Correspondence
* 2014 Lippincott Williams & Wilkins
impactful in communities than looking for genetic hieroglyphics common in false groupings like racial classifications. Genetic research has already defanged much of the racial haranguing that even science has fostered throughout our history. Ethnic variations as illumined by Dr. Parsikia and his colleagues are indeed real and vastly improve our understand-
ing of cultural dynamics that impact in very real and substantial ways the best approach to all of our patients. Joseph Keith Melancon George Washington University Hospital Washington D.C. The author declares no funding or conflicts of interest.
e61
Address correspondence to: Joseph Keith Melancon, M.D., George Washington Medical Faculty Associates, 2150 Pennsylvania Avenue NW suite 6B-412 Washington D.C. 20037. E-mail: [email protected] Received 10 February 2014. Revision requested 11 February 2014. Accepted 19 February 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9710-e60 DOI: 10.1097/TP.0000000000000135
CDC Crossmatch and C1qSCREEN in Liver Transplantation
I
read with interest the recent paper by Kubal et al reporting for the first time the impact of preformed C1q-fixing positive donor-specific antibodies (C1q-DSA) using C1qScreen in liver transplantation (1).
In their introduction, the authors erroneously cite a paper by Sutherland et al (2) on kidney transplantation to support their hypothesis that preformed C1q-DSA are associated with ACR: actually, both Sutherland et al (2) and, more recently, other investigators (3) have shown that de novo (not preformed, as studied by Kubal et al) C1q-DSA associate with AMR, not ACR, in kidney and other types of solid organ transplantation. In Table 2, the authors report the parameter ‘‘percentage of cumulative MFI of DSA fixing C1q’’(1): that parameter is a biological nonsense because the MFI of LabScreen and C1qScreen are not directly comparable for percentage calculations. The authors report that ‘‘patients with autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis as a group had a tendency toward [flow cytometry] CM+ status’’ (19% vs. 9%). This finding can be explained only assuming a high prevalence of innocuous antilymphocyte (non-antiHLA) autoantibodies, commonly found in autoimmune diseases, which could have been discriminated by CDC autocrossmatching. They also report that these autoimmune liver disease recipients had a tendency to develop ACR (9% vs. 2%): it remains to be established whether those were true ACR or rather relapses of the underlying cell-mediated hepatic autoimmune disease (4). The authors conclude that ‘‘With the use of rabbit antithymocyte globulinT rituximab induction, overall low rejection rates can be achieved in CM+ LT.’’ Because these therapies are also effective against the underlying autoimmune liver disease, although the clinical benefit is
out of discussion, from a mechanistic point of view, it remains to be understood whether these immunosuppressants are only preventing the ACR or also treating (and preventing recurrence of) the underlying autoimmune disease. Furthermore, because rabbit ATG also has anti-CD20 activity (5), and actually both rituximab-treated and Yuntreated recipients showed drops in CD19+ B-lymphocyte counts at month 1, I wonder whether addition of rituximab to induction is really worth the cost (1). The authors report that ‘‘Only 2 out of 112 CM+ patients developed antibody-mediated rejection (AMR).’’ Such very low positive predictive values of flow-cytometry crossmatch (FC-XM) (G2% for AMR, G5% for ACR) should encourage discontinuation of FC-XM (and of the less-sensitive and less-specific CDC-XM) testing in liver transplantation in the setting of universal induction therapy. On the contrary, based on exciting results from the kidney transplantation field and encouraging preliminary results in the liver transplantation field, prospective clinical trials implementing conventional IgG Luminex-based virtual crossmatches (6Y10) and tailor-made induction immunosuppression and trials implementing C1qScreen for posttransplantation monitoring and tailor-made maintenance immunosuppression (3, 11) should be started.
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9710-e61 DOI: 10.1097/TP.0000000000000095
REFERENCES 1.
2.
3.
4. 5.
6.
7.
8.
9.
