Renal Allograft Outcome in Recipients of Positive-Crossmatch Combined Liver-Kidney Transplantation R.K. Parasuraman, K.K. Venkat, M. Abouljoud, D. Samarapungavan, L. Rocher, and A.J. Koffron ABSTRACT Background. Successful kidney transplantation despite positive crossmatch (þCXM) before transplantation is well recognized in combined liver-kidney transplant (CLKT) recipients. This is probably due to immunologic protection of the renal allograft (RA) conferred by the liver allograft. However, occurrences of antibody-mediated rejection and poor long-term RA outcome is also documented with þCXM CLKT recipients, suggesting that such immunologic protection may not be universal. Methods. A total of 1,401 CLKT recipients with known status of pre-transplantation CXM were identified from the United Network for Organ Sharing registry from January 1, 1986, to December 31, 2006. Univariate analysis for significant differences in clinical variables and Kaplan-Meier estimate for patient and graft survivals were performed. The results were compared between positive and negative CXM groups. Results. Pre-transplantation þCXM was seen in 17.3% (242/1401) of CLKT recipients studied. The demographic and clinical characteristics were similar between the groups, except for higher panel reactive antibody level and CXM positivity in female recipients. Outcome analysis showed higher RA rejection (19.3% vs 10.8%; P ¼ .026) and increased hospital length of stay (37.3 46.0 vs 28.8 33.2 days; P ¼ .028) in the þCXM group. RA survivals at 1, 3, and 5 years were 8%, 7%, and 6% lower in the þCXM group. The patient and liver allograft survivals were not different between the groups. Conclusions. In CLKT recipients with pre-transplantation þCXM, the immunologic protection of RA conferred by the liver allograft is less robust than previously perceived and may lead to higher rejection rate and poor RA outcome. This can be mitigated with routine pre-transplantation CXM.
R
ENAL transplantation in the presence of positive crossmatch (þCXM) mediated by donor-specific antibodies (DSA) to human leukocyte antigen (HLA) commonly results in graft loss from either hyperacute or acute rejection.1 In contrast, combined liver-kidney transplantation (CLKT) from the same donor across þCXM commonly results in acceptance of the renal allograft (RA). This phenomenon of immunologic protection of the RA is thought to be conferred by the liver allograft (LA).2e5 In fact, there are well documented cases of þCXM before orthotopic liver transplantation (LT) that became negative after LT, suggesting that the anti-HLA antibodies are neutralized and/ or eliminated from circulation by liver allografts.3,6 Other possible mechanisms could include secretion of soluble HLA antigens by the LA that can neutralize circulating DSA, and liver Kupffer cells eliminating the circulating reactive DSA by
phagocytosis.7,8 Clinical evidence to support this hypothesis can be seen in several reports of successful CLKT despite þCXM.5,9e15 Based on these reports and immunologic studies, crossmatch is not routinely performed before CLKT when both organs are from the same donor.
From the Division of Nephrology and Transplantation, WilliamBeaumont Hospital, Royal Oak, Michigan (R.K.P., D.S., L.R., A.J.K.); and Transplant Institute, Henry Ford Hospital, Detroit, Michigan (K.K.V., M.A.). Address reprint requests to Ravi Parasuraman, MD, MRCP, Director, Kidney Transplant Outreach Program, Associate Professor of Medicine, Oakland University William Beaumont School of Medicine, William Beaumont Hospital, Royal Oak, MI 48703. E-mail: [email protected]
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.05.003
Transplantation Proceedings, 45, 3269e3272 (2013)
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PARASURAMAN, VENKAT, ABOULJOUD ET AL Table 1. Clinical Characteristics and Outcomes Clinical Variables
Negative CXM N ¼ 1159
Positive CXM N ¼ 242
p-value
Gender: Female Class I PRA Class II PRA Renal allograft rejection rate Mean length of stay in hospital Admission to discharge (days) Graft failure rate at 9 yrs
32.2 % (n ¼ 374) 26.5% 29.3% 10.83% (69/637) 28.8 33.2 (N ¼ 838) 14.70% (144/979)
56.19 % (n ¼ 136) 40.5% 36.3% 19.32 % (24/124) 37.3 46.0 (N ¼ 155) 20.72% (40/193)
.001 .001 .013 .026 .028 .078
Table includes only those clinical characteristics and outcomes that were significantly different between positive and negative crossmatch (CSM) groups in combined liver-kidney transplant recipients. Abbreviation: PRA, panel reactive antibody.
Nevertheless, there are case reports of severe antibodymediated rejection (AMR) of RA in this setting.10,11,16,17 We have observed 2 such cases of severe AMR of RA resulting in allograft loss in the immediate posttransplantation period despite vigorous therapy. The RA biopsy of 1 such case is shown in Fig 1, which demonstrates all the histologic characteristics of AMR. Retrospectively, both cases demonstrated þCXM with the pre-transplantation serum. This experience led us to analyze, with the use of United Network for Organ Sharing (UNOS) data, the impact of þCXM on RA outcome in CLKT recipients.
variables were used in univariate analysis. The 1-, 3-, and 5-year renal allograft survival rates were estimated with the use of the Kaplan-Meier method. The crossmatch status was stratified further by kidney rejection status by creating the following 4 strata: 1) þCXM with treatment for kidney rejection; 2) þCXM with no kidney rejection treatment; 3) CXM with treatment for kidney rejection; 4) CXM with no kidney rejection treatment. The RA survival among the groups stratified by rejection treatment was analyzed with the use of a log-rank test. Patient survival and LA failure (patient death and retransplantation) were analyzed with the use of Kaplan-Meier survival estimates. Our hospital Institutional Review Board approved the study.
MATERIALS AND METHODS
RESULTS
A total of 1,401 CLKT with known status on pre-transplantation CXM were identified from the UNOS registry for the study period ranging from January 1, 1986, to December 31, 2006. Among these recipients, 17.3% (242/1,401) were identified to have þCXM by antihuman globulin complement-dependent cytotoxicity (AHG-CDC) and/or flow cytometry (FCXM) methods. All CLKT recipients with any degree of CXM positivity were included in the study. The outcome data were compared between the þCXM and CXM groups. Student 2-sample t test for normally distributed numeric variables, Cochran-Mantel-Haenszel test for non-normally distributed numeric variables, and chi-square test for categoric
A total of 1,401 CLKT recipients with known pretransplantation CXM status byAHG-CDC and/or FCXM were studied. Among these recipients, 17.3% (242/1,401) had þCXM and the remaining 82.7% (1,159/1,401) CXM. Demographic and clinical characteristics, including the etiologic factors for renal failure, were generally similar between the positive and negative CXM groups except for those indicated in Table 1. Cold ischemia time and delayed graft function (requirement for dialysis within 1 week after transplantation) were not significantly different between the
Fig 1. Renal allograft biopsy.
RENAL ALLOGRAFT OUTCOME
3271
Fig 2. Renal allograft survival in combined liver-kidney transplantation (CLKT) by CXM status.
Fig 3. Patient survival in combined liver-kidney transplantation (CLKT) by CXM status.
groups. The key outcome measures studied to appraise the impact of þCXM on renal allograft included RA rejection rate, length of stay in hospital, and the patient and RA survivals.
