- Email: [email protected]
Influence of pretransplant panel reactive antibodies on the posttransplant sensitization status
Influence of Pretransplant Panel Reactive Antibodies on the Posttransplant Sensitization Status R. Deka, A. Panigrahi, S.K. Aggarwal, S. Guleria, S.C. Dash, S.N. Mehta, R.M. Pandey, and N.K. Mehra
A
MAJOR RISK factor influencing graft survival in transplantation is previous allosensitization. The pretransplant sensitization status of an individual reflects his immune status in terms of alloreactivity and may pose a virtually insurmountable barrier to kidney transplantation. This factor has been shown to have a significant negative impact on the outcomes of living related as well as unrelated donor grafts due to a higher incidence of acute rejection episodes leading to a longer hospital stay.1 The augmented efficacy of newer immunosuppressive protocols comprised of cyclosporine, azathioprine, prednisolone, and antilymphocyte agents (antithymocyte, antilymphocyte globulin, or anti CD3 monoclonal antibodies) has been documented by many investigators during the last decade2–5 and shown to also improve graft outcomes in preimmunized recipients. In the low-risk nonsensitized recipients these agents delay the onset of acute rejection episodes.6 Earlier studies have shown that nearly 25% of all renal recipients develop alloantibodies,7 and that posttransplant antidonor B cell IgG antibodies are associated with chronic rejection.8 Recently it has been observed that antibodies detected by the complement-dependent cytotoxicity (CDC)-panel reactive antibody (PRA) test but not detected by an ELISA technique are also clinically relevant.9 The present study is aimed at evaluating the impact of an individual’s pretransplant PRA profile on his posttransplant sensitization status and resultant graft outcome in terms of acute rejection episodes, chronic rejection, and ultimate graft survival. PATIENTS AND METHODS Serum samples from 169 renal graft recipients (139 men, 30 women) with a mean age of 31.7 years (31.7 ⫾ 11.1) were screened for their PRA status against a random cell panel from 50 HLAtyped healthy individuals using the CDC method. The donor categories included 119 living related, 47 living unrelated, and 3 cadaver donors with a mean age of 43 years (43 ⫾ 11). The highest pretransplant PRA status (peak PRA) was analyzed in relation to acute rejection episodes, chronic rejection, and graft survival. Serial posttransplant PRA determinations were performed on 123 patients and screening tests on 267 serum samples taken at different time points, including the immediate posttransplant period, within 1 to 3 months, the late posttransplant period within a year, and after 1 year. In addition, we tested serum samples obtained at the time of acute rejection episodes. Graft outcome was correlated with 1 year posttransplant serum samples in the majority of the patients (n ⫽ 109); the PRA levels of the last
samples collected before death in the remaining 14 patients were evaluated when death occurred before 1 year. Most patients received a triple-drug immunosuppressive protocol including cyclosporine, azathioprine, and prednisolone except for a few cases who suffered from drug toxicity. An acute rejection episode was diagnosed clinically by a rise in the serum creatinine level and later confirmed by biopsy. Chronic rejection, diagnosed by a persistent increase in creatinine levels for 3 to 4 months without an identifiable irreversible cause was biopsy proven in some cases.
