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Panel Reactive Antibody Responses Against Influenza Vaccination in Kidney Transplant Recipients
Panel Reactive Antibody Responses Against Influenza Vaccination in Kidney Transplant Recipients B. Khishigsurena, E. Demira,*, S.U. Akgulb, S. Temurhanb, A.R. Ucara, A.B. Dirima, N.M. Catikkasa, A. Bayraktarc, Y. Caliskana, H. Yazicia, F.S. Oguzb, A. Turkmena, and M.S. Severa a
Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University Istanbul, Turkey; Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; and cDepartment of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey b
ABSTRACT Introduction. Seasonal influenza is an important cause of morbidity and mortality in the post-transplant period; therefore, the influenza vaccination has been recommended for all kidney transplant recipients before the influenza season. However, at least theoretically, the introduction of antigens via vaccines may trigger rejection attacks by causing an antibody response. In this study, we examined the development of de novo panel reactive antibody (PRA) development against the influenza vaccine in kidney transplant recipients. Materials and Methods. Overall, 41 kidney transplant recipients who received the influenza vaccination and 50 kidney transplant recipients (study group) who refused to receive the influenza vaccination (control group) were enrolled in the study. Following basal biochemistry examination, the inactivated trivalent influenza vaccine was administered intramuscularly. Panel reactive antibodies were screened in all patients before and after vaccination on days 30 and 180. The primary outcome variable was development of de novo panel reactive antibodies. Results. One patient in the study group developed de novo class I and II PRA at 6 months after vaccination (P > .05), while no antibody development was noted in the control group. Graft dysfunction or biopsy-confirmed rejection was not observed during the follow-up period in both groups. Conclusion. The influenza vaccination is generally effective and safe in solid organ transplant recipients. The vaccination procedure has the potential to trigger antibody development and occurrence of rejection. Therefore, vaccinated kidney transplant recipients should be monitored more carefully with regard to PRA; if the graft deteriorates, a rapid transplant biopsy should be performed.
K
IDNEY transplantation is the preferred treatment method for end-stage renal disease [1]. The improvement in immunosuppressive treatment, technical advancements in immunologic investigations, development of desensitization protocols, and chemoprophylaxis against opportunistic infections increased patient and graft survival rates gradually [2]. On the other hand, the risk of infection remains the principal complication for kidney transplant recipients [1,2]. Pretransplant donor and recipient screening, vaccinations, and other prophylactic treatments ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 1115e1117 (2019)
are performed to prevent infection in the post-transplant period [2,3]. Seasonal influenza is an important cause of morbidity and mortality in the post-transplant period;
*Address correspondence to Erol Demir, MD, Istanbul University, Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Fatih/Istanbul, Turkey. Tel: 090 212 414 20 00/33040; Fax: 090 212 414 20 28. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.02.009
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therefore, the influenza vaccination has been recommended for all kidney transplant recipients before the influenza season [3]. However, at least theoretically, the introduction of antigens via vaccines may trigger rejection attacks by causing an antibody response. In this study, we examined the development of de novo panel reactive antibody (PRA) development against influenza vaccine in kidney transplant recipients. MATERIALS AND METHODS Study Population All patients 18 years of age and older who underwent kidney transplantation and received or refused the influenza vaccination were included in this study. Patients with a history of rejection, active infection, malignancy in the last 3 months, or blood transfusion during the study period were excluded from the study. Overall, 41 kidney transplant recipients who received the influenza vaccination (workgroup) and 50 kidney transplant recipients who refused to receive the influenza vaccination (control group) were enrolled in the study. Demographic and clinical data included age at kidney transplantation, gender, the cause of end-stage renal disease, prior renal replacement treatment history, and post-transplant follow-up duration and complications. Hemogram, serum creatinine, blood urea nitrogen, glucose, albumin, calcium, phosphorus, triglyceride, total cholesterol, and high- and low-density lipoprotein levels were measured every 3 months after kidney transplantation. Following a basal biochemistry examination, the inactivated trivalent influenza vaccine (Vaxigrip; Sanofi Pasteur SA, Lyon, France) was administered intramuscularly. PRAs were screened in all patients before and after vaccination on days 30 and 180. Luminex solid-phase assay was used to investigate class I and class II PRA. Written informed consent was obtained from all participants. The study was approved by the local ethics committee.
Study Endpoints The primary outcome variable was the development of de novo PRAs. The secondary endpoints were the occurrence of biopsyproven rejection and influenza infection. PRA levels more than 1000 mean fluorescence intensity were accepted as PRA positive.
KHISHIGSUREN, DEMIR, AKGUL ET AL Table 1. Demographic Characteristics of Study Group (Received Vaccination) and Control Groups (Refused Vaccination) Study Group Control Group (n ¼ 41) (n ¼ 50)
Mean age (years) 42.8 8.8 40.7 11.6 Sex Female 17 (41%) 21 (42%) Male 24 (59%) 29 (58%) Type of donor Living 20 (49%) 37 (74%) Deceased 21 (51%) 13 (26%) Etiology of CKD (n) CAKUT 7 (17%) 11 (22%) Chronic glomerulonephritis 6 (15%) 9 (18%) Hypertensive nephrosclerosis 3 (7%) 3 (6%) Others 6 (12%) 7 (10%) Unknown 19 (46%) 20 (40%) Post-transplant follow-up period (months) 78 66 81 58 Abbreviations: CAKUT, congenital anomalies of the kidney and the urinary tract; CKD, chronic kidney disease.
group, respectively (P ¼ .328). This parameter was 1.2 0.5 mg/dL for the study group and 1.4 0.4 mg/dL for the control group after 6 months of vaccination (P ¼ .106). In the study group, 4 patients had class I, 1 patient had class II, and 1 patient had both class I and II PRA test before vaccination. Only 1 patient in the study group developed de novo class I and II PRA at 6 months after vaccination (P > .05), while no antibody development was noted in the control group. Graft dysfunction or biopsyconfirmed rejection was not observed during the follow-up period in both groups. The prevalence of the influenza infection was 34% in the study and 16% in the control group during follow-up (P ¼ .044). None of the patients had hospitalized due to respiratory tract infection.
DISCUSSION Statistical Analysis Statistical analysis was performed using SPSS (version 21.0; IBM, Armonk, NY, United States). Results are reported as mean standard deviation when normally distributed or as median (interquartile range). Comparisons of continuous variables between the 2 groups were assessed by using the Student t test or the MannWhitney U test, where appropriate. Pearson’s c2 test was used to analyze differences among categorical variables. Univariate survival comparisons were made by using the log-rank test.
RESULTS
Demographic characteristics of the study and the control groups are shown in Table 1. Groups were matched with regard to age, gender, and post-transplant follow-up (P ¼ .407, P ¼ .762, and P ¼ .237, respectively). Patient and control groups were followed for 6 months after vaccination. Prevaccination mean serum creatinine levels were 1.3 0.5 mg/dL and 1.4 0.5 mg/dL in the study and control
In the present study, 41 kidney transplant recipients who were vaccinated and another 50 transplant recipients who refused vaccination (thus served as control cases) were enrolled in this study. All patients were followed during the first 6 months. Only 1 patient in the vaccinated group developed de novo PRA. Influenza is an important infection in immunocompromised patients and also increases mortality and morbidity in the general population. Influenza vaccination is generally effective and safe in solid organ transplant recipients [4,5]. Surprisingly, in the present study, influenza infection was more frequent in the vaccination group, which can be explained only by coincidence and the low number of patients. The vaccination procedure has the potential for triggering antibody development and the occurrence of rejection. A limited number of studies reported that there is an increased risk of rejection [6,7], although this risk is not uniform and not accepted by all authors. According to
PANEL REACTIVE ANTIBODY RESPONSES
Kidney Disease Improving Global Outcomes guidelines, the relationship between the influenza vaccination and the occurrence of rejection in kidney transplant recipients has not been proven [8]. Therefore, the influenza vaccination has been recommended for kidney transplant recipients and their relatives every year [3]. Since transplantation practice and risk of infection show considerable difference across countries, general recommendations may not be applicable for all countries [8]. Therefore, we aimed to investigate the development of PRA in our patient population after the vaccination and noted that PRA appeared in 1 of the patients. Of course, this seems to be nonsignificant. However, one should consider that the patients in this study group characterized by low immunological risk; actually, this risk may be higher in patients with high immunological risk. Therefore, vaccinated kidney transplant recipients should be monitored more carefully with regard to PRA; if the graft deteriorates, a rapid transplant biopsy should be performed [6,9]. There are important limitations to the present study. Our study population is very small to obtain accurate results. In addition, protective antibody titrations against vaccine antigens were not measured in our study. Moreover, as cited above, vaccination may be risky in immunologically highrisk patients. Therefore, further studies that include a higher number of patients and also target immunologically high-risk patients are needed. In conclusion, the influenza vaccination does not trigger a humoral alloimmune response and is safe in kidney transplant recipients.
