- Email: [email protected]
Differences in immunoactivation between heart and liver transplanted patients
Differences in Immunoactivation Between Heart and Liver Transplanted Patients E. Erez, E. Sharoni, A. Erman, Z. Ben Ari, G. Sahar, R. Tur-Kaspa, B.A. Vidne, and D. Aravot
H
EART and liver transplantation have become the treatment of choice in end-stage heart or liver failure.1,2 Advances in surgical technique and the introduction of cyclosporine A have improved survival following transplantation, but allograft rejection is still common and remains a major cause of morbidity and late graft failure.2,3 Transplantation results in the recipient’s immune activation, however, because of baseline immunosuppressive therapy only some recipients manifest clinical symptoms of rejection. Induction immunosuppression after heart and liver transplantation has mainly been based on regimens previously used in renal transplantation. Modern regimens use triple-drug treatment: cyclosporine or FK 506, prednisone, and azathioprine for almost all organ recipients without questioning basic differences in immunoactivation. Beta-2-microglobulin (B2m) is a low molecular weight protein associated with HLA class I antigens and is of value for immunologic monitoring.4 B2m has been shown to significantly increase after heart, liver, or renal transplantation without clinical evidence for rejection.5 The purpose of this study was to explore differences in immunoactivation between stable heart and liver transplanted patients to improve long-term monitoring and immunosuppressive therapy.
Statistically significant differences in mean creatinine and serum B2m levels between the four groups were observed (P 5 .01). The group of liver transplanted patients with normal renal function (LTxnor) had a mean serum creatinine, 1.086 6 0.2 mg/dL, which was similar to the group of heart transplanted patients (HTx), 1.16 6 0.07 mg/dL. However, serum B2m in LTxnor was 3.7 6 0.8 mg/mL, statistically higher than the Htxnor group, 2.6 6 0.9 mg/mL, P # .05. The LTx group with abnormal renal function (LTxabnor) had a mean serum creatinine, 1.61 6 1.2 mg/dL, comparable to that of the Htxabnor group, 1.73 6 0.2 mg/dL, but their serum B2m, 5.87 6 2.6 mg/mL, was statistically higher compared to the HTx patients, 4.2 6 1.3 mg/mL, P # .02.
PATIENTS AND METHODS
DISCUSSION
Twenty-nine heart transplanted patients (HTx), aged 54 6 10 years, with good graft function, were studied. Their graft function was evaluated by echocardiography and heart biopsies, and at the time of their evaluation they had no evidence of rejection. HTx patients were maintained on cyclosporine A (29 of 29), azathioprine (26 of 29), and prednisone (10 of 29). The HTx patients were compared to 36 liver transplanted patients (LTx), age and sex matched. LTx graft function was evaluated by prothrombin time and liver biopsies, and at the time of their evaluation there was no evidence of rejection. LTx patients were maintained on cyclosporine A (21 of 36), FK 506 (15 of 36), azathioprine (2 of 36), and prednisone (34 of 36). All transplanted patients were evaluated for at least 3 months posttransplantation (HTx: mean 32 months, range 3– 84 months; LTx: mean 37 months, range 8 –92 months) and were receiving maintenance doses of immunosuppressive therapy. Both groups of patients were divided into two subgroups: HTxnor (n 5 7), LTxnor (n 5 21)–normal renal function (serum creatinine [SCr] # 1.35 mg/dL) and HTxabnor (n 5 22), LTxabnor (n 5 15)–impaired renal function (SCr $ 1.35). Serum creatinine was measured using a Beckman creatinine analyzer. Serum samples
for B2m measurements were collected at the time of clinical and laboratory evaluation and kept at 220°C until determination by immunoradiometric assay (Coat-A-Count B2m IRMA kit, Diagnostic Products Corp, Los Angeles, Calif). Serum B2m and creatinine were expressed as mean 6 SD. To analyze statistical differences in mean serum B2m and creatinine, analysis of variance was performed using the Duncan multiple comparison option. P # .05 was considered statistically significant.