RESULTS
Based on their pretransplant peak PRA, patients were classified into group I (PRA 1% to 10%, n ⫽ 136), group II (PRA 11% to 50%, n ⫽ 24) or group III (PRA ⬎ 50%, n ⫽ 9) and designated as nonsensitized, moderate, or highly sensitized groups, respectively. Posttransplant follow-up was performed on 96 patients in group I, 18 in group II, and 9 in group III (Table 1). The nonsensitized group included 73(76%) with follow-up, whereas 22(23%) of them developed moderate sensitization and one patient reached the highly sensitized category. Conversely, six (67%) of the nine patients in the highly sensitized category continued to display high sensitization during posttransplant screening, and only three (33%) showed a lower level of sensitization. Despite this, one patient who attained a nonsensitized status lost his graft within 1 month of transplantation. Patients in the intermediate group, however, moved either way: 11(61%) lost antibodies joining the nonsensitized group, whereas three (17%) developed antibodies included in the highly sensitized group posttransplant. Only four (22%) patients maintained a status quo. Thus, among 123 patients studied posttransplant, 85(69%) had posttransplant PRA, ⬍10%; 10 (8%) PRA ⬎50%, while the remaining 28 (23%) patients were in the intermediate range (11% to 50%). From the Departments of Transplantation Immunology and Immunogenetics, Nephrology, Surgery, and Biostatistics, All India Institute of Medical Sciences, New Delhi, India. Supported by a grant from the Department of Biotechnology, government of India. Address reprint requests to Prof N. K. Mehra, Head, Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India. E-mail: [email protected]
0041-1345/02/$–see front matter PII S0041-1345(02)03676-X
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
3082
Transplantation Proceedings, 34, 3082–2083 (2002)
PRETRANSPLANT PANEL REACTIVE ANTIBODIES
3083
Table 1. Impact of Pre- and Posttransplant PRA on GS, AR, and CR PRA groups (No tested Pre Tx.)
No. tested Post-Tx
Post-Tx PRA Status
I (0 –10) (N ⫽ 136)
96
73 11 1
56 7 —
74%
13 1 1
18%
18 — 1
22%
II (11–50) (N ⫽ 24)
18
22 4 2
18 3 1
78%
9 1 1
39%
11 — 1
43%
1 3 6
1 1 1
33%
1 2 5
80%
— 2 3
56%
III (51–100) (N ⫽ 9)
9
GS* N (%)
AR** N (%)
CR*** N (%)
Abbreviations: PRA, panel reactive antibodies; GS, graft survival; ar, acute rejection; CR, chronic rejection. *I vs II vs III ⫽ 9.43, P ⫽ .009; I vs II ⫽ P ⫽ .64; I vs III ⫽ P ⬍ .01; II vs II ⫽ P ⱕ .01. **I vs II vs III ⫽ 6.53, P ⫽ .038; I vs II ⫽ P ⬍ .05; I vs III ⫽ P ⬍ .0001; II vs III P ⫽ .06. ***I vs II vs III ⫽ 6.53, P ⫽ .038; I vs II ⫽ P ⬍ .05; I vs III ⫽ P ⬍ .05; II vs III P ⫽ .98.
Graft survival was analyzed in relation to posttransplant PRA at a mean follow-up of 25.7 ⫾ 16.7 months (range 0.05 to 76 months). Kaplan-Meier survival analysis and log rank test indicated that overall graft survival was significantly compromised in the highly sensitized group (group III) compared to the other two groups (overall chi-square ⫽ 9.98, P ⫽ .0068; I vs II: P ⫽ .09; I vs III: P ⫽ .02; II vs III: P ⫽ .0046). Most highly sensitized patients (PRA tested during either pre- or posttransplant periods) experienced acute rejection episodes, namely a significant difference in the incidence of AR in group I vs group II (P ⬍ .05) and group I vs group III (P ⬍ .0001). Graft survival among patients with high PRA values was also inferior to that of the nonsensitized category (group I vs group III, P ⬍ .01). Similarly, the incidence of chronic rejection was also significantly higher among sensitized patients (P ⬍ .05). DISCUSSION
Various factors including infections, blood transfusions, previous transplants, and so on have been recognized to cause sensitization leading to antibodies, mostly of the IgG type. This sensitization exerts a significant negative impact on the outcome of haploidentical living related donor renal grafts, leading to a higher incidence of acute rejection episodes within the first 3 months following transplantation and longer hospital stays. Earlier studies suggested that patients displaying ⬎10% PRA during the first week following transplantation have a tendency to display primary nonfunctioning kidneys.10 The results of our study suggests that the posttransplant sensitization status of an individual differs only to a limited extent from the pretransplant (peak) state. Most patients who were not sensitized pretransplant remained so in the posttransplant stage. Indeed more than one third of the sensitized patients (36%) lost their antibodies during the posttransplant follow-up, an incidence that is similar to the 26% previously reported.11 However, one highly sensitized patient who lost antibodies and was found to be nonsensitized in the posttransplant stage, lost his graft in the early posttransplant period, thus
further emphasizing the importance of the pretransplant peak PRA status as a prognostic factor for graft outcome. Our results also suggest that patients with a moderate to highly sensitized state pretransplant have a greater tendency to develop antibodies posttransplant compared to nonsensitized patients. The former group displayed a higher incidences of acute rejection episodes, and chronic rejection as well as a poor graft survival rate. Such patients may benefit from the tailored immunosuppressive protocol reported recently12 and by the use of uncompromised donor grafts.13 Thus, the pretransplant sensitization status has a definite bearing on the posttransplant alloantibody level of an individual, which subsequently has a major role on the ultimate graft outcome. The study suggests that a meticulous evaluation of the sensitization status of renal recipients both in the pretransplant as well as the post transplant periods may provide a good prediction of allosensitization and potentially for the graft survival. ACKNOWLEDGMENT The authors thank Mrs. Esther Philip and Mr. Sunil Kumar for technical assistance.
REFERENCES 1. Barama A, Oza U, Panek R, et al: Clin Transplantation 14:212, 2000 2. DeMasi R, et al: Transplant Proc 21:1729, 1989 3. Vela C, Cristol JP, Chong G, et al: Transpl Int 7(suppl 1):S259, 1994 4. Opelz G: Transplantation 60:1220, 1995 5. Szczech LA, et al: Ann Intern Med 128:817, 1998 6. Vincenti F, Kirkman R, Light S, et al: N Engl J Med 338:161, 1998 7. Scornik JC, Salomom DR, Lim PB, et al: Transplantation 47:287, 1989 8. Abe M, et al: Transplantation 63:1616, 1997 9. Su ¨sal C, Opelz G: Transplantation 73:1269, 2002 10. Monteiro F, et al: Transplant Proc 29:1433, 1997 11. Patrice KH, Patrick WA, Ronald P, et al: Ashi Quarterly Second Quarter:28, 2000 12. Hong JC, Kahan BD: Transplantation 71:1320, 2001 13. Gjertson DW, Cecka JM: Kidney Int 58:491, 2000
A
MAJOR RISK factor influencing graft survival in transplantation is previous allosensitization. The pretransplant sensitization status of an individual reflects his immune status in terms of alloreactivity and may pose a virtually insurmountable barrier to kidney transplantation. This factor has been shown to have a significant negative impact on the outcomes of living related as well as unrelated donor grafts due to a higher incidence of acute rejection episodes leading to a longer hospital stay.1 The augmented efficacy of newer immunosuppressive protocols comprised of cyclosporine, azathioprine, prednisolone, and antilymphocyte agents (antithymocyte, antilymphocyte globulin, or anti CD3 monoclonal antibodies) has been documented by many investigators during the last decade2–5 and shown to also improve graft outcomes in preimmunized recipients. In the low-risk nonsensitized recipients these agents delay the onset of acute rejection episodes.6 Earlier studies have shown that nearly 25% of all renal recipients develop alloantibodies,7 and that posttransplant antidonor B cell IgG antibodies are associated with chronic rejection.8 Recently it has been observed that antibodies detected by the complement-dependent cytotoxicity (CDC)-panel reactive antibody (PRA) test but not detected by an ELISA technique are also clinically relevant.9 The present study is aimed at evaluating the impact of an individual’s pretransplant PRA profile on his posttransplant sensitization status and resultant graft outcome in terms of acute rejection episodes, chronic rejection, and ultimate graft survival. PATIENTS AND METHODS Serum samples from 169 renal graft recipients (139 men, 30 women) with a mean age of 31.7 years (31.7 ⫾ 11.1) were screened for their PRA status against a random cell panel from 50 HLAtyped healthy individuals using the CDC method. The donor categories included 119 living related, 47 living unrelated, and 3 cadaver donors with a mean age of 43 years (43 ⫾ 11). The highest pretransplant PRA status (peak PRA) was analyzed in relation to acute rejection episodes, chronic rejection, and graft survival. Serial posttransplant PRA determinations were performed on 123 patients and screening tests on 267 serum samples taken at different time points, including the immediate posttransplant period, within 1 to 3 months, the late posttransplant period within a year, and after 1 year. In addition, we tested serum samples obtained at the time of acute rejection episodes. Graft outcome was correlated with 1 year posttransplant serum samples in the majority of the patients (n ⫽ 109); the PRA levels of the last
samples collected before death in the remaining 14 patients were evaluated when death occurred before 1 year. Most patients received a triple-drug immunosuppressive protocol including cyclosporine, azathioprine, and prednisolone except for a few cases who suffered from drug toxicity. An acute rejection episode was diagnosed clinically by a rise in the serum creatinine level and later confirmed by biopsy. Chronic rejection, diagnosed by a persistent increase in creatinine levels for 3 to 4 months without an identifiable irreversible cause was biopsy proven in some cases.
RESULTS
Based on their pretransplant peak PRA, patients were classified into group I (PRA 1% to 10%, n ⫽ 136), group II (PRA 11% to 50%, n ⫽ 24) or group III (PRA ⬎ 50%, n ⫽ 9) and designated as nonsensitized, moderate, or highly sensitized groups, respectively. Posttransplant follow-up was performed on 96 patients in group I, 18 in group II, and 9 in group III (Table 1). The nonsensitized group included 73(76%) with follow-up, whereas 22(23%) of them developed moderate sensitization and one patient reached the highly sensitized category. Conversely, six (67%) of the nine patients in the highly sensitized category continued to display high sensitization during posttransplant screening, and only three (33%) showed a lower level of sensitization. Despite this, one patient who attained a nonsensitized status lost his graft within 1 month of transplantation. Patients in the intermediate group, however, moved either way: 11(61%) lost antibodies joining the nonsensitized group, whereas three (17%) developed antibodies included in the highly sensitized group posttransplant. Only four (22%) patients maintained a status quo. Thus, among 123 patients studied posttransplant, 85(69%) had posttransplant PRA, ⬍10%; 10 (8%) PRA ⬎50%, while the remaining 28 (23%) patients were in the intermediate range (11% to 50%). From the Departments of Transplantation Immunology and Immunogenetics, Nephrology, Surgery, and Biostatistics, All India Institute of Medical Sciences, New Delhi, India. Supported by a grant from the Department of Biotechnology, government of India. Address reprint requests to Prof N. K. Mehra, Head, Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India. E-mail: [email protected]
0041-1345/02/$–see front matter PII S0041-1345(02)03676-X
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
3082
Transplantation Proceedings, 34, 3082–2083 (2002)
PRETRANSPLANT PANEL REACTIVE ANTIBODIES
3083
Table 1. Impact of Pre- and Posttransplant PRA on GS, AR, and CR PRA groups (No tested Pre Tx.)
No. tested Post-Tx
Post-Tx PRA Status
I (0 –10) (N ⫽ 136)
96
73 11 1
56 7 —
74%
13 1 1
18%
18 — 1
22%
II (11–50) (N ⫽ 24)
18
22 4 2
18 3 1
78%
9 1 1
39%
11 — 1
43%
1 3 6
1 1 1
33%
1 2 5
80%
— 2 3
56%
III (51–100) (N ⫽ 9)
9
GS* N (%)
AR** N (%)
CR*** N (%)
Abbreviations: PRA, panel reactive antibodies; GS, graft survival; ar, acute rejection; CR, chronic rejection. *I vs II vs III ⫽ 9.43, P ⫽ .009; I vs II ⫽ P ⫽ .64; I vs III ⫽ P ⬍ .01; II vs II ⫽ P ⱕ .01. **I vs II vs III ⫽ 6.53, P ⫽ .038; I vs II ⫽ P ⬍ .05; I vs III ⫽ P ⬍ .0001; II vs III P ⫽ .06. ***I vs II vs III ⫽ 6.53, P ⫽ .038; I vs II ⫽ P ⬍ .05; I vs III ⫽ P ⬍ .05; II vs III P ⫽ .98.
Graft survival was analyzed in relation to posttransplant PRA at a mean follow-up of 25.7 ⫾ 16.7 months (range 0.05 to 76 months). Kaplan-Meier survival analysis and log rank test indicated that overall graft survival was significantly compromised in the highly sensitized group (group III) compared to the other two groups (overall chi-square ⫽ 9.98, P ⫽ .0068; I vs II: P ⫽ .09; I vs III: P ⫽ .02; II vs III: P ⫽ .0046). Most highly sensitized patients (PRA tested during either pre- or posttransplant periods) experienced acute rejection episodes, namely a significant difference in the incidence of AR in group I vs group II (P ⬍ .05) and group I vs group III (P ⬍ .0001). Graft survival among patients with high PRA values was also inferior to that of the nonsensitized category (group I vs group III, P ⬍ .01). Similarly, the incidence of chronic rejection was also significantly higher among sensitized patients (P ⬍ .05). DISCUSSION
Various factors including infections, blood transfusions, previous transplants, and so on have been recognized to cause sensitization leading to antibodies, mostly of the IgG type. This sensitization exerts a significant negative impact on the outcome of haploidentical living related donor renal grafts, leading to a higher incidence of acute rejection episodes within the first 3 months following transplantation and longer hospital stays. Earlier studies suggested that patients displaying ⬎10% PRA during the first week following transplantation have a tendency to display primary nonfunctioning kidneys.10 The results of our study suggests that the posttransplant sensitization status of an individual differs only to a limited extent from the pretransplant (peak) state. Most patients who were not sensitized pretransplant remained so in the posttransplant stage. Indeed more than one third of the sensitized patients (36%) lost their antibodies during the posttransplant follow-up, an incidence that is similar to the 26% previously reported.11 However, one highly sensitized patient who lost antibodies and was found to be nonsensitized in the posttransplant stage, lost his graft in the early posttransplant period, thus
further emphasizing the importance of the pretransplant peak PRA status as a prognostic factor for graft outcome. Our results also suggest that patients with a moderate to highly sensitized state pretransplant have a greater tendency to develop antibodies posttransplant compared to nonsensitized patients. The former group displayed a higher incidences of acute rejection episodes, and chronic rejection as well as a poor graft survival rate. Such patients may benefit from the tailored immunosuppressive protocol reported recently12 and by the use of uncompromised donor grafts.13 Thus, the pretransplant sensitization status has a definite bearing on the posttransplant alloantibody level of an individual, which subsequently has a major role on the ultimate graft outcome. The study suggests that a meticulous evaluation of the sensitization status of renal recipients both in the pretransplant as well as the post transplant periods may provide a good prediction of allosensitization and potentially for the graft survival. ACKNOWLEDGMENT The authors thank Mrs. Esther Philip and Mr. Sunil Kumar for technical assistance.
REFERENCES 1. Barama A, Oza U, Panek R, et al: Clin Transplantation 14:212, 2000 2. DeMasi R, et al: Transplant Proc 21:1729, 1989 3. Vela C, Cristol JP, Chong G, et al: Transpl Int 7(suppl 1):S259, 1994 4. Opelz G: Transplantation 60:1220, 1995 5. Szczech LA, et al: Ann Intern Med 128:817, 1998 6. Vincenti F, Kirkman R, Light S, et al: N Engl J Med 338:161, 1998 7. Scornik JC, Salomom DR, Lim PB, et al: Transplantation 47:287, 1989 8. Abe M, et al: Transplantation 63:1616, 1997 9. Su ¨sal C, Opelz G: Transplantation 73:1269, 2002 10. Monteiro F, et al: Transplant Proc 29:1433, 1997 11. Patrice KH, Patrick WA, Ronald P, et al: Ashi Quarterly Second Quarter:28, 2000 12. Hong JC, Kahan BD: Transplantation 71:1320, 2001 13. Gjertson DW, Cecka JM: Kidney Int 58:491, 2000