robust an immunologic protection to RA among þCXM CLKT recipients as earlier thought. Recent literature supports this conclusion of inadequate immunologic protection of RA by LA in þCXM CLKT recipients. Olausson et al16 performed renal transplantation in 7 highly sensitized patients with additional partial auxiliary LA from the same donors with the sole purpose of overcoming the harmful effects of donor-specific anti-HLA antibodies on the kidney. In that study, 5/7 RAs functioned well despite þCXM, with the CXM becoming negative after LT. In the remaining 2/7 patients, the RA failed because of AMR, a conclusion based on the clinical and histologic features. In both of those patients the CXM was persistently positive after transplantation.16 In a study by Saidman et al,11 38 sequentially placed liver and kidney allografts were evaluated to assess the influence of preformed lymphocytotoxic antibodies on patient and graft survivals. After 50 months of follow-up, the patient and kidney allograft survival rates were 33% and 17%, respectively, in the þCXM group compared with 78% and 75% in the CXM group. In that study, panel reactive antibody level >10% appeared to have a deleterious effect on survival, and the majority of the patients with graft
Renal Allograft Rejection Rate (Table 1)
The RA rejection rate (documented in the registry as treated for rejection) was statistically significantly higher, at 19.3% (24/124), in þCXM group compared with 10.83% (69/637) in the CXM group (P ¼ .026). The mean hospital length of stay from the time of transplantation to discharge was statistically significantly higher in the þCXM (37.3 46 d) compared with the CXM group (28.8 33.2 d; P ¼ .028). Renal Allograft Survival in CLKT Recipients
The kidney graft survival rates were consistently lower among positive þCXM compared to CXM group, as shown in Fig 2. At 1, 3, and 5 years after transplantation, the RA survival rate was 8%, 7%, and 6% lower in the þCXM group, but this did not reach statistical significance according to the log-rank test (P ¼ .11) possibly owing to lower numbers. The long-term RA loss rate was higher, at 20.72% (40/193), in the þCXM compared with 14.70% (144/979) in the CXM group (P ¼ .07). The time to graft failure and the impact of rejection treatment on graft survival were not different between the groups, but the numbers were insufficient. The recipient and LA survival according to KaplanMeier estimates were lower in the þCXM group than in the CXM group, as shown in Figs 3 and 4, but did not reach statistical significance. DISCUSSION
The results of our study showed significantly higher RA rejection rate and longer length of stay in the hospital after CLKT transplantation in þCXM compared with CXM recipients. The doubling of the rejection rates in the þCXM group likely resulted in the observed diminution of RA survival. These results suggest that LA does not provide as
Fig 4. Liver allograft survival in combined liver-kidney transplantation (CLKT) by CXM status.
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failure had þCXM.11 Recently, Askar et al in their scientific registry of transplant recipients data analysis showed pretransplantation allosensitization to be associated with increase in patient death (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.04e1.43) and RA failure (HR 1.16, 95% CI 1.0e1.36) in CLKT recipients.17 Two additional studies have also reported findings of hyperacute rejection and poor long-term RA function in þCXM CLKT recipients.10,11 Reichman et al18 reported a case of acute AMR of RA in an ABO-compatible CLKT recipient in the presence of donor secondspecific anti-HLA antibodies before transplantation. In that case, despite treatment with plasmapheresis, intravenous immunoglobulin, and anti-CD20 antibody administration, the kidney rapidly progressed to chronic allograft nephropathy.18 The rate of CLKT has steadily increased from 2% to 6% for patients with end-stage liver disease and renal dysfunction.19e21 Although this increase in combined organ transplantation may be essential because renal dysfunction has a negative impact on patient outcome, it is prudent to mitigate the added risk factors for RA loss. This is particularly important at a time when demand and supply for deceased-donor renal transplants is at a crisis level. In this respect, routine use of pre-transplantation CXM in CLKT patients, particularly in those who are highly sensitized, may lead to improved patient outcome. Knowledge of CXM and mitigation of factors that may overcome the immunologic protection mediated by LA needs further study, including the strength of DSA, antibody specificities, and LA variables such as volume or size.11,16 In addition, surveillance and management strategies for AMR, such as plasmapheresis, intravenous immunoglobulin, and rituximab therapy, should be readily available. The limitations of the present study include those inherent to any retrospective analysis of registry data, especially incomplete availability of information. Details of CXM positivity such as the strength, antibody titer, specificities, sensitizing events, and the volume of the LA may have provided more insight in to the role of þCXM and outcome. In addition, the type and severity of rejection episodes and the details of rejection treatment were not available. Prospective multicenter studies would offer a better understanding of the impact of pre-transplantation þCXM on CLKT outcomes. ACKNOWLEDGEMENTS The data reported were supplied by the United Network for Organ Sharing (UNOS). The interpretation and reporting of these data are the responsibility of the authors and in no way represent an official policy or interpretation of the US Government. Parts of this study were presented in abstract form at the Annual Meeting of the American Transplant Congress 2008 at Toronto.
REFERENCES 1. Terasaki PI. Humoral theory of transplantation. Am J Transplant. 2003;3(6):665.
PARASURAMAN, VENKAT, ABOULJOUD ET AL 2. Gordon RD, Fung JJ, Markus B, et al. The antibody crossmatch in liver transplantation. Surgery. 1986;100(4):705. 3. Manez R, Kelly RH, Kobayashi M, et al. Immunoglobulin G lymphocytotoxic antibodies in clinical liver transplantation: studies toward further defining their significance. Hepatology. 1995;21(5): 1345. 4. Hathaway M, Gunson BK, Keogh AC, Briggs D, McMaster P, Neuberger JM. A positive crossmatch in liver transplantationdno effect or inappropriate analysis? A prospective study. Transplantation. 1997;64(1):54. 5. Neumann UP, Lang M, Moldenhauer A, et al. Significance of a T-lymphocytotoxic crossmatch in liver and combined liver-kidney transplantation. Transplantation. 2001;71(8):1163. 6. Fung J, Makowka L, Tzakis A, et al. Combined liver-kidney transplantation: analysis of patients with preformed lymphocytotoxic antibodies. Transplant Proc. 1988;20(1 Suppl 1):88. 7. McMillan RW, Gelder FB, Zibari GB, Aultman DF, Adamashvili I, McDonald JC. Soluble fraction of class I human histocompatibility leukocyte antigens in the serum of liver transplant recipients. Clin Transplant. 1997;11(2):98. 8. Starzl TE, Valdivia LA, Murase N, et al. The biological basis of and strategies for clinical xenotransplantation. Immunol Rev. 1994;141:213. 9. Flye MW, Duffy BF, Phelan DL, Ratner LE, Mohanakumar T. Protective effects of liver transplantation on a simultaneously transplanted kidney in a highly sensitized patient. Transplantation. 1990;50(6):1051. 10. Eid A, Moore SB, Wiesner RH, DeGoey SR, Nielson A, Krom RA. Evidence that the liver does not always protect the kidney from hyperacute rejection in combined liver-kidney transplantation across a positive lymphocyte crossmatch. Transplantation. 1990;50(2):331. 11. Saidman SL, Duquesnoy RJ, Demetris AJ, et al. Combined liver-kidney transplantation and the effect of preformed lymphocytotoxic antibodies. Transpl Immunol. 1994;2(1):61. 12. Mjornstedt L, Friman S, Backman L, Rydberg L, Olausson M. Combined liver and kidney transplantation against a positive cross match in a patient with multispecific HLA-antibodies. Transplant Proc. 1997;29(7):3164. 13. Morrissey PE, Gordon F, Shaffer D, et al. Combined liverkidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation. Liver Transpl Surg. 1998;4(5):363. 14. Pollack MS. The very rapid loss of donor specific antibodies from the circulation after liver transplantation allows successful kidney transplantation from the same donor for even the most highly sensitized patients. Hum Immunol. 2003;64(10 Suppl):S62. 15. Gutierrez A, Crespo M, Mila J, Torregrosa JV, Martorell J, Oppenheimer F. Outcome of simultaneous liver-kidney transplantation in highly sensitized, crossmatch-positive patients. Transplant Proc. 2003;35(5):1861. 16. Olausson M, Mjornstedt L, Norden G, et al. Successful combined partial auxiliary liver and kidney transplantation in highly sensitized cross-match positive recipients. Am J Transplant. 2007;7(1):130. 17. Askar M, Schold JD, Eghtesad B, et al. Combined liverkidney transplants: allosensitization and recipient outcomes. Transplantation. 2011;91(11):1286. 18. Reichman TW, Marino SR, Milner J, et al. Acute humoral rejection in an ABO compatible combined liver-kidney transplantd the kidney is not always protected. Am J Transplant. 2009;9(8):1957. 19. Narayanan Menon KV, Nyberg SL, Harmsen WS, et al. MELD and other factors associated with survival after liver transplantation. Am J Transplant. 2004;4(5):819. 20. Salizzoni M, Gennari F, Liddo G, et al. Sequential liverkidney transplantation. Transplant Proc. 2004;36(3):543. 21. Moreno-Gonzalez E, Meneu-Diaz JC, Garcia G, et al. Simultaneous liver-kidney transplant for combined renal and hepatic end-stage disease. Transplant Proc. 2003;35(5):1863.
R
ENAL transplantation in the presence of positive crossmatch (þCXM) mediated by donor-specific antibodies (DSA) to human leukocyte antigen (HLA) commonly results in graft loss from either hyperacute or acute rejection.1 In contrast, combined liver-kidney transplantation (CLKT) from the same donor across þCXM commonly results in acceptance of the renal allograft (RA). This phenomenon of immunologic protection of the RA is thought to be conferred by the liver allograft (LA).2e5 In fact, there are well documented cases of þCXM before orthotopic liver transplantation (LT) that became negative after LT, suggesting that the anti-HLA antibodies are neutralized and/ or eliminated from circulation by liver allografts.3,6 Other possible mechanisms could include secretion of soluble HLA antigens by the LA that can neutralize circulating DSA, and liver Kupffer cells eliminating the circulating reactive DSA by
phagocytosis.7,8 Clinical evidence to support this hypothesis can be seen in several reports of successful CLKT despite þCXM.5,9e15 Based on these reports and immunologic studies, crossmatch is not routinely performed before CLKT when both organs are from the same donor.
From the Division of Nephrology and Transplantation, WilliamBeaumont Hospital, Royal Oak, Michigan (R.K.P., D.S., L.R., A.J.K.); and Transplant Institute, Henry Ford Hospital, Detroit, Michigan (K.K.V., M.A.). Address reprint requests to Ravi Parasuraman, MD, MRCP, Director, Kidney Transplant Outreach Program, Associate Professor of Medicine, Oakland University William Beaumont School of Medicine, William Beaumont Hospital, Royal Oak, MI 48703. E-mail: [email protected]
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.05.003
Transplantation Proceedings, 45, 3269e3272 (2013)
3269
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PARASURAMAN, VENKAT, ABOULJOUD ET AL Table 1. Clinical Characteristics and Outcomes Clinical Variables
Negative CXM N ¼ 1159
Positive CXM N ¼ 242
p-value
Gender: Female Class I PRA Class II PRA Renal allograft rejection rate Mean length of stay in hospital Admission to discharge (days) Graft failure rate at 9 yrs
32.2 % (n ¼ 374) 26.5% 29.3% 10.83% (69/637) 28.8 33.2 (N ¼ 838) 14.70% (144/979)
56.19 % (n ¼ 136) 40.5% 36.3% 19.32 % (24/124) 37.3 46.0 (N ¼ 155) 20.72% (40/193)
.001 .001 .013 .026 .028 .078
Table includes only those clinical characteristics and outcomes that were significantly different between positive and negative crossmatch (CSM) groups in combined liver-kidney transplant recipients. Abbreviation: PRA, panel reactive antibody.
Nevertheless, there are case reports of severe antibodymediated rejection (AMR) of RA in this setting.10,11,16,17 We have observed 2 such cases of severe AMR of RA resulting in allograft loss in the immediate posttransplantation period despite vigorous therapy. The RA biopsy of 1 such case is shown in Fig 1, which demonstrates all the histologic characteristics of AMR. Retrospectively, both cases demonstrated þCXM with the pre-transplantation serum. This experience led us to analyze, with the use of United Network for Organ Sharing (UNOS) data, the impact of þCXM on RA outcome in CLKT recipients.
variables were used in univariate analysis. The 1-, 3-, and 5-year renal allograft survival rates were estimated with the use of the Kaplan-Meier method. The crossmatch status was stratified further by kidney rejection status by creating the following 4 strata: 1) þCXM with treatment for kidney rejection; 2) þCXM with no kidney rejection treatment; 3) CXM with treatment for kidney rejection; 4) CXM with no kidney rejection treatment. The RA survival among the groups stratified by rejection treatment was analyzed with the use of a log-rank test. Patient survival and LA failure (patient death and retransplantation) were analyzed with the use of Kaplan-Meier survival estimates. Our hospital Institutional Review Board approved the study.
MATERIALS AND METHODS
RESULTS
A total of 1,401 CLKT with known status on pre-transplantation CXM were identified from the UNOS registry for the study period ranging from January 1, 1986, to December 31, 2006. Among these recipients, 17.3% (242/1,401) were identified to have þCXM by antihuman globulin complement-dependent cytotoxicity (AHG-CDC) and/or flow cytometry (FCXM) methods. All CLKT recipients with any degree of CXM positivity were included in the study. The outcome data were compared between the þCXM and CXM groups. Student 2-sample t test for normally distributed numeric variables, Cochran-Mantel-Haenszel test for non-normally distributed numeric variables, and chi-square test for categoric
A total of 1,401 CLKT recipients with known pretransplantation CXM status byAHG-CDC and/or FCXM were studied. Among these recipients, 17.3% (242/1,401) had þCXM and the remaining 82.7% (1,159/1,401) CXM. Demographic and clinical characteristics, including the etiologic factors for renal failure, were generally similar between the positive and negative CXM groups except for those indicated in Table 1. Cold ischemia time and delayed graft function (requirement for dialysis within 1 week after transplantation) were not significantly different between the
Fig 1. Renal allograft biopsy.
RENAL ALLOGRAFT OUTCOME
3271
Fig 2. Renal allograft survival in combined liver-kidney transplantation (CLKT) by CXM status.
Fig 3. Patient survival in combined liver-kidney transplantation (CLKT) by CXM status.
groups. The key outcome measures studied to appraise the impact of þCXM on renal allograft included RA rejection rate, length of stay in hospital, and the patient and RA survivals.
robust an immunologic protection to RA among þCXM CLKT recipients as earlier thought. Recent literature supports this conclusion of inadequate immunologic protection of RA by LA in þCXM CLKT recipients. Olausson et al16 performed renal transplantation in 7 highly sensitized patients with additional partial auxiliary LA from the same donors with the sole purpose of overcoming the harmful effects of donor-specific anti-HLA antibodies on the kidney. In that study, 5/7 RAs functioned well despite þCXM, with the CXM becoming negative after LT. In the remaining 2/7 patients, the RA failed because of AMR, a conclusion based on the clinical and histologic features. In both of those patients the CXM was persistently positive after transplantation.16 In a study by Saidman et al,11 38 sequentially placed liver and kidney allografts were evaluated to assess the influence of preformed lymphocytotoxic antibodies on patient and graft survivals. After 50 months of follow-up, the patient and kidney allograft survival rates were 33% and 17%, respectively, in the þCXM group compared with 78% and 75% in the CXM group. In that study, panel reactive antibody level >10% appeared to have a deleterious effect on survival, and the majority of the patients with graft
Renal Allograft Rejection Rate (Table 1)
The RA rejection rate (documented in the registry as treated for rejection) was statistically significantly higher, at 19.3% (24/124), in þCXM group compared with 10.83% (69/637) in the CXM group (P ¼ .026). The mean hospital length of stay from the time of transplantation to discharge was statistically significantly higher in the þCXM (37.3 46 d) compared with the CXM group (28.8 33.2 d; P ¼ .028). Renal Allograft Survival in CLKT Recipients
The kidney graft survival rates were consistently lower among positive þCXM compared to CXM group, as shown in Fig 2. At 1, 3, and 5 years after transplantation, the RA survival rate was 8%, 7%, and 6% lower in the þCXM group, but this did not reach statistical significance according to the log-rank test (P ¼ .11) possibly owing to lower numbers. The long-term RA loss rate was higher, at 20.72% (40/193), in the þCXM compared with 14.70% (144/979) in the CXM group (P ¼ .07). The time to graft failure and the impact of rejection treatment on graft survival were not different between the groups, but the numbers were insufficient. The recipient and LA survival according to KaplanMeier estimates were lower in the þCXM group than in the CXM group, as shown in Figs 3 and 4, but did not reach statistical significance. DISCUSSION
The results of our study showed significantly higher RA rejection rate and longer length of stay in the hospital after CLKT transplantation in þCXM compared with CXM recipients. The doubling of the rejection rates in the þCXM group likely resulted in the observed diminution of RA survival. These results suggest that LA does not provide as
Fig 4. Liver allograft survival in combined liver-kidney transplantation (CLKT) by CXM status.
3272
failure had þCXM.11 Recently, Askar et al in their scientific registry of transplant recipients data analysis showed pretransplantation allosensitization to be associated with increase in patient death (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.04e1.43) and RA failure (HR 1.16, 95% CI 1.0e1.36) in CLKT recipients.17 Two additional studies have also reported findings of hyperacute rejection and poor long-term RA function in þCXM CLKT recipients.10,11 Reichman et al18 reported a case of acute AMR of RA in an ABO-compatible CLKT recipient in the presence of donor secondspecific anti-HLA antibodies before transplantation. In that case, despite treatment with plasmapheresis, intravenous immunoglobulin, and anti-CD20 antibody administration, the kidney rapidly progressed to chronic allograft nephropathy.18 The rate of CLKT has steadily increased from 2% to 6% for patients with end-stage liver disease and renal dysfunction.19e21 Although this increase in combined organ transplantation may be essential because renal dysfunction has a negative impact on patient outcome, it is prudent to mitigate the added risk factors for RA loss. This is particularly important at a time when demand and supply for deceased-donor renal transplants is at a crisis level. In this respect, routine use of pre-transplantation CXM in CLKT patients, particularly in those who are highly sensitized, may lead to improved patient outcome. Knowledge of CXM and mitigation of factors that may overcome the immunologic protection mediated by LA needs further study, including the strength of DSA, antibody specificities, and LA variables such as volume or size.11,16 In addition, surveillance and management strategies for AMR, such as plasmapheresis, intravenous immunoglobulin, and rituximab therapy, should be readily available. The limitations of the present study include those inherent to any retrospective analysis of registry data, especially incomplete availability of information. Details of CXM positivity such as the strength, antibody titer, specificities, sensitizing events, and the volume of the LA may have provided more insight in to the role of þCXM and outcome. In addition, the type and severity of rejection episodes and the details of rejection treatment were not available. Prospective multicenter studies would offer a better understanding of the impact of pre-transplantation þCXM on CLKT outcomes. ACKNOWLEDGEMENTS The data reported were supplied by the United Network for Organ Sharing (UNOS). The interpretation and reporting of these data are the responsibility of the authors and in no way represent an official policy or interpretation of the US Government. Parts of this study were presented in abstract form at the Annual Meeting of the American Transplant Congress 2008 at Toronto.
REFERENCES 1. Terasaki PI. Humoral theory of transplantation. Am J Transplant. 2003;3(6):665.
PARASURAMAN, VENKAT, ABOULJOUD ET AL 2. Gordon RD, Fung JJ, Markus B, et al. The antibody crossmatch in liver transplantation. Surgery. 1986;100(4):705. 3. Manez R, Kelly RH, Kobayashi M, et al. Immunoglobulin G lymphocytotoxic antibodies in clinical liver transplantation: studies toward further defining their significance. Hepatology. 1995;21(5): 1345. 4. Hathaway M, Gunson BK, Keogh AC, Briggs D, McMaster P, Neuberger JM. A positive crossmatch in liver transplantationdno effect or inappropriate analysis? A prospective study. Transplantation. 1997;64(1):54. 5. Neumann UP, Lang M, Moldenhauer A, et al. Significance of a T-lymphocytotoxic crossmatch in liver and combined liver-kidney transplantation. Transplantation. 2001;71(8):1163. 6. Fung J, Makowka L, Tzakis A, et al. Combined liver-kidney transplantation: analysis of patients with preformed lymphocytotoxic antibodies. Transplant Proc. 1988;20(1 Suppl 1):88. 7. McMillan RW, Gelder FB, Zibari GB, Aultman DF, Adamashvili I, McDonald JC. Soluble fraction of class I human histocompatibility leukocyte antigens in the serum of liver transplant recipients. Clin Transplant. 1997;11(2):98. 8. Starzl TE, Valdivia LA, Murase N, et al. The biological basis of and strategies for clinical xenotransplantation. Immunol Rev. 1994;141:213. 9. Flye MW, Duffy BF, Phelan DL, Ratner LE, Mohanakumar T. Protective effects of liver transplantation on a simultaneously transplanted kidney in a highly sensitized patient. Transplantation. 1990;50(6):1051. 10. Eid A, Moore SB, Wiesner RH, DeGoey SR, Nielson A, Krom RA. Evidence that the liver does not always protect the kidney from hyperacute rejection in combined liver-kidney transplantation across a positive lymphocyte crossmatch. Transplantation. 1990;50(2):331. 11. Saidman SL, Duquesnoy RJ, Demetris AJ, et al. Combined liver-kidney transplantation and the effect of preformed lymphocytotoxic antibodies. Transpl Immunol. 1994;2(1):61. 12. Mjornstedt L, Friman S, Backman L, Rydberg L, Olausson M. Combined liver and kidney transplantation against a positive cross match in a patient with multispecific HLA-antibodies. Transplant Proc. 1997;29(7):3164. 13. Morrissey PE, Gordon F, Shaffer D, et al. Combined liverkidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation. Liver Transpl Surg. 1998;4(5):363. 14. Pollack MS. The very rapid loss of donor specific antibodies from the circulation after liver transplantation allows successful kidney transplantation from the same donor for even the most highly sensitized patients. Hum Immunol. 2003;64(10 Suppl):S62. 15. Gutierrez A, Crespo M, Mila J, Torregrosa JV, Martorell J, Oppenheimer F. Outcome of simultaneous liver-kidney transplantation in highly sensitized, crossmatch-positive patients. Transplant Proc. 2003;35(5):1861. 16. Olausson M, Mjornstedt L, Norden G, et al. Successful combined partial auxiliary liver and kidney transplantation in highly sensitized cross-match positive recipients. Am J Transplant. 2007;7(1):130. 17. Askar M, Schold JD, Eghtesad B, et al. Combined liverkidney transplants: allosensitization and recipient outcomes. Transplantation. 2011;91(11):1286. 18. Reichman TW, Marino SR, Milner J, et al. Acute humoral rejection in an ABO compatible combined liver-kidney transplantd the kidney is not always protected. Am J Transplant. 2009;9(8):1957. 19. Narayanan Menon KV, Nyberg SL, Harmsen WS, et al. MELD and other factors associated with survival after liver transplantation. Am J Transplant. 2004;4(5):819. 20. Salizzoni M, Gennari F, Liddo G, et al. Sequential liverkidney transplantation. Transplant Proc. 2004;36(3):543. 21. Moreno-Gonzalez E, Meneu-Diaz JC, Garcia G, et al. Simultaneous liver-kidney transplant for combined renal and hepatic end-stage disease. Transplant Proc. 2003;35(5):1863.
