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Impact of HLA matching upon outcome after liver transplantation
Impact of HLA Matching Upon Outcome After Liver Transplantation U.P. Neumann, J.M. Langrehr, M. Lang, V. Schmitz, S. Menzel, T. Steinmueller, and P. Neuhaus
H
LA MATCHING has been proven to increase graft survival after kidney, heart, and bone marrow transplantation and to reduce the incidence of acute and chronic rejection. In contrast to kidney transplants, the number of HLA mismatches has not been shown to predict the risk of acute or chronic rejection in liver transplant patients. The first study in a large patient population by Markus et al revealed a dual effect of HLA-DR typing but not of HLA-A and HLA-B typing on the outcome of liver transplants.1 Despite a reduced incidence of rejection-related graft failures, the mortality rate in better-matched transplants was increased due to a higher number of septic complications. Chen et al observed no association between HLA-A, -B, -DR mismatches and the occurrence of acute rejection episodes or outcome,2 while Nikaein et al demonstrated that transplants across more HLA compatibilities significantly prolonged graft survival.3 Furthermore, Wiesner et al reported that an increased number of HLA-DR compatibilities was associated with a decreased risk of development of an acute rejection episode.4 The disparate results on HLA typing in liver transplants may be explained by the quality of HLA typing in the early years of liver transplantation. The aim of this retrospective study was to examine whether immunogenetic donor/recipient variables like HLA matching using new typing methods affect the outcome of OLT patients. PATIENTS AND METHODS Study Population Between September 1988 and May 2000, 924 liver transplants were performed in 836 patients in whom complete HLA typing of both donor and recipient had been performed in our hospital. The series included (378 women) and 548 men (ratio 1/1, 4) and a median age of 48.7 years (range 0.9 to 77.2 years). The follow-up period ranged from 1 to 144.8 months (median ⫽ 66 months). The Standard immunosuppressive regimen was either cyclosporine A (CsA) or tacrolimus (Tac). Acute rejection episodes in liver grafts were suspected based upon rising liver serum enzymes, reduced bile flow, altered bile color, fever, or clinical deterioration and were confirmed by graft biopsy. HLA typing was performed using a standard lymphocytotoxicity test and confirmed by polymerase chain reactions. In the early part of the study HLA-DR typing was performed using cytotoxicity and then by PCR-SSP for most typings. Data are shown as median and range. Yates-corrected chi-square test and Fisher’s exact test were performed for dichotomous variables and likelihood ratio chisquare test for higher dimensional (2 ⫻ 3) tables. Cumulative © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 1499 –1500 (2002)
survivals were assessed by applying the Kaplan-Meier technique. Data were defined as significant when P ⬍ .05.
RESULTS
Overall 1-, 3-, and 5-year graft survivals were 88%, 82%, and 78.7%, respectively. We found no statistical correlation between graft or patient survival and number of HLA compatibilities (Fig 1). Additionally, there were no significant differences when analyzing cumulative HLA-A, -B, and -DR compatibilities alone. No specific donor or recipient HLA allele significantly influenced the outcome after OLT. Rejection episodes occurred in 417/924 transplants (45%) among which 348 (83.4%) responded to steroid treatment and 69 (16.5%) required OKT3 treatment. Overall the rejection probability decreased with higher numbers of HLA compatibilities (P ⬍ .05%, Table 1). However, there was no influence of the cumulative HLA-A, -B, and -DR matching on the number of recurrent or steroid-resistant rejection episodes. There was no relation between the incidence of rejection and compatibility for any specific HLA allele (data not shown). DISCUSSION
Immunological risk factors like a positive T- or B-cell cross-match have been verified in kidney and heart transplantation but could not be confirmed in liver transplants. Additionally, the impact of HLA compatibilities has been proven to increase graft survival after kidney and heart transplantation, but the matter is controversial after liver transplantation.1,4 There are a large number of studies showing an adverse effect of HLA matching on the outcomes after liver transplantation, including decreased survival, increased number of chronic rejections, and greater numbers of arterial thrombosis. In 1988 Markus et al1 observed a higher incidence of early liver graft failures in patients with HLA-DR-compatible grafts. However, the poor quality of serological From the Chirurgische Klinik und Poliklinik, Charite´, Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Berlin, Germany. Address reprint requests to U. Neumann, MD, Chirurgische Klinik und Poliklinik, Charite´, Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: [email protected] 0041-1345/02/$–see front matter PII S0041-1345(02)02946-9 1499
1500
NEUMANN, LANGREHR, LANG ET AL
Fig 1. The overall cumulative graft survival demonstrated no correlation between the degree of HLA matching in 924 liver transplants in Berlin.
HLA-DR matching techniques in this era may have contributed to these results. The reason for the impaired survival in this study was the high incidence of septic complications. All further studies on the impact of HLA compatibilities were unable to confirm these results.3–5 Our present study comprising more than 900 transplants clearly
demonstrated that HLA matching did not impair graft survival but rather decreased the incidence of rejection episodes. However a greater number of HLA compatibilities did not appear to be associated with chronic immunological complications. REFERENCES
Table 1. Incidence of Acute Rejection HLA Compatibilities
Acute Rejection (n ⫽ 417)
OKT3 Treatment (n ⫽ 69)
No compatibility One compatibility Two compatibilities ⬎ Two compatibilities
50.6%* (161/318) 45.4% (158/348) 37.7% (71/188) 38.5% (27/70)
9.7% (31/318) 6.6% (23/348) 4.8% (9/188) 8.5% (6/70)
*P ⬍ .05.
1. Markus BH, Duquesnoy RJ, Gordon RD, et al: Transplantation 46:372, 1988 2. Chen M, Wade J, Levy GA, et al: Transplant Proc 26:2695, 1994 3. Nikaein A, Backman L, Jennings L, et al: Transplantation 58:786, 1994 4. Wiesner RH, Demetris AJ, Belle SH, et al: Hepatology 28:638, 1998 5. Doran TJ, Geczy AF, Painter D, et al: Transplantation 69:1491, 2000
H
LA MATCHING has been proven to increase graft survival after kidney, heart, and bone marrow transplantation and to reduce the incidence of acute and chronic rejection. In contrast to kidney transplants, the number of HLA mismatches has not been shown to predict the risk of acute or chronic rejection in liver transplant patients. The first study in a large patient population by Markus et al revealed a dual effect of HLA-DR typing but not of HLA-A and HLA-B typing on the outcome of liver transplants.1 Despite a reduced incidence of rejection-related graft failures, the mortality rate in better-matched transplants was increased due to a higher number of septic complications. Chen et al observed no association between HLA-A, -B, -DR mismatches and the occurrence of acute rejection episodes or outcome,2 while Nikaein et al demonstrated that transplants across more HLA compatibilities significantly prolonged graft survival.3 Furthermore, Wiesner et al reported that an increased number of HLA-DR compatibilities was associated with a decreased risk of development of an acute rejection episode.4 The disparate results on HLA typing in liver transplants may be explained by the quality of HLA typing in the early years of liver transplantation. The aim of this retrospective study was to examine whether immunogenetic donor/recipient variables like HLA matching using new typing methods affect the outcome of OLT patients. PATIENTS AND METHODS Study Population Between September 1988 and May 2000, 924 liver transplants were performed in 836 patients in whom complete HLA typing of both donor and recipient had been performed in our hospital. The series included (378 women) and 548 men (ratio 1/1, 4) and a median age of 48.7 years (range 0.9 to 77.2 years). The follow-up period ranged from 1 to 144.8 months (median ⫽ 66 months). The Standard immunosuppressive regimen was either cyclosporine A (CsA) or tacrolimus (Tac). Acute rejection episodes in liver grafts were suspected based upon rising liver serum enzymes, reduced bile flow, altered bile color, fever, or clinical deterioration and were confirmed by graft biopsy. HLA typing was performed using a standard lymphocytotoxicity test and confirmed by polymerase chain reactions. In the early part of the study HLA-DR typing was performed using cytotoxicity and then by PCR-SSP for most typings. Data are shown as median and range. Yates-corrected chi-square test and Fisher’s exact test were performed for dichotomous variables and likelihood ratio chisquare test for higher dimensional (2 ⫻ 3) tables. Cumulative © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 1499 –1500 (2002)
survivals were assessed by applying the Kaplan-Meier technique. Data were defined as significant when P ⬍ .05.
RESULTS
Overall 1-, 3-, and 5-year graft survivals were 88%, 82%, and 78.7%, respectively. We found no statistical correlation between graft or patient survival and number of HLA compatibilities (Fig 1). Additionally, there were no significant differences when analyzing cumulative HLA-A, -B, and -DR compatibilities alone. No specific donor or recipient HLA allele significantly influenced the outcome after OLT. Rejection episodes occurred in 417/924 transplants (45%) among which 348 (83.4%) responded to steroid treatment and 69 (16.5%) required OKT3 treatment. Overall the rejection probability decreased with higher numbers of HLA compatibilities (P ⬍ .05%, Table 1). However, there was no influence of the cumulative HLA-A, -B, and -DR matching on the number of recurrent or steroid-resistant rejection episodes. There was no relation between the incidence of rejection and compatibility for any specific HLA allele (data not shown). DISCUSSION
Immunological risk factors like a positive T- or B-cell cross-match have been verified in kidney and heart transplantation but could not be confirmed in liver transplants. Additionally, the impact of HLA compatibilities has been proven to increase graft survival after kidney and heart transplantation, but the matter is controversial after liver transplantation.1,4 There are a large number of studies showing an adverse effect of HLA matching on the outcomes after liver transplantation, including decreased survival, increased number of chronic rejections, and greater numbers of arterial thrombosis. In 1988 Markus et al1 observed a higher incidence of early liver graft failures in patients with HLA-DR-compatible grafts. However, the poor quality of serological From the Chirurgische Klinik und Poliklinik, Charite´, Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Berlin, Germany. Address reprint requests to U. Neumann, MD, Chirurgische Klinik und Poliklinik, Charite´, Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: [email protected] 0041-1345/02/$–see front matter PII S0041-1345(02)02946-9 1499
1500
NEUMANN, LANGREHR, LANG ET AL
Fig 1. The overall cumulative graft survival demonstrated no correlation between the degree of HLA matching in 924 liver transplants in Berlin.
HLA-DR matching techniques in this era may have contributed to these results. The reason for the impaired survival in this study was the high incidence of septic complications. All further studies on the impact of HLA compatibilities were unable to confirm these results.3–5 Our present study comprising more than 900 transplants clearly
demonstrated that HLA matching did not impair graft survival but rather decreased the incidence of rejection episodes. However a greater number of HLA compatibilities did not appear to be associated with chronic immunological complications. REFERENCES
Table 1. Incidence of Acute Rejection HLA Compatibilities
Acute Rejection (n ⫽ 417)
OKT3 Treatment (n ⫽ 69)
No compatibility One compatibility Two compatibilities ⬎ Two compatibilities
50.6%* (161/318) 45.4% (158/348) 37.7% (71/188) 38.5% (27/70)
9.7% (31/318) 6.6% (23/348) 4.8% (9/188) 8.5% (6/70)
*P ⬍ .05.
1. Markus BH, Duquesnoy RJ, Gordon RD, et al: Transplantation 46:372, 1988 2. Chen M, Wade J, Levy GA, et al: Transplant Proc 26:2695, 1994 3. Nikaein A, Backman L, Jennings L, et al: Transplantation 58:786, 1994 4. Wiesner RH, Demetris AJ, Belle SH, et al: Hepatology 28:638, 1998 5. Doran TJ, Geczy AF, Painter D, et al: Transplantation 69:1491, 2000