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REFERENCES [1] Pruthi R, Steenkamp R, Feest T. UK Renal Registry 16th annual report: chapter 8 survival and cause of death of UK adult patients on renal replacement therapy in 2012: national and centrespecific analyses. Nephron Clin Pract 2013;125:139e69. [2] Kazancioglu R, Sever MS, Yuksel-Onel D, Eraksoy H, Yildiz A, Celik AV, et al. Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine. Clin Transplant 2000;14:61e5. [3] Sever MS, Yildiz A, Eraksoy H, Badur S, Yuksel-Onel D, Gorcin B, et al. Immune response to Haemophilus influenzae type B vaccination in renal transplant recipients with well-functioning allografts. Nephron 1999;81:55e9. [4] Keshtkar-Jahromi M, Argani H, Rahnavardi M, Mirchi E, Atabak S, Tara SA, et al. Antibody response to influenza immunization in kidney transplant recipients receiving either azathioprine or mycophenolate: a controlled trial. Am J Nephrol 2008;28: 654e60. [5] Sanchez-Fructuoso AI, Prats D, Naranjo P, FernándezPérez C, González MJ, Mariano A, et al. Influenza virus immunization effectivity in kidney transplant patients subjected to two different triple-drug therapy immunosuppression protocols: mycophenolate versus azathioprine. Transplantation 2000;69:436e40. [6] Wiebe C, Nickerson P. Posttransplant monitoring of de novo human leukocyte antigen donor-specific antibodies in kidney transplantation. Curr Opin Organ Transplant 2013;18:470e7. [7] Ginevri F, Nocera A, Comoli P, Innocente A, Cioni M, Parodi A, et al. Posttransplant de novo donor-specific HLA antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection. Am J Transplant 2012;12:3355e62. [8] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9:1e155. [9] Tait BD, Susal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013;95:19e47.
Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University Istanbul, Turkey; Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; and cDepartment of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey b
ABSTRACT Introduction. Seasonal influenza is an important cause of morbidity and mortality in the post-transplant period; therefore, the influenza vaccination has been recommended for all kidney transplant recipients before the influenza season. However, at least theoretically, the introduction of antigens via vaccines may trigger rejection attacks by causing an antibody response. In this study, we examined the development of de novo panel reactive antibody (PRA) development against the influenza vaccine in kidney transplant recipients. Materials and Methods. Overall, 41 kidney transplant recipients who received the influenza vaccination and 50 kidney transplant recipients (study group) who refused to receive the influenza vaccination (control group) were enrolled in the study. Following basal biochemistry examination, the inactivated trivalent influenza vaccine was administered intramuscularly. Panel reactive antibodies were screened in all patients before and after vaccination on days 30 and 180. The primary outcome variable was development of de novo panel reactive antibodies. Results. One patient in the study group developed de novo class I and II PRA at 6 months after vaccination (P > .05), while no antibody development was noted in the control group. Graft dysfunction or biopsy-confirmed rejection was not observed during the follow-up period in both groups. Conclusion. The influenza vaccination is generally effective and safe in solid organ transplant recipients. The vaccination procedure has the potential to trigger antibody development and occurrence of rejection. Therefore, vaccinated kidney transplant recipients should be monitored more carefully with regard to PRA; if the graft deteriorates, a rapid transplant biopsy should be performed.