Daniele Focosi Division of Transfusion Medicine and Transplant Biology Azienda Ospedaliero-Universitaria Pisana Pisa, Italy The authors declare no funding or conflicts of interest. Address correspondence to: Daniele Focosi, M.D., via Paradisa 2, 56124 Pisa, Italy. E-mail [email protected] Received 7 January 2014. Accepted 28 January 2014.
10.
11.
Kubal CA, Mangus RS, Saxena R, et al. Crossmatch-positive liver transplantation in patients receiving thymoglobulin-rituximab induction. Transplantation 2014; 97: 56. Sutherland SM, Chen G, Sequeira FA, et al. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. Pediatr Transplant 2012; 16: 12. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med 2013; 369: 1215. Carbone M, Neuberger JM. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014; 60: 210. Zand MS, Vo T, Huggins J, et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 2005; 79: 1507. Abu-Elmagd KM, Wu G, Costa G, et al. Preformed and de novo donor specific antibodies in visceral transplantation: longterm outcome with special reference to the liver. Am J Transplant 2012; 12: 3047. Perera M, Silva M, Murphy N, et al. Influence of preformed donor-specific antibodies and C4d on early liver allograft function. Scand J Gastroenterol 2013; 48: 1444. Yoshizawa A, Egawa H, Yurugi K, et al. Significance of semiquantitative assessment of preformed donor-specific antibody using luminex single bead assay in living related liver transplantation. Clin Dev Immunol 2013; 2013: 972705. Musat AI, Agni RM, Wai PY, et al. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011; 11: 500. Musat AI, Pigott CM, Ellis TM, et al. Pretransplant donor-specific anti-HLA antibodies as predictors of early allograft rejection in ABO-compatible liver transplantation. Liver Transpl 2013; 19: 1132. Kaneku H, O’Leary JG, Taniguchi M, et al. Donor-specific human leukocyte antigen antibodies of the immunoglobulin G3 subclass are associated with chronic rejection and graft loss after liver transplantation. Liver Transpl 2012; 18: 984.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
* 2014 Lippincott Williams & Wilkins
impactful in communities than looking for genetic hieroglyphics common in false groupings like racial classifications. Genetic research has already defanged much of the racial haranguing that even science has fostered throughout our history. Ethnic variations as illumined by Dr. Parsikia and his colleagues are indeed real and vastly improve our understand-
ing of cultural dynamics that impact in very real and substantial ways the best approach to all of our patients. Joseph Keith Melancon George Washington University Hospital Washington D.C. The author declares no funding or conflicts of interest.
e61
Address correspondence to: Joseph Keith Melancon, M.D., George Washington Medical Faculty Associates, 2150 Pennsylvania Avenue NW suite 6B-412 Washington D.C. 20037. E-mail: [email protected] Received 10 February 2014. Revision requested 11 February 2014. Accepted 19 February 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9710-e60 DOI: 10.1097/TP.0000000000000135
CDC Crossmatch and C1qSCREEN in Liver Transplantation
I
read with interest the recent paper by Kubal et al reporting for the first time the impact of preformed C1q-fixing positive donor-specific antibodies (C1q-DSA) using C1qScreen in liver transplantation (1).
