Delayed Immunosuppression Withdrawal Preserves Nonsensitization Status after Kidney Transplant Failure

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Delayed Immunosuppression Withdrawal Preserves Nonsensitization Status after Kidney Transplant Failure
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english
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Casey, Michael Jin
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University of Florida
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Master's ( M.S.)
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University of Florida
Degree Disciplines:
Medical Sciences, Clinical Investigation (IDP)
Committee Chair:
Nelson, David R
Committee Members:
Segal, Mark S
Scornik, Juan C

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immunosuppression -- kidney -- sensitization -- transplant -- withdrawal
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
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Abstract:
When kidney transplants fail, transplant medications are stopped to reduce risks associated with immunosuppression. However, retransplantation candidates are at high risk for sensitization which delayed immunosuppression withdrawal may minimize. We hypothesize that for patients with graft failure referred for retransplantation, delayed immunosuppression withdrawal preserves nonsensitization (PRA 0%) better than early immunosuppression withdrawal.   We retrospectively examined subjects transplanted at a single center between Aug. 1999 and Jan. 2011 with non-death related graft loss. Subjects were stratified by time to immunosuppression withdrawal after graft loss: >3 months, 1-3 months, and less than or equal to 1 month. Retransplant candidates were eligible for the main study where the primary outcome was nonsensitization at retransplantation evaluation. Subjects not referred for retransplantation were included in the safety analysis.   We found 102 patients, with 49 eligible for the main study. Nonsensitization rates at retransplantation evaluation were 66%, 38%, and 25% for immunosuppression withdrawal >3 months, 1-3 months, and less than or equal to 1 month respectively (p = 0.041).  After adjusting for cofactors such as blood transfusion and allograft nephrectomy, immunosuppression withdrawal >3 months remained significant for nonsensitization (adjusted odds ratio=5.09, 95% C.I. 1.09-23.72). Mortality and infection-related death were not associated with delayed immunosuppression withdrawal in the main study group or total study population.   In this study, delayed immunosuppression withdrawal appears safe as a strategy to minimize sensitization in low risk retransplantation candidates. No adverse safety signals were seen, but further investigation with larger sample size is needed.
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Statement of Responsibility:
by Michael Jin Casey.
Thesis:
Thesis (M.S.)--University of Florida, 2012.
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Adviser: Nelson, David R.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-06-30

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1 DELAYED IMMUNOSUPPRESSION WITHDRAWAL PRESERVES NONSENSITIZATION STATUS AFTER KIDNEY TRANSPLANT FAILURE By MICHAEL JIN CