in both the article and editorial. However, the editorial raised 3 key points that require further clarification. First, the authors identified concerns regarding failure to report/use a universal mean fluorescent intensity (MFI) antibody titer threshold. The National HLA Advisory Committee of the Canadian Blood Services conducts ongoing proficiency testing in all Canadian HLA laboratories to ensure precision in antibody identification. Using MFI thresholds alone to determine antibody presence results in significant inter-center variability, whereas consideration of laboratory-specific test performance results in much greater standardization.3 Furthermore, the classification of an antigen as unacceptable for inclusion in calculated panel-reactive antibody (cPRA) must involve both the laboratory assessment and the program’s clinical consideration in a given patient. Conversely, if a program wishes to cross an antibody in a patient, then that specific antibody will not be included in the cPRA calculation contributing to priority status. Second, the authors raised concerns about the potential for disadvantaging critically ill patients in favor of “stable” highly sensitized Status 4S patients. The CCTN has mandated discussion prior to allocation of donor hearts out of the procurement region. Hence, if a patient is perceived to
Comments and Opinions
1043
be at higher risk than a “stable” 4S patient, the heart would be allocated to the high-risk patient. The prospect of disadvantaging a sicker patient in favor of a stable 4S patient is discouraged. In addition, it is statistically improbable that a patient with a cPRA of ⬎80% will receive a heart ahead of a more critically ill non-sensitized patient for a given donor heart offer. We agree that ongoing discussion regarding the allocation system to identify and minimize disadvantaged groups is important. The 4S is an improvement on the previous system and a good example of collaboration between centers and Organ Procurement Organizations for broadening organ availability. The CCTN in changing the allocation system has a mandate to re-evaluate prioritization, wait times by diagnosis, blood group and by status (4 and 4S), and to review the allocation of organs and ensure ongoing equity and access for all potential recipients. Each allocation algorithm decision is revisited every 6 months. Third, the authors suggest that all eligible highly sensitized patients be desensitized prior to listing 4S. Given the costs, potential toxicity and absence of large multicenter and/or randomized, controlled data for desensitization, the CCTN considered the 4S strategy to be the more reasonable approach. However, individual centers may undertake desensitization in lieu of 4S listing. Importantly, the long-term results of sensitized patients transplanted with a negative virtual crossmatch are comparable to those of patients with no antibody.4
We agree that robust research is needed to clarify what constitutes a “bad” antibody. Moreover, the community needs to determine the best approach for each patient depending on their mortality risk while waiting, their candidacy for a ventricular assist device (which can extend their ability to wait for a negative crossmatch5), and the breadth and depth of sensitization.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Kfoury AG, Kobashigawa JA. Prioritizing sensitized heart transplant candidates: a sensitive affair. J Heart Lung Transplant 2012;3:677-8. 2. Chih S, Ross HJ, McDonald MA, Isaac DL. Highly sensitized patients in cardiac transplantation: early outcomes from the Canadian prioritized organ sharing program. J Heart Lung Transplant 2012;31:780-2. 3. Tinckam K, Campbell P, Eckels D, et al. Canadian proficiency testing III—standardizing Luminex Ab data is possible. Hum Immunol 2009; 70(suppl 1):S44. 4. Amico P, Hirt-Minkowski P, Hönger G, et al. Risk stratification by the virtual crossmatch: a prospective study in 233 renal transplantations. Transpl Int 2011;24:560-9. 5. Ross H, Tinckam K, Rao V, et al. In praise of ventricular assist devices—mechanical bridge to virtual crossmatch for the sensitized patient. J Heart Lung Transplant 2010;29:728-30.
ERRATUM Drazner MH, Brown RN, Kaiser PA, Cabuay B, Lewis NP, Semigran MJ, Torre-Amione G, Naftel DC, Kirklin JK. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multiinstitutional analysis. J Heart Lung Transplant. 2012 Jan;31(1):67-72. In the published version of the above article, there was a typographical error in the word “Conclusions” in the abstract. The correct heading appears below:
CONCLUSIONS: RAP and PCWP remain concordant in most heart failure patients, supporting the ongoing use of JVP to estimate PCWP. Easily identifiable patient characteristics were associated with an increased RAP/PCWP ratio, and their presence should alert clinicians that PCWP may be overestimated by JVP assessment. A higher RAP/PCWP ratio was an adverse risk factor for post-cardiac transplant survival.