In their introduction, the authors erroneously cite a paper by Sutherland et al (2) on kidney transplantation to support their hypothesis that preformed C1q-DSA are associated with ACR: actually, both Sutherland et al (2) and, more recently, other investigators (3) have shown that de novo (not preformed, as studied by Kubal et al) C1q-DSA associate with AMR, not ACR, in kidney and other types of solid organ transplantation. In Table 2, the authors report the parameter ‘‘percentage of cumulative MFI of DSA fixing C1q’’(1): that parameter is a biological nonsense because the MFI of LabScreen and C1qScreen are not directly comparable for percentage calculations. The authors report that ‘‘patients with autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis as a group had a tendency toward [flow cytometry] CM+ status’’ (19% vs. 9%). This finding can be explained only assuming a high prevalence of innocuous antilymphocyte (non-antiHLA) autoantibodies, commonly found in autoimmune diseases, which could have been discriminated by CDC autocrossmatching. They also report that these autoimmune liver disease recipients had a tendency to develop ACR (9% vs. 2%): it remains to be established whether those were true ACR or rather relapses of the underlying cell-mediated hepatic autoimmune disease (4). The authors conclude that ‘‘With the use of rabbit antithymocyte globulinT rituximab induction, overall low rejection rates can be achieved in CM+ LT.’’ Because these therapies are also effective against the underlying autoimmune liver disease, although the clinical benefit is
out of discussion, from a mechanistic point of view, it remains to be understood whether these immunosuppressants are only preventing the ACR or also treating (and preventing recurrence of) the underlying autoimmune disease. Furthermore, because rabbit ATG also has anti-CD20 activity (5), and actually both rituximab-treated and Yuntreated recipients showed drops in CD19+ B-lymphocyte counts at month 1, I wonder whether addition of rituximab to induction is really worth the cost (1). The authors report that ‘‘Only 2 out of 112 CM+ patients developed antibody-mediated rejection (AMR).’’ Such very low positive predictive values of flow-cytometry crossmatch (FC-XM) (G2% for AMR, G5% for ACR) should encourage discontinuation of FC-XM (and of the less-sensitive and less-specific CDC-XM) testing in liver transplantation in the setting of universal induction therapy. On the contrary, based on exciting results from the kidney transplantation field and encouraging preliminary results in the liver transplantation field, prospective clinical trials implementing conventional IgG Luminex-based virtual crossmatches (6Y10) and tailor-made induction immunosuppression and trials implementing C1qScreen for posttransplantation monitoring and tailor-made maintenance immunosuppression (3, 11) should be started.
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9710-e61 DOI: 10.1097/TP.0000000000000095
REFERENCES 1.
2.
3.
4. 5.
6.
7.
8.
9.
Daniele Focosi Division of Transfusion Medicine and Transplant Biology Azienda Ospedaliero-Universitaria Pisana Pisa, Italy The authors declare no funding or conflicts of interest. Address correspondence to: Daniele Focosi, M.D., via Paradisa 2, 56124 Pisa, Italy. E-mail [email protected] Received 7 January 2014. Accepted 28 January 2014.
10.
11.
Kubal CA, Mangus RS, Saxena R, et al. Crossmatch-positive liver transplantation in patients receiving thymoglobulin-rituximab induction. Transplantation 2014; 97: 56. Sutherland SM, Chen G, Sequeira FA, et al. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. Pediatr Transplant 2012; 16: 12. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med 2013; 369: 1215. Carbone M, Neuberger JM. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014; 60: 210. Zand MS, Vo T, Huggins J, et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 2005; 79: 1507. Abu-Elmagd KM, Wu G, Costa G, et al. Preformed and de novo donor specific antibodies in visceral transplantation: longterm outcome with special reference to the liver. Am J Transplant 2012; 12: 3047. Perera M, Silva M, Murphy N, et al. Influence of preformed donor-specific antibodies and C4d on early liver allograft function. Scand J Gastroenterol 2013; 48: 1444. Yoshizawa A, Egawa H, Yurugi K, et al. Significance of semiquantitative assessment of preformed donor-specific antibody using luminex single bead assay in living related liver transplantation. Clin Dev Immunol 2013; 2013: 972705. Musat AI, Agni RM, Wai PY, et al. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011; 11: 500. Musat AI, Pigott CM, Ellis TM, et al. Pretransplant donor-specific anti-HLA antibodies as predictors of early allograft rejection in ABO-compatible liver transplantation. Liver Transpl 2013; 19: 1132. Kaneku H, O’Leary JG, Taniguchi M, et al. Donor-specific human leukocyte antigen antibodies of the immunoglobulin G3 subclass are associated with chronic rejection and graft loss after liver transplantation. Liver Transpl 2012; 18: 984.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
