- Email: [email protected]
Predictive Factors of Acute Rejection in Low Immunologic Risk Kidney Transplant Recipients Receiving Basiliximab
Predictive Factors of Acute Rejection in Low Immunologic Risk Kidney Transplant Recipients Receiving Basiliximab M. Pereira*, J. Guerra, M. Neves, J. Gonçalves, A. Santana, C. Nascimento, and A.G. da Costa Nephrology and Kidney Transplantation Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
ABSTRACT Introduction. The optimal immunosuppressive induction therapy in kidney transplant recipients with low immunologic risk of acute rejection (AR) is still controversial. The use of basiliximab (BSX) has led to a significant decrease of AR with a low side effect profile. Objective. This study sought to evaluate predictive risk factors for AR in low immunologic risk patients subjected to immunosuppressive induction therapy with BSX. Methods. We reviewed all low immunologic risk patients (panel reactive antibody [PRA] level <50%, who had undergone a first deceased-donor transplant) subjected to immunosuppressive induction therapy with BSX, calcineurin inhibitor, mycophenolate mofetil, and prednisolone (n ¼ 346). AR was defined as any rejection occurring until 12 months posttransplantation. Predictive risk factors for AR were evaluated by logistic regression and, to find the best cut-off of PRA related to a higher incidence of AR, receiver-operator characteristic (ROC) curve analysis was performed. Results. The rate of AR was 7.8%. Multivariate logistic regression analysis identified age at the time of transplantation (P ¼ .040) and PRA level (P ¼ .001) as independent risk factors for AR. ROC curve analysis confirmed that PRA >10% was related to an increased incidence of AR (19.2% vs 6.0%, P ¼ .005). Conclusions. A higher incidence of AR was observed in low immunologic risk kidney transplant patients with a PRA level >10%. These data support the use of more intensive immunosuppressive induction therapy in patients with low immunologic risk and a PRA level >10%.
P
RETRANSPLANTATION sensitization is a risk factor for the occurrence of acute rejections (AR) [1e3], which can be partially prevented by immunosuppressive induction therapy. Usually, high immunologic risk patients undergo induction therapy with rabbit antithymocyte globulin (rATG), a lymphocyte-depleting polyclonal antibody that targets multiple immunologic epitopes. In low immunologic risk patients, there is no agreement on which immunosuppressive strategy is the best. The use of basiliximab (BSX), a nonelymphocyte-depleting monoclonal antibody targeting the interleukin-2 receptor, as induction therapy in kidney transplantation has proven its effectiveness in reducing the incidence of AR [4,5]. Some investigators have shown that lymphocyte depletion therapy was superior to BSX in preventing AR [6e9], mainly when there is a high immunologic risk [6]. However, at high doses 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.06.022
2280
(6 mg/kg, total dose) rATG has been associated with a significantly increased risk of infectious [6,10] and malignant diseases [11]. Due to its reduced side effect profile and good tolerability [5], BSX has been used, rather than rATG, in induction therapy in low immunologic risk patients. As we have previously described, the introduction of BSX in our unit for patients with a <50% level of sensitization allowed a reduction in AR from 23.7% to 10.8%, and an improved graft function after 5 years [4]. With the current immunosuppressive strategies, the factors that can predict AR have not been fully identified. Their recognition is
*Address correspondence to Marta Pereira, Hospital de Santa Maria, Serviço de Nefrologia e Transplantação Renal, Avenida Egas Moniz, 1649-035 Lisboa. E-mail: [email protected] ª 2016 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 2280e2283 (2016)
PREDICTIVE FACTORS OF ACUTE REJECTION
2281
Table 1. Baseline Characteristics of the Recipients Total n ¼ 346
Age at time of transplantation (y) Male sex Black race Panel reactive antibody (%) Number of human leukocyte antigen mismatches Delayed graft function Length of hospital stay (d) Acute rejection Time to acute rejection (d) Creatinine year 1 (mg/dL)
45.9 13.1 202 (58.4%) 51 (14.7%) 4.4 10.0 2.1 1.4 36 (10.4%) 21.7 11.3 27 (7.8%) 50.4 61.4 1.4 0.6
crucial for improving long-term results. In this study we assessed the predictive factors for AR in low immunologic risk patients who received induction therapy with BSX.
