In the Literature Is There a Role for Detection of Complement-Binding Antibodies in Kidney Transplantation? Commentary on Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-1226.
A
ntibody-mediated vascular injury typically occurs through a complement-dependent mechanism and is associated with significant kidney transplant dysfunction and transplant loss.1 Diagnosis is dependent on detection of circulating donor-specific anti-HLA antibodies (DSAs), as well as complement activation and inflammation within the transplant.2 DSAs can exist at the time of transplantation or develop de novo in the posttransplantation setting. Understanding which antibodies are pathogenic is critical to optimizing kidney transplant outcomes. To date, antibody class, specificity, and strength have been used to predict risk of antibody-mediated rejection and transplant loss, but these measures are imperfect.3,4 More recently, the role of complement-fixing antibodies in the pathogenesis of antibody-mediated rejection has been better elucidated, and complement inhibition has proved to be an effective treatment for antibody-mediated rejection.1 In an effort to improve the predictive power of antibody detection, the ability of antibodies to fix complement has become a major focus in the field of immunogenetics, and a complement-binding (C1q) assay has been developed.
WHAT DOES THIS IMPORTANT STUDY SHOW? Recently, Loupy et al5 examined the association between the complement-binding capacity of DSAs and transplant outcomes in a prospective cohort study of 1,106 kidney transplant recipients. The study determined that C1q-binding DSAs, detectable in 77 of the 1,106 patients, were associated with significantly lower 5-year transplant survival (54% vs 93%; log-rank P , 0.001) and a 4.8-fold higher risk of transplant loss (adjusted hazard ratio, 4.78; 95% confidence interval, 2.69-8.49; Fig 1). Among patients with C1q-binding DSAs, the rate of antibody-mediated rejection was higher (48% vs 16%; P , 0.001) and rejection was more severe, as evidenced by extensive microvascular inflammation and increased deposition of C4d within peritubular capillaries. Furthermore, complement fixation correlated with DSA strength, as Originally published online January 30, 2014. Address correspondence to Dorry Segev, MD, PhD, Director of Clinical Research, Transplant Surgery, Johns Hopkins Medical Institutions, 720 Rutland Ave, Ross 771B, Baltimore, MD 21205. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.01.007 558
measured by median fluorescence intensity, such that .67% of patients with detectable C1q-fixing antibodies had median fluorescence intensity values greater than 6,000 compared to only 10% of patients with non–complement-fixing antibodies. Moreover, the presence of C1q-binding DSAs after transplantation was associated with transplant loss independent of whether they were detected in the presence or absence of clinical loss of kidney function. Based on these results, the authors concluded that identifying C1q-binding antibodies improved risk stratification for patients at highest risk for kidney transplant loss. Although important, several limitations of this study also are important to note. First, the C1q-binding assay does not detect non-HLA antibodies that may be pathogenic through non–complement-fixing mechanisms or the presence of multiple low-titer DSAs that individually do not bind complement. Furthermore, follow-up for the study was relatively short, and as such, the slower kinetics of injury associated with class II anti-HLA antibodies may not be well captured. Finally, Racusen and Leffell6 importantly have raised the question of whether detection of complementbinding antibodies improves risk prediction more than the traditional approach of titer strength, given the relative colinearity of complement binding and increasing DSA levels.
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? The study by Loupy et al5 represents the largest cohort study to date examining the role of C1q-binding antibody detection and prediction of kidney transplant outcomes. These findings confirm that detecting C1q-binding DSAs at any time during the first posttransplantation year is associated strongly with transplant loss. The findings are consistent with previous smaller studies of posttransplantation complementbinding DSAs and risk for transplant loss. Specifically, Sutherland et al7 compared 15 children who received kidney transplants who had C1q-binding antibodies posttransplantation with 20 recipients who did not have C1q-binding antibodies, and reported that the presence of C1q-binding antibodies was predictive of an increased risk for transplant loss. In a separate study, the authors found that the presence of C1q-binding antibody was associated with chronic transplant glomerulopathy.8 Am J Kidney Dis. 2014;63(4):558-560
In the Literature
Figure 1. The impact of donor-specific antibodies on longterm kidney transplant survival. Complement-binding (C1q) donor-specific anti-HLA antibodies (DSAs) are associated with significantly lower transplant survival compared with non–C1qbinding DSAs or the absence of DSAs.