RESULTS
Transplantation has become a standard treatment in endstage failure of many organs. However, the follow-up of patients after transplantation is a complex process that involves monitoring a wide array of parameters, such as clinical status, serum chemical values, and organ biopsy (liver or heart).2,3 One of the major difficulties in the long-term follow-up of transplanted patients is the adequacy of the immunosuppressive therapy. There is an individual immunologic reaction to the presence of a foreign organ that has the potential to result in graft dysfuncFrom the Department of Cardiothoracic Surgery (E.E, E.S., G.S., B.V., D.A.), Institute of Liver Diseases (Z.B., R.T.-K.), and Institute of Nephrology & Hypertension (A.E.) Rabin Medical Center (Beilinson Campus), Petah Tikva, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel. Address reprint requests to Dr E Erez, Rabin Medical Center, Cardiothoracic Surgery, Petah-Tikva, Israel.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00198-0
Transplantation Proceedings, 31, 1883–1884 (1999)
1883
1884
tion, yet, due to standard baseline immunosuppressive therapy only some recipients manifest clinical symptoms of allograft rejection. Long-term immunosuppressive treatments are composed of a combination of three drugs. One such regimen consists of low dose cyclosporine A, prednisone, and azathioprine. The major advantage of this regimen is the decreased dosage of cyclosporine to avoid renal toxicity and hypertension. Transplanted patients can be over- or underimmunosuppressed, thus putting them at risk for renal failure, infection, tumors, or rejection. In view of the complexity of follow-up and treatment of transplanted patients, it seems necessary to find a simple immunologic marker to evaluate the state of immunoactivation of these patients. B2m has been shown to be elevated after successful renal, liver, or heart transplantation, moreover, it has been proved useful in distinguishing between acute allograft rejection and infection.6 B2m is filtered (95%) at the glomerulus and reabsorbed (99.9%) by the proximal tubule where it is catabolized. Increased serum B2m levels reflect increased synthesis or defect of glomerular filtration.7,8 It has been shown previously that transplanted patients with impaired renal function due to cyclosporin A treatment have elevated serum B2m compared to transplanted patients with normal renal function. Yet the correlation between creatinine and B2m is weaker in transplanted patients compared to nontransplanted patients with comparable serum creatinine. It seems that during follow-up the relationship between B2m and creatinine is important for the diagnosis of rejection or renal failure. In our study we compared the basic immunoactivation between stable heart and liver transplanted patients. Patients were divided according to their renal function, and we
EREZ, SHARONI, ERMAN ET AL
Fig 1. Individual values of B2m.
found that stable liver transplanted patients are more immunoactivated than stable heart transplanted patients (Fig 1). This finding stresses the fact that the process of immunoactivation differs between individual patients and type of organ transplanted, and although all patients are treated by the same drugs, there is a need to tailor individual immunosuppressive therapy. In our opinion this approach will improve long-term allograft survival. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.
Keogh AM: Am J Cardiol 65:903, 1990 Wiesner RH: Clin Chem 40:2174, 1994 Johnson DE: J Heart Transplant 8:349, 1989 Fields BL: Transplant Proc 16:1591, 1984 Erez E: Transplant Proc 29:2700, 1997 Teufelsbauer H: Circulation 80:1681, 1989 Pacmeco-Silva A: Transplantation 59:914, 1995 Woo KT: Nephron 39:223, 1985
H
EART and liver transplantation have become the treatment of choice in end-stage heart or liver failure.1,2 Advances in surgical technique and the introduction of cyclosporine A have improved survival following transplantation, but allograft rejection is still common and remains a major cause of morbidity and late graft failure.2,3 Transplantation results in the recipient’s immune activation, however, because of baseline immunosuppressive therapy only some recipients manifest clinical symptoms of rejection. Induction immunosuppression after heart and liver transplantation has mainly been based on regimens previously used in renal transplantation. Modern regimens use triple-drug treatment: cyclosporine or FK 506, prednisone, and azathioprine for almost all organ recipients without questioning basic differences in immunoactivation. Beta-2-microglobulin (B2m) is a low molecular weight protein associated with HLA class I antigens and is of value for immunologic monitoring.4 B2m has been shown to significantly increase after heart, liver, or renal transplantation without clinical evidence for rejection.5 The purpose of this study was to explore differences in immunoactivation between stable heart and liver transplanted patients to improve long-term monitoring and immunosuppressive therapy.
Statistically significant differences in mean creatinine and serum B2m levels between the four groups were observed (P 5 .01). The group of liver transplanted patients with normal renal function (LTxnor) had a mean serum creatinine, 1.086 6 0.2 mg/dL, which was similar to the group of heart transplanted patients (HTx), 1.16 6 0.07 mg/dL. However, serum B2m in LTxnor was 3.7 6 0.8 mg/mL, statistically higher than the Htxnor group, 2.6 6 0.9 mg/mL, P # .05. The LTx group with abnormal renal function (LTxabnor) had a mean serum creatinine, 1.61 6 1.2 mg/dL, comparable to that of the Htxabnor group, 1.73 6 0.2 mg/dL, but their serum B2m, 5.87 6 2.6 mg/mL, was statistically higher compared to the HTx patients, 4.2 6 1.3 mg/mL, P # .02.
PATIENTS AND METHODS
DISCUSSION
Twenty-nine heart transplanted patients (HTx), aged 54 6 10 years, with good graft function, were studied. Their graft function was evaluated by echocardiography and heart biopsies, and at the time of their evaluation they had no evidence of rejection. HTx patients were maintained on cyclosporine A (29 of 29), azathioprine (26 of 29), and prednisone (10 of 29). The HTx patients were compared to 36 liver transplanted patients (LTx), age and sex matched. LTx graft function was evaluated by prothrombin time and liver biopsies, and at the time of their evaluation there was no evidence of rejection. LTx patients were maintained on cyclosporine A (21 of 36), FK 506 (15 of 36), azathioprine (2 of 36), and prednisone (34 of 36). All transplanted patients were evaluated for at least 3 months posttransplantation (HTx: mean 32 months, range 3– 84 months; LTx: mean 37 months, range 8 –92 months) and were receiving maintenance doses of immunosuppressive therapy. Both groups of patients were divided into two subgroups: HTxnor (n 5 7), LTxnor (n 5 21)–normal renal function (serum creatinine [SCr] # 1.35 mg/dL) and HTxabnor (n 5 22), LTxabnor (n 5 15)–impaired renal function (SCr $ 1.35). Serum creatinine was measured using a Beckman creatinine analyzer. Serum samples
for B2m measurements were collected at the time of clinical and laboratory evaluation and kept at 220°C until determination by immunoradiometric assay (Coat-A-Count B2m IRMA kit, Diagnostic Products Corp, Los Angeles, Calif). Serum B2m and creatinine were expressed as mean 6 SD. To analyze statistical differences in mean serum B2m and creatinine, analysis of variance was performed using the Duncan multiple comparison option. P # .05 was considered statistically significant.
RESULTS
Transplantation has become a standard treatment in endstage failure of many organs. However, the follow-up of patients after transplantation is a complex process that involves monitoring a wide array of parameters, such as clinical status, serum chemical values, and organ biopsy (liver or heart).2,3 One of the major difficulties in the long-term follow-up of transplanted patients is the adequacy of the immunosuppressive therapy. There is an individual immunologic reaction to the presence of a foreign organ that has the potential to result in graft dysfuncFrom the Department of Cardiothoracic Surgery (E.E, E.S., G.S., B.V., D.A.), Institute of Liver Diseases (Z.B., R.T.-K.), and Institute of Nephrology & Hypertension (A.E.) Rabin Medical Center (Beilinson Campus), Petah Tikva, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel. Address reprint requests to Dr E Erez, Rabin Medical Center, Cardiothoracic Surgery, Petah-Tikva, Israel.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00198-0
Transplantation Proceedings, 31, 1883–1884 (1999)
1883
1884
tion, yet, due to standard baseline immunosuppressive therapy only some recipients manifest clinical symptoms of allograft rejection. Long-term immunosuppressive treatments are composed of a combination of three drugs. One such regimen consists of low dose cyclosporine A, prednisone, and azathioprine. The major advantage of this regimen is the decreased dosage of cyclosporine to avoid renal toxicity and hypertension. Transplanted patients can be over- or underimmunosuppressed, thus putting them at risk for renal failure, infection, tumors, or rejection. In view of the complexity of follow-up and treatment of transplanted patients, it seems necessary to find a simple immunologic marker to evaluate the state of immunoactivation of these patients. B2m has been shown to be elevated after successful renal, liver, or heart transplantation, moreover, it has been proved useful in distinguishing between acute allograft rejection and infection.6 B2m is filtered (95%) at the glomerulus and reabsorbed (99.9%) by the proximal tubule where it is catabolized. Increased serum B2m levels reflect increased synthesis or defect of glomerular filtration.7,8 It has been shown previously that transplanted patients with impaired renal function due to cyclosporin A treatment have elevated serum B2m compared to transplanted patients with normal renal function. Yet the correlation between creatinine and B2m is weaker in transplanted patients compared to nontransplanted patients with comparable serum creatinine. It seems that during follow-up the relationship between B2m and creatinine is important for the diagnosis of rejection or renal failure. In our study we compared the basic immunoactivation between stable heart and liver transplanted patients. Patients were divided according to their renal function, and we
EREZ, SHARONI, ERMAN ET AL
Fig 1. Individual values of B2m.
found that stable liver transplanted patients are more immunoactivated than stable heart transplanted patients (Fig 1). This finding stresses the fact that the process of immunoactivation differs between individual patients and type of organ transplanted, and although all patients are treated by the same drugs, there is a need to tailor individual immunosuppressive therapy. In our opinion this approach will improve long-term allograft survival. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.
Keogh AM: Am J Cardiol 65:903, 1990 Wiesner RH: Clin Chem 40:2174, 1994 Johnson DE: J Heart Transplant 8:349, 1989 Fields BL: Transplant Proc 16:1591, 1984 Erez E: Transplant Proc 29:2700, 1997 Teufelsbauer H: Circulation 80:1681, 1989 Pacmeco-Silva A: Transplantation 59:914, 1995 Woo KT: Nephron 39:223, 1985