USA). Statistical significance level was set at P < .05. Continuous variables are expressed as the mean standard deviation and were compared using Student’s t-test. Categorical variables are expressed as the number and proportion of cases and were compared using Chi-squared test. KaplanMeier survival curve was used to study time to graft loss. For this analysis, we excluded kidney recipients whose grafts were lost due to surgical complications. Multivariate logistic regression analysis was performed to assess factors that influenced the incidence of AR. Variables included in the model were selected based on their significance in the univariate analysis. The final model included the recipient’s age, pre-transplantation sensitization and DGF. A receiver operating characteristic (ROC curve) analysis was performed to determine the best cut-off of PRA for the prediction of AR. RESULTS
METHODS We retrospectively reviewed medical records of all patients with low immunologic risk who underwent ABO-compatible kidney transplantation from deceased donors between January 2003 and December 2014 at our unit, subjected to immunosuppressive induction therapy with BSX (20 mg on days 0 and 4), calcineurin inhibitor (tacrolimus or cyclosporine), mycophenolate mofetil, and prednisolone (n ¼ 346). Low immunologic risk patients were defined as first kidney transplants with a panel reactive antibody (PRA) <50%. ARs occurring up to 12 months after transplantation were included in the analysis, being defined by clinical and/or histological criteria, the latter according to Banff classification. In patients with contraindications for kidney biopsy, AR was defined by creatinine elevation not explained otherwise and improved with immunosuppressive therapy intensification. Data collected included recipient age at the time of transplantation, sex, race, pretransplantation sensitization by PRA, number of human leukocyte antigen (HLA) mismatches, occurrence of delayed graft function (DGF), length of initial hospitalization, time between transplantation and first AR episode, and serum creatinine at one year posttransplantation. Data concerning time until graft failure and patient death were also recorded. Table 1 describes the features of the included population.
STATISTICAL ANALYSIS
All statistical analysis was performed using the commercially available SPSS 19.0 software package (SPSS Inc, Chicago, IL,
The incidence of AR in the first year posttransplantation was 7.8%, and graft survival was 97.8%, 90.5%, and 83.4% at 12 months, 5 years, and 10 years posttransplantation, respectively. The 346 patients analyzed were divided into 2 groups: group 1 included patients with AR, n ¼ 27; and group 2 consisted of the other 319 patients without episodes of AR. Sex and race were similar between groups. In group 1, patients were significantly younger (41.0 15.2 vs 46.3 12.8, P ¼ .04) and had a higher incidence of DGF (22.0% vs 9.5%, P ¼ .04). No difference was observed in the mean number of HLA mismatches; however, mean PRA was higher in patients in group 1 (11.6 18.1 vs 3.8 8.8, P ¼ .00) (Table 2). After adjusting for other variables, only the recipient’s age at the time of transplantation (P ¼ .04) and PRA value (P ¼ .001) remained as predictive risk factors for AR (Table 2). Patients with PRA 0% had an AR rate of 5.9%, compared with 11.9% (P ¼ .004) of AR in patients with PRA higher than 0%. The ROC curve analysis (Fig 1, area of 0.63; P ¼ .04; 95% confidence interval 0.49 to 0.74) confirmed that PRA 10% was the best cut-off for AR prediction, with a positive predictive value of 19.1 and a negative predictive value of 94. Patients with a PRA level higher than 10% had a significantly higher AR rate, 19.2%, compared to 6.0% (P ¼ .005) rate of AR in patients with a PRA level lower than 10%. Patients with a PRA level higher
Table 2. Comparison of Demographic and Clinical Variables Between Group 1 (Acute Rejection) and Group 2 (No Acute Rejection) in Univariate and Multivariate Logistic Regression Analysis
Age (y) Male sex Black race Panel reactive antibody (%) Number of human leukocyte antigen mismatches Delayed graft function
Group 1 (n ¼ 27)
Group 2 (n ¼ 319)
Univariate Analysis P Value
Multivariate Analysis P Value
41.0 15.2 14 (51.9%) 3 (11.1%) 11.6 18.1 2.0 1.2
46.3 12.8 188 (58.9%) 48 (15.0%) 3.8 8.8 2.1 1.5
.04 .54 .82 .00 .74
.04 .00 -
6 (22.2%)
30 (9.5%)
.04
.07
2282
Fig 1. Area under the receiver-operator characteristic (AuROC) curve for acute rejection prediction (area ¼ 0.63; P ¼ .04; 95% confidence interval 0.49 to 0.74).
than 10% had a relative risk of AR of 3.2 (95% confidence interval 1.52 to 6.65). No correlation (P ¼ .35) was found between age and a PRA level higher or lower than 10%. DISCUSSION
Episodes of AR are associated with a decrease in renal graft survival [1,12e14]. Risk factors for AR have been identified in several studies [1e3,14e17], enabling the adoption of strategies to improve long-term outcomes of kidney transplantation. One of the most well-established risk factors for AR is the degree of sensitization [1e3,17]. Patients with high PRA benefit from induction immunosuppression with lymphocyte-depleting therapy [6]. According to current immunosuppressive strategies, there is a consensus to carry out induction therapy even in patients with low immunologic risk. In this group BSX is an alternative given its reduced side effects, although it has not been proven that this is the optimal strategy. With this retrospective analysis, we aimed to identify predictive factors for AR in a population with a PRA level lower than 50% and subjected to induction therapy with BSX. Despite the fact that modern immunosuppressive therapy has minimized the importance of some risk factors for AR identified in the past, according to our results, even in patients considered at low immunologic risk, recipients’ sensitization and age remain as factors associated with a higher incidence of AR. Several studies have demonstrated a decreased incidence of AR in elderly recipients [18e20]. Our results support such data, as the group of patients with AR was significantly younger. The proliferative response of the T cells and
PEREIRA, GUERRA, NEVES ET AL
interleukin-2 activity decreases with advancing age, and these changes create a state of physiological immunosuppression. This finding, associated with greater vulnerability to infections in older patients [18], has allowed the reduction of immunosuppressive therapy in this age group with excellent outcomes [21]. Our results showed that even in low immunologic risk patients, pretransplantation sensitization is a key factor for the occurrence of AR. There was a significantly lower rate of AR in nonsensitized patients than in the group of sensitized patients (5.9% vs 11.9%, P ¼ .004). Lee et al. obtained similar results in a prior study, with 8.6% of AR in nonsensitized patients and 20% in patients sensitized with a PRA <50% [3]. According to our results, patients with a PRA between 10% and 50% have an increased immunologic risk, expressed as a higher incidence of AR, even when receiving induction therapy with BSX. As previously shown by some investigators, AR in low immunologic risk patients is effectively prevented by induction therapy with low doses of rATG [7,9,10,22]. Recently, Yang et al. showed the advantages of using low doses of rATG (2.5 mg/kg, total dose) compared to the standard dose (6 mg/kg, total dose). According to these investigators, low doses of rATG were associated with AR rates similar to those with standard doses (17.9% vs 16.7%, P > .05) and significantly lower incidence of infections (10.3% vs 30%, P < .05), which was overlapping to the group of patients not subjected to induction therapy (10.3% vs 9.9%, P > .05) [10]. Laftavi et al. showed the superiority of low doses of rATG (3 to 5 mg/kg, total dose) compared to BSX in preventing AR and graft survival, with overlapping viral infection and cancer rates after 8 years of follow-up [7]. Previously, Martínez et al. also showed similar results in a smaller group of patients [9]. Thus, we conclude that patients with PRA between 10% and 50% have an increased immunologic risk and can benefit from induction therapy with low-dose rATG, without increased side effects, and lower costs [8,23]. This strategy may not be appropriate in patients with advanced age because of their greater vulnerability to the side effects of immunosuppressive therapy and their state of immune senescence. Although this study presents some limitations, namely its retrospective, single-center nature and relatively small sample size, it is, to the best of our knowledge, the only published study in which sensitization intervals have been set to guide the implementation of different induction immunosuppressive strategies in low immunologic risk patients. We conclude that the recipient’s age and pretransplantation sensitization level remain predictive factors for AR in patients with PRA level lower than 50%, who were considered patients at lower immunologic risk in this study, and who received immunosuppressive induction therapy with BSX. Because patients with a PRA between 10% and 50% show an increased risk of AR, we suggest that these patients receive rATG, especially in younger age
PREDICTIVE FACTORS OF ACUTE REJECTION
groups. Further studies will be necessary to confirm that the immunosuppressive strategy suggested for this population is the most appropriate, thereby allowing for better renal outcomes without added adverse events.
REFERENCES [1] Mateu LMP, Calabuig AS, Plaza LC, et al. Acute rejection and late renal transplant failure: risk factors and prognosis. Nephrol Dial Transplant 2004;19:iii38e42. [2] Domingues EM, Matuck T, Graciano ML, et al. Panel reactive HLA antibodies, soluble CD30 levels, and acute rejection six months following renal transplant. Clin Transplant 2010;24: 821e9. [3] Lee KW, Kim SJ, Lee DS, et al. Effect of panel-reactive antibody positivity on graft rejection before or after kidney transplantation. Transplant Proc 2004;26:2009e10. [4] Teixeira C, Bouazzaoui Z, Guerra J, et al. Are there real advantages of induction therapy with basiliximab in renal transplantation? Transplant Proc 2013;45:1073e5. [5] Lawen JG, Davies EA, Mourad G, et al. Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation. Transplantation 2003;75:37e43. [6] Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin vs basiliximab in renal transplantation. N Engl J Med 2006;355:1967e77. [7] Laftavi MR, Alnimri M, Weber-Shrikant E, et al. Low-dose rabbit antithymocyte globulin vs basiliximab induction therapy in low-risk renal transplant recipients: 8-year follow-up. Transplant Proc 2011;43:458e61. [8] Patel HV, Kute VB, Vanikar AV, et al. Low-dose rabbit anti thymoglobin globulin vs basiliximab for induction therapy in kidney transplantation. Saudi J Kidney Dis Transpl 2014;25:819e22. [9] Martínez EG, Calabuig AS, Quesada VE, et al. Induction therapy with low-dose thymoglobulin or basilixamab in renal transplants from older donors. Transplant Proc 2008;40:2900e2. [10] Yang J, Wang J, Men T, et al. Comparison of clinical outcome of low-dose and high-dose rabbit antithymovyte globulin induction therapy in renal transplantation: a single-center experience. Ann Transplant 2014;19:277e82.
2283 [11] Kirk AD, Cherikh WS, Ring M, et al. Dissociation of T-cell depletion and post transplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant 2007;7: 2619e25. [12] Jalalzadeh M, Mousavinasab N, Peyrovi S, et al. The impact of acute rejection in kidney transplantation on longterm allograft and patient outcome. Nephrourol Mon 2015;7: e24439. [13] Joseph JT, Kingsmore DB, Junor BJ, et al. The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant 2001;15:221e7. [14] Eid L, Tuchman S, Moudgil A. Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant 2014;18:155e62. [15] Cole EH, Johnston O, Rose CL, et al. Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival. Clin J Am Soc Nephrol 2008;3: 814e21. [16] Dunn TB, Noreen H, Gillingham K, et al. Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant 2011;11:2132e43. [17] Woodle ES, Alloway RR, Buell JF, et al. Multivariate analysis of risk factors for acute rejection in early corticosteroid cessation regimens under modern immunosuppression. Am J Transplant 2005;5:2740e4. [18] Patel SJ, Knight RJ, Suki WN, et al. Rabbit antithymocyte induction and dosing in deceased donor renal transplant recipients over 60 yr of age. Clin Transplant 2011;25:E250e6. [19] Moore PS, Farney AC, Hartmann EL, et al. Experience with deceased donor kidney transplantation in 114 patients over age 60. Surgery 2007;142:514e23. [20] Pedroso S, Martins L, Fonseca I, et al. Renal transplantation in patients over 60 years of age: a single-center experience. Transplant Proc 2006;38:1885e9. [21] Badowski M, Gurk-Turner C, Cangro C, et al. The impact of reduced immunosuppression on graft outcomes in elderly renal transplant recipients. Clin Transplant 2009;23:930e7. [22] Khosroshahi HT, Tubbs RS, Shoja MM, et al. Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of acute kidney allograft rejection. Transplant Proc 2008;40: 137e9. [23] Popat R, Syed A, Puliatti C, et al. Outcome and cost analysis of induction immunosuppression with IL2Mab or ATG in DCD kidney transplants. Transplantation 2014;97:1161e5.
ABSTRACT Introduction. The optimal immunosuppressive induction therapy in kidney transplant recipients with low immunologic risk of acute rejection (AR) is still controversial. The use of basiliximab (BSX) has led to a significant decrease of AR with a low side effect profile. Objective. This study sought to evaluate predictive risk factors for AR in low immunologic risk patients subjected to immunosuppressive induction therapy with BSX. Methods. We reviewed all low immunologic risk patients (panel reactive antibody [PRA] level <50%, who had undergone a first deceased-donor transplant) subjected to immunosuppressive induction therapy with BSX, calcineurin inhibitor, mycophenolate mofetil, and prednisolone (n ¼ 346). AR was defined as any rejection occurring until 12 months posttransplantation. Predictive risk factors for AR were evaluated by logistic regression and, to find the best cut-off of PRA related to a higher incidence of AR, receiver-operator characteristic (ROC) curve analysis was performed. Results. The rate of AR was 7.8%. Multivariate logistic regression analysis identified age at the time of transplantation (P ¼ .040) and PRA level (P ¼ .001) as independent risk factors for AR. ROC curve analysis confirmed that PRA >10% was related to an increased incidence of AR (19.2% vs 6.0%, P ¼ .005). Conclusions. A higher incidence of AR was observed in low immunologic risk kidney transplant patients with a PRA level >10%. These data support the use of more intensive immunosuppressive induction therapy in patients with low immunologic risk and a PRA level >10%.
P
RETRANSPLANTATION sensitization is a risk factor for the occurrence of acute rejections (AR) [1e3], which can be partially prevented by immunosuppressive induction therapy. Usually, high immunologic risk patients undergo induction therapy with rabbit antithymocyte globulin (rATG), a lymphocyte-depleting polyclonal antibody that targets multiple immunologic epitopes. In low immunologic risk patients, there is no agreement on which immunosuppressive strategy is the best. The use of basiliximab (BSX), a nonelymphocyte-depleting monoclonal antibody targeting the interleukin-2 receptor, as induction therapy in kidney transplantation has proven its effectiveness in reducing the incidence of AR [4,5]. Some investigators have shown that lymphocyte depletion therapy was superior to BSX in preventing AR [6e9], mainly when there is a high immunologic risk [6]. However, at high doses 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.06.022
2280
(6 mg/kg, total dose) rATG has been associated with a significantly increased risk of infectious [6,10] and malignant diseases [11]. Due to its reduced side effect profile and good tolerability [5], BSX has been used, rather than rATG, in induction therapy in low immunologic risk patients. As we have previously described, the introduction of BSX in our unit for patients with a <50% level of sensitization allowed a reduction in AR from 23.7% to 10.8%, and an improved graft function after 5 years [4]. With the current immunosuppressive strategies, the factors that can predict AR have not been fully identified. Their recognition is
*Address correspondence to Marta Pereira, Hospital de Santa Maria, Serviço de Nefrologia e Transplantação Renal, Avenida Egas Moniz, 1649-035 Lisboa. E-mail: [email protected] ª 2016 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 2280e2283 (2016)
PREDICTIVE FACTORS OF ACUTE REJECTION
2281
Table 1. Baseline Characteristics of the Recipients Total n ¼ 346
Age at time of transplantation (y) Male sex Black race Panel reactive antibody (%) Number of human leukocyte antigen mismatches Delayed graft function Length of hospital stay (d) Acute rejection Time to acute rejection (d) Creatinine year 1 (mg/dL)
45.9 13.1 202 (58.4%) 51 (14.7%) 4.4 10.0 2.1 1.4 36 (10.4%) 21.7 11.3 27 (7.8%) 50.4 61.4 1.4 0.6
crucial for improving long-term results. In this study we assessed the predictive factors for AR in low immunologic risk patients who received induction therapy with BSX.
USA). Statistical significance level was set at P < .05. Continuous variables are expressed as the mean standard deviation and were compared using Student’s t-test. Categorical variables are expressed as the number and proportion of cases and were compared using Chi-squared test. KaplanMeier survival curve was used to study time to graft loss. For this analysis, we excluded kidney recipients whose grafts were lost due to surgical complications. Multivariate logistic regression analysis was performed to assess factors that influenced the incidence of AR. Variables included in the model were selected based on their significance in the univariate analysis. The final model included the recipient’s age, pre-transplantation sensitization and DGF. A receiver operating characteristic (ROC curve) analysis was performed to determine the best cut-off of PRA for the prediction of AR. RESULTS
METHODS We retrospectively reviewed medical records of all patients with low immunologic risk who underwent ABO-compatible kidney transplantation from deceased donors between January 2003 and December 2014 at our unit, subjected to immunosuppressive induction therapy with BSX (20 mg on days 0 and 4), calcineurin inhibitor (tacrolimus or cyclosporine), mycophenolate mofetil, and prednisolone (n ¼ 346). Low immunologic risk patients were defined as first kidney transplants with a panel reactive antibody (PRA) <50%. ARs occurring up to 12 months after transplantation were included in the analysis, being defined by clinical and/or histological criteria, the latter according to Banff classification. In patients with contraindications for kidney biopsy, AR was defined by creatinine elevation not explained otherwise and improved with immunosuppressive therapy intensification. Data collected included recipient age at the time of transplantation, sex, race, pretransplantation sensitization by PRA, number of human leukocyte antigen (HLA) mismatches, occurrence of delayed graft function (DGF), length of initial hospitalization, time between transplantation and first AR episode, and serum creatinine at one year posttransplantation. Data concerning time until graft failure and patient death were also recorded. Table 1 describes the features of the included population.
STATISTICAL ANALYSIS
All statistical analysis was performed using the commercially available SPSS 19.0 software package (SPSS Inc, Chicago, IL,
The incidence of AR in the first year posttransplantation was 7.8%, and graft survival was 97.8%, 90.5%, and 83.4% at 12 months, 5 years, and 10 years posttransplantation, respectively. The 346 patients analyzed were divided into 2 groups: group 1 included patients with AR, n ¼ 27; and group 2 consisted of the other 319 patients without episodes of AR. Sex and race were similar between groups. In group 1, patients were significantly younger (41.0 15.2 vs 46.3 12.8, P ¼ .04) and had a higher incidence of DGF (22.0% vs 9.5%, P ¼ .04). No difference was observed in the mean number of HLA mismatches; however, mean PRA was higher in patients in group 1 (11.6 18.1 vs 3.8 8.8, P ¼ .00) (Table 2). After adjusting for other variables, only the recipient’s age at the time of transplantation (P ¼ .04) and PRA value (P ¼ .001) remained as predictive risk factors for AR (Table 2). Patients with PRA 0% had an AR rate of 5.9%, compared with 11.9% (P ¼ .004) of AR in patients with PRA higher than 0%. The ROC curve analysis (Fig 1, area of 0.63; P ¼ .04; 95% confidence interval 0.49 to 0.74) confirmed that PRA 10% was the best cut-off for AR prediction, with a positive predictive value of 19.1 and a negative predictive value of 94. Patients with a PRA level higher than 10% had a significantly higher AR rate, 19.2%, compared to 6.0% (P ¼ .005) rate of AR in patients with a PRA level lower than 10%. Patients with a PRA level higher
Table 2. Comparison of Demographic and Clinical Variables Between Group 1 (Acute Rejection) and Group 2 (No Acute Rejection) in Univariate and Multivariate Logistic Regression Analysis
Age (y) Male sex Black race Panel reactive antibody (%) Number of human leukocyte antigen mismatches Delayed graft function
Group 1 (n ¼ 27)
Group 2 (n ¼ 319)
Univariate Analysis P Value
Multivariate Analysis P Value
41.0 15.2 14 (51.9%) 3 (11.1%) 11.6 18.1 2.0 1.2
46.3 12.8 188 (58.9%) 48 (15.0%) 3.8 8.8 2.1 1.5
.04 .54 .82 .00 .74
.04 .00 -
6 (22.2%)
30 (9.5%)
.04
.07
2282
Fig 1. Area under the receiver-operator characteristic (AuROC) curve for acute rejection prediction (area ¼ 0.63; P ¼ .04; 95% confidence interval 0.49 to 0.74).
than 10% had a relative risk of AR of 3.2 (95% confidence interval 1.52 to 6.65). No correlation (P ¼ .35) was found between age and a PRA level higher or lower than 10%. DISCUSSION
Episodes of AR are associated with a decrease in renal graft survival [1,12e14]. Risk factors for AR have been identified in several studies [1e3,14e17], enabling the adoption of strategies to improve long-term outcomes of kidney transplantation. One of the most well-established risk factors for AR is the degree of sensitization [1e3,17]. Patients with high PRA benefit from induction immunosuppression with lymphocyte-depleting therapy [6]. According to current immunosuppressive strategies, there is a consensus to carry out induction therapy even in patients with low immunologic risk. In this group BSX is an alternative given its reduced side effects, although it has not been proven that this is the optimal strategy. With this retrospective analysis, we aimed to identify predictive factors for AR in a population with a PRA level lower than 50% and subjected to induction therapy with BSX. Despite the fact that modern immunosuppressive therapy has minimized the importance of some risk factors for AR identified in the past, according to our results, even in patients considered at low immunologic risk, recipients’ sensitization and age remain as factors associated with a higher incidence of AR. Several studies have demonstrated a decreased incidence of AR in elderly recipients [18e20]. Our results support such data, as the group of patients with AR was significantly younger. The proliferative response of the T cells and
PEREIRA, GUERRA, NEVES ET AL
interleukin-2 activity decreases with advancing age, and these changes create a state of physiological immunosuppression. This finding, associated with greater vulnerability to infections in older patients [18], has allowed the reduction of immunosuppressive therapy in this age group with excellent outcomes [21]. Our results showed that even in low immunologic risk patients, pretransplantation sensitization is a key factor for the occurrence of AR. There was a significantly lower rate of AR in nonsensitized patients than in the group of sensitized patients (5.9% vs 11.9%, P ¼ .004). Lee et al. obtained similar results in a prior study, with 8.6% of AR in nonsensitized patients and 20% in patients sensitized with a PRA <50% [3]. According to our results, patients with a PRA between 10% and 50% have an increased immunologic risk, expressed as a higher incidence of AR, even when receiving induction therapy with BSX. As previously shown by some investigators, AR in low immunologic risk patients is effectively prevented by induction therapy with low doses of rATG [7,9,10,22]. Recently, Yang et al. showed the advantages of using low doses of rATG (2.5 mg/kg, total dose) compared to the standard dose (6 mg/kg, total dose). According to these investigators, low doses of rATG were associated with AR rates similar to those with standard doses (17.9% vs 16.7%, P > .05) and significantly lower incidence of infections (10.3% vs 30%, P < .05), which was overlapping to the group of patients not subjected to induction therapy (10.3% vs 9.9%, P > .05) [10]. Laftavi et al. showed the superiority of low doses of rATG (3 to 5 mg/kg, total dose) compared to BSX in preventing AR and graft survival, with overlapping viral infection and cancer rates after 8 years of follow-up [7]. Previously, Martínez et al. also showed similar results in a smaller group of patients [9]. Thus, we conclude that patients with PRA between 10% and 50% have an increased immunologic risk and can benefit from induction therapy with low-dose rATG, without increased side effects, and lower costs [8,23]. This strategy may not be appropriate in patients with advanced age because of their greater vulnerability to the side effects of immunosuppressive therapy and their state of immune senescence. Although this study presents some limitations, namely its retrospective, single-center nature and relatively small sample size, it is, to the best of our knowledge, the only published study in which sensitization intervals have been set to guide the implementation of different induction immunosuppressive strategies in low immunologic risk patients. We conclude that the recipient’s age and pretransplantation sensitization level remain predictive factors for AR in patients with PRA level lower than 50%, who were considered patients at lower immunologic risk in this study, and who received immunosuppressive induction therapy with BSX. Because patients with a PRA between 10% and 50% show an increased risk of AR, we suggest that these patients receive rATG, especially in younger age
PREDICTIVE FACTORS OF ACUTE REJECTION
groups. Further studies will be necessary to confirm that the immunosuppressive strategy suggested for this population is the most appropriate, thereby allowing for better renal outcomes without added adverse events.
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