However, studies examining the correlation between pretransplantation C1q-binding DSAs and transplant loss have reported conflicting results to date. Crespo et al9 studied 28 patients with detectable pretransplantation DSAs, of whom 15 had C1q-binding antibodies, and reported that the capacity of DSAs to fix complement did not correlate with rejection, transplant function, or transplant loss. Similarly, Otten et al10 found that the strength of pretransplantation DSAs correlated with transplant survival, whereas the C1qbinding attribute of the DSAs did not. However, others have reported a strong correlation between the presence of pretransplantation C1q-binding DSAs and transplant outcomes: 2 studies examining outcomes in children receiving heart transplants found a higher incidence of antibody-mediated rejection among those with evidence of C1q-binding DSAs prior to transplantation,11,12 and a study of sensitized kidney transplant recipients found that the presence of pretransplantation C1q-binding DSAs was associated with increased delayed transplant function.13
WHAT SHOULD CLINICIANS AND RESEARCHERS DO? The study by Loupy et al5 motivates future research to separate the role of C1q binding from other already known attributes of DSAs, namely antibody class, specificity, and strength. However, several limitations of the study preclude a strong recommendation to base clinical practice on C1q binding. In particular, only 77 patients had evidence of C1q-binding DSAs, and as such, the study lacks statistical power to definitively conclude that the presence of C1qbinding DSAs is a more sensitive and specific tool for predicting transplant loss compared to DSA strength alone. Further, the strong correlation between DSA strength and C1q binding in this study makes it difficult to separate the individual roles of these Am J Kidney Dis. 2014;63(4):558-560
2 attributes in predicting transplant injury and loss in the setting of clinical dysfunction and detectable DSAs. However, in the absence of clinical dysfunction, the ability to detect the presence of C1q-binding DSAs may help identify patients who would benefit most from aggressive treatment to prevent long-term transplant dysfunction. In addition, among highly sensitized patients, the ability to detect C1q-binding antibodies may help refine unacceptable antigens and determine the feasibility of desensitization for a given recipient. Much is left to learn about the role of C1q-binding DSAs in the development and treatment of antibodymediated rejection. In the meantime, clinicians who measure this attribute should consider it another piece of information about DSAs in addition to the currently measured standards of class, specificity, and strength. Future clinical trials aimed at studying treatment and outcomes in antibody-mediated rejection should include detection of C1q-binding DSAs as part of the protocol design. Jayme E. Locke, MD, MPH University of Alabama at Birmingham Birmingham, Alabama Dorry L. Segev, MD, PhD Johns Hopkins University Baltimore, Maryland
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Locke JE, Magro CM, Singer AL, et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009;9(1):231-235. 2. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant. 2003;3(6):708-714. 3. Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505-1513. 4. Smith JD, Hamour IM, Banner NR, Rose ML. C4d fixing, luminex binding antibodies—a new tool for prediction of graft failure after heart transplantation. Am J Transplant. 2007;7(12): 2809-2815. 5. Loupy A, Lefaucheur C, Vernerey D, et al. Complementbinding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-1226. 6. Racusen LC, Leffell MS. C1q-binding antibodies in kidney transplantation. N Engl J Med. 2013;369(13):1266-1267. 7. Sutherland SM, Chen G, Sequeira FA, Lou CD, Alexander SR, Tyan DB. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. Pediatr Transplant. 2012;16(1):12-17. 559
Locke and Segev 8. Yabu JM, Higgins JP, Chen G, Sequeira F, Busque S, Tyan DB. C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure after kidney transplantation. Transplantation. 2011;91(3): 342-347. 9. Crespo M, Torio A, Mas V, et al. Clinical relevance of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter. Transplant Immunol. 2013;29(1-4):28-33. 10. Otten HG, Verhaar MC, Borst HP, Hene RJ, van Zuilen AD. Pretransplant donor-specific HLA class-I and -II antibodies are associated with an increased risk for kidney graft failure. Am J Transplant. 2012;12(6):1618-1623.
560
11. Chin C, Chen G, Sequeria F, et al. Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. J Heart Lung Transplant. 2011;30(2):158-163. 12. Zeevi A, Lunz J, Feingold B, et al. Persistent strong antiHLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant. 2013;32(1):98-105. 13. Ata P, Canbakan M, Kara M, Ozel L, Unal E, Titiz MI. Serum flow cytometric C1q binding antibody analysis of renal recipients with low levels of sensitization. Transplant Proc. 2012;44(6):1652-1655.
Am J Kidney Dis. 2014;63(4):558-560
A
ntibody-mediated vascular injury typically occurs through a complement-dependent mechanism and is associated with significant kidney transplant dysfunction and transplant loss.1 Diagnosis is dependent on detection of circulating donor-specific anti-HLA antibodies (DSAs), as well as complement activation and inflammation within the transplant.2 DSAs can exist at the time of transplantation or develop de novo in the posttransplantation setting. Understanding which antibodies are pathogenic is critical to optimizing kidney transplant outcomes. To date, antibody class, specificity, and strength have been used to predict risk of antibody-mediated rejection and transplant loss, but these measures are imperfect.3,4 More recently, the role of complement-fixing antibodies in the pathogenesis of antibody-mediated rejection has been better elucidated, and complement inhibition has proved to be an effective treatment for antibody-mediated rejection.1 In an effort to improve the predictive power of antibody detection, the ability of antibodies to fix complement has become a major focus in the field of immunogenetics, and a complement-binding (C1q) assay has been developed.
WHAT DOES THIS IMPORTANT STUDY SHOW? Recently, Loupy et al5 examined the association between the complement-binding capacity of DSAs and transplant outcomes in a prospective cohort study of 1,106 kidney transplant recipients. The study determined that C1q-binding DSAs, detectable in 77 of the 1,106 patients, were associated with significantly lower 5-year transplant survival (54% vs 93%; log-rank P , 0.001) and a 4.8-fold higher risk of transplant loss (adjusted hazard ratio, 4.78; 95% confidence interval, 2.69-8.49; Fig 1). Among patients with C1q-binding DSAs, the rate of antibody-mediated rejection was higher (48% vs 16%; P , 0.001) and rejection was more severe, as evidenced by extensive microvascular inflammation and increased deposition of C4d within peritubular capillaries. Furthermore, complement fixation correlated with DSA strength, as Originally published online January 30, 2014. Address correspondence to Dorry Segev, MD, PhD, Director of Clinical Research, Transplant Surgery, Johns Hopkins Medical Institutions, 720 Rutland Ave, Ross 771B, Baltimore, MD 21205. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.01.007 558
measured by median fluorescence intensity, such that .67% of patients with detectable C1q-fixing antibodies had median fluorescence intensity values greater than 6,000 compared to only 10% of patients with non–complement-fixing antibodies. Moreover, the presence of C1q-binding DSAs after transplantation was associated with transplant loss independent of whether they were detected in the presence or absence of clinical loss of kidney function. Based on these results, the authors concluded that identifying C1q-binding antibodies improved risk stratification for patients at highest risk for kidney transplant loss. Although important, several limitations of this study also are important to note. First, the C1q-binding assay does not detect non-HLA antibodies that may be pathogenic through non–complement-fixing mechanisms or the presence of multiple low-titer DSAs that individually do not bind complement. Furthermore, follow-up for the study was relatively short, and as such, the slower kinetics of injury associated with class II anti-HLA antibodies may not be well captured. Finally, Racusen and Leffell6 importantly have raised the question of whether detection of complementbinding antibodies improves risk prediction more than the traditional approach of titer strength, given the relative colinearity of complement binding and increasing DSA levels.
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? The study by Loupy et al5 represents the largest cohort study to date examining the role of C1q-binding antibody detection and prediction of kidney transplant outcomes. These findings confirm that detecting C1q-binding DSAs at any time during the first posttransplantation year is associated strongly with transplant loss. The findings are consistent with previous smaller studies of posttransplantation complementbinding DSAs and risk for transplant loss. Specifically, Sutherland et al7 compared 15 children who received kidney transplants who had C1q-binding antibodies posttransplantation with 20 recipients who did not have C1q-binding antibodies, and reported that the presence of C1q-binding antibodies was predictive of an increased risk for transplant loss. In a separate study, the authors found that the presence of C1q-binding antibody was associated with chronic transplant glomerulopathy.8 Am J Kidney Dis. 2014;63(4):558-560
In the Literature
Figure 1. The impact of donor-specific antibodies on longterm kidney transplant survival. Complement-binding (C1q) donor-specific anti-HLA antibodies (DSAs) are associated with significantly lower transplant survival compared with non–C1qbinding DSAs or the absence of DSAs.