K
IDNEY transplantation is the preferred treatment method for end-stage renal disease [1]. The improvement in immunosuppressive treatment, technical advancements in immunologic investigations, development of desensitization protocols, and chemoprophylaxis against opportunistic infections increased patient and graft survival rates gradually [2]. On the other hand, the risk of infection remains the principal complication for kidney transplant recipients [1,2]. Pretransplant donor and recipient screening, vaccinations, and other prophylactic treatments ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 1115e1117 (2019)
are performed to prevent infection in the post-transplant period [2,3]. Seasonal influenza is an important cause of morbidity and mortality in the post-transplant period;
*Address correspondence to Erol Demir, MD, Istanbul University, Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Fatih/Istanbul, Turkey. Tel: 090 212 414 20 00/33040; Fax: 090 212 414 20 28. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.02.009
1115
1116
therefore, the influenza vaccination has been recommended for all kidney transplant recipients before the influenza season [3]. However, at least theoretically, the introduction of antigens via vaccines may trigger rejection attacks by causing an antibody response. In this study, we examined the development of de novo panel reactive antibody (PRA) development against influenza vaccine in kidney transplant recipients. MATERIALS AND METHODS Study Population All patients 18 years of age and older who underwent kidney transplantation and received or refused the influenza vaccination were included in this study. Patients with a history of rejection, active infection, malignancy in the last 3 months, or blood transfusion during the study period were excluded from the study. Overall, 41 kidney transplant recipients who received the influenza vaccination (workgroup) and 50 kidney transplant recipients who refused to receive the influenza vaccination (control group) were enrolled in the study. Demographic and clinical data included age at kidney transplantation, gender, the cause of end-stage renal disease, prior renal replacement treatment history, and post-transplant follow-up duration and complications. Hemogram, serum creatinine, blood urea nitrogen, glucose, albumin, calcium, phosphorus, triglyceride, total cholesterol, and high- and low-density lipoprotein levels were measured every 3 months after kidney transplantation. Following a basal biochemistry examination, the inactivated trivalent influenza vaccine (Vaxigrip; Sanofi Pasteur SA, Lyon, France) was administered intramuscularly. PRAs were screened in all patients before and after vaccination on days 30 and 180. Luminex solid-phase assay was used to investigate class I and class II PRA. Written informed consent was obtained from all participants. The study was approved by the local ethics committee.
Study Endpoints The primary outcome variable was the development of de novo PRAs. The secondary endpoints were the occurrence of biopsyproven rejection and influenza infection. PRA levels more than 1000 mean fluorescence intensity were accepted as PRA positive.
KHISHIGSUREN, DEMIR, AKGUL ET AL Table 1. Demographic Characteristics of Study Group (Received Vaccination) and Control Groups (Refused Vaccination) Study Group Control Group (n ¼ 41) (n ¼ 50)
Mean age (years) 42.8 8.8 40.7 11.6 Sex Female 17 (41%) 21 (42%) Male 24 (59%) 29 (58%) Type of donor Living 20 (49%) 37 (74%) Deceased 21 (51%) 13 (26%) Etiology of CKD (n) CAKUT 7 (17%) 11 (22%) Chronic glomerulonephritis 6 (15%) 9 (18%) Hypertensive nephrosclerosis 3 (7%) 3 (6%) Others 6 (12%) 7 (10%) Unknown 19 (46%) 20 (40%) Post-transplant follow-up period (months) 78 66 81 58 Abbreviations: CAKUT, congenital anomalies of the kidney and the urinary tract; CKD, chronic kidney disease.
group, respectively (P ¼ .328). This parameter was 1.2 0.5 mg/dL for the study group and 1.4 0.4 mg/dL for the control group after 6 months of vaccination (P ¼ .106). In the study group, 4 patients had class I, 1 patient had class II, and 1 patient had both class I and II PRA test before vaccination. Only 1 patient in the study group developed de novo class I and II PRA at 6 months after vaccination (P > .05), while no antibody development was noted in the control group. Graft dysfunction or biopsyconfirmed rejection was not observed during the follow-up period in both groups. The prevalence of the influenza infection was 34% in the study and 16% in the control group during follow-up (P ¼ .044). None of the patients had hospitalized due to respiratory tract infection.
DISCUSSION Statistical Analysis Statistical analysis was performed using SPSS (version 21.0; IBM, Armonk, NY, United States). Results are reported as mean standard deviation when normally distributed or as median (interquartile range). Comparisons of continuous variables between the 2 groups were assessed by using the Student t test or the MannWhitney U test, where appropriate. Pearson’s c2 test was used to analyze differences among categorical variables. Univariate survival comparisons were made by using the log-rank test.