However, studies examining the correlation between pretransplantation C1q-binding DSAs and transplant loss have reported conflicting results to date. Crespo et al9 studied 28 patients with detectable pretransplantation DSAs, of whom 15 had C1q-binding antibodies, and reported that the capacity of DSAs to fix complement did not correlate with rejection, transplant function, or transplant loss. Similarly, Otten et al10 found that the strength of pretransplantation DSAs correlated with transplant survival, whereas the C1qbinding attribute of the DSAs did not. However, others have reported a strong correlation between the presence of pretransplantation C1q-binding DSAs and transplant outcomes: 2 studies examining outcomes in children receiving heart transplants found a higher incidence of antibody-mediated rejection among those with evidence of C1q-binding DSAs prior to transplantation,11,12 and a study of sensitized kidney transplant recipients found that the presence of pretransplantation C1q-binding DSAs was associated with increased delayed transplant function.13
WHAT SHOULD CLINICIANS AND RESEARCHERS DO? The study by Loupy et al5 motivates future research to separate the role of C1q binding from other already known attributes of DSAs, namely antibody class, specificity, and strength. However, several limitations of the study preclude a strong recommendation to base clinical practice on C1q binding. In particular, only 77 patients had evidence of C1q-binding DSAs, and as such, the study lacks statistical power to definitively conclude that the presence of C1qbinding DSAs is a more sensitive and specific tool for predicting transplant loss compared to DSA strength alone. Further, the strong correlation between DSA strength and C1q binding in this study makes it difficult to separate the individual roles of these Am J Kidney Dis. 2014;63(4):558-560
2 attributes in predicting transplant injury and loss in the setting of clinical dysfunction and detectable DSAs. However, in the absence of clinical dysfunction, the ability to detect the presence of C1q-binding DSAs may help identify patients who would benefit most from aggressive treatment to prevent long-term transplant dysfunction. In addition, among highly sensitized patients, the ability to detect C1q-binding antibodies may help refine unacceptable antigens and determine the feasibility of desensitization for a given recipient. Much is left to learn about the role of C1q-binding DSAs in the development and treatment of antibodymediated rejection. In the meantime, clinicians who measure this attribute should consider it another piece of information about DSAs in addition to the currently measured standards of class, specificity, and strength. Future clinical trials aimed at studying treatment and outcomes in antibody-mediated rejection should include detection of C1q-binding DSAs as part of the protocol design. Jayme E. Locke, MD, MPH University of Alabama at Birmingham Birmingham, Alabama Dorry L. Segev, MD, PhD Johns Hopkins University Baltimore, Maryland
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Locke JE, Magro CM, Singer AL, et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009;9(1):231-235. 2. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant. 2003;3(6):708-714. 3. Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505-1513. 4. Smith JD, Hamour IM, Banner NR, Rose ML. C4d fixing, luminex binding antibodies—a new tool for prediction of graft failure after heart transplantation. Am J Transplant. 2007;7(12): 2809-2815. 5. Loupy A, Lefaucheur C, Vernerey D, et al. Complementbinding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-1226. 6. Racusen LC, Leffell MS. C1q-binding antibodies in kidney transplantation. N Engl J Med. 2013;369(13):1266-1267. 7. Sutherland SM, Chen G, Sequeira FA, Lou CD, Alexander SR, Tyan DB. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. Pediatr Transplant. 2012;16(1):12-17. 559
Locke and Segev 8. Yabu JM, Higgins JP, Chen G, Sequeira F, Busque S, Tyan DB. C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure after kidney transplantation. Transplantation. 2011;91(3): 342-347. 9. Crespo M, Torio A, Mas V, et al. Clinical relevance of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter. Transplant Immunol. 2013;29(1-4):28-33. 10. Otten HG, Verhaar MC, Borst HP, Hene RJ, van Zuilen AD. Pretransplant donor-specific HLA class-I and -II antibodies are associated with an increased risk for kidney graft failure. Am J Transplant. 2012;12(6):1618-1623.
560
11. Chin C, Chen G, Sequeria F, et al. Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. J Heart Lung Transplant. 2011;30(2):158-163. 12. Zeevi A, Lunz J, Feingold B, et al. Persistent strong antiHLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant. 2013;32(1):98-105. 13. Ata P, Canbakan M, Kara M, Ozel L, Unal E, Titiz MI. Serum flow cytometric C1q binding antibody analysis of renal recipients with low levels of sensitization. Transplant Proc. 2012;44(6):1652-1655.
Am J Kidney Dis. 2014;63(4):558-560