RESULTS
Demographic characteristics of the study and the control groups are shown in Table 1. Groups were matched with regard to age, gender, and post-transplant follow-up (P ¼ .407, P ¼ .762, and P ¼ .237, respectively). Patient and control groups were followed for 6 months after vaccination. Prevaccination mean serum creatinine levels were 1.3 0.5 mg/dL and 1.4 0.5 mg/dL in the study and control
In the present study, 41 kidney transplant recipients who were vaccinated and another 50 transplant recipients who refused vaccination (thus served as control cases) were enrolled in this study. All patients were followed during the first 6 months. Only 1 patient in the vaccinated group developed de novo PRA. Influenza is an important infection in immunocompromised patients and also increases mortality and morbidity in the general population. Influenza vaccination is generally effective and safe in solid organ transplant recipients [4,5]. Surprisingly, in the present study, influenza infection was more frequent in the vaccination group, which can be explained only by coincidence and the low number of patients. The vaccination procedure has the potential for triggering antibody development and the occurrence of rejection. A limited number of studies reported that there is an increased risk of rejection [6,7], although this risk is not uniform and not accepted by all authors. According to
PANEL REACTIVE ANTIBODY RESPONSES
Kidney Disease Improving Global Outcomes guidelines, the relationship between the influenza vaccination and the occurrence of rejection in kidney transplant recipients has not been proven [8]. Therefore, the influenza vaccination has been recommended for kidney transplant recipients and their relatives every year [3]. Since transplantation practice and risk of infection show considerable difference across countries, general recommendations may not be applicable for all countries [8]. Therefore, we aimed to investigate the development of PRA in our patient population after the vaccination and noted that PRA appeared in 1 of the patients. Of course, this seems to be nonsignificant. However, one should consider that the patients in this study group characterized by low immunological risk; actually, this risk may be higher in patients with high immunological risk. Therefore, vaccinated kidney transplant recipients should be monitored more carefully with regard to PRA; if the graft deteriorates, a rapid transplant biopsy should be performed [6,9]. There are important limitations to the present study. Our study population is very small to obtain accurate results. In addition, protective antibody titrations against vaccine antigens were not measured in our study. Moreover, as cited above, vaccination may be risky in immunologically highrisk patients. Therefore, further studies that include a higher number of patients and also target immunologically high-risk patients are needed. In conclusion, the influenza vaccination does not trigger a humoral alloimmune response and is safe in kidney transplant recipients.
1117
REFERENCES [1] Pruthi R, Steenkamp R, Feest T. UK Renal Registry 16th annual report: chapter 8 survival and cause of death of UK adult patients on renal replacement therapy in 2012: national and centrespecific analyses. Nephron Clin Pract 2013;125:139e69. [2] Kazancioglu R, Sever MS, Yuksel-Onel D, Eraksoy H, Yildiz A, Celik AV, et al. Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine. Clin Transplant 2000;14:61e5. [3] Sever MS, Yildiz A, Eraksoy H, Badur S, Yuksel-Onel D, Gorcin B, et al. Immune response to Haemophilus influenzae type B vaccination in renal transplant recipients with well-functioning allografts. Nephron 1999;81:55e9. [4] Keshtkar-Jahromi M, Argani H, Rahnavardi M, Mirchi E, Atabak S, Tara SA, et al. Antibody response to influenza immunization in kidney transplant recipients receiving either azathioprine or mycophenolate: a controlled trial. Am J Nephrol 2008;28: 654e60. [5] Sanchez-Fructuoso AI, Prats D, Naranjo P, FernándezPérez C, González MJ, Mariano A, et al. Influenza virus immunization effectivity in kidney transplant patients subjected to two different triple-drug therapy immunosuppression protocols: mycophenolate versus azathioprine. Transplantation 2000;69:436e40. [6] Wiebe C, Nickerson P. Posttransplant monitoring of de novo human leukocyte antigen donor-specific antibodies in kidney transplantation. Curr Opin Organ Transplant 2013;18:470e7. [7] Ginevri F, Nocera A, Comoli P, Innocente A, Cioni M, Parodi A, et al. Posttransplant de novo donor-specific HLA antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection. Am J Transplant 2012;12:3355e62. [8] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9:1e155. [9] Tait BD, Susal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013;95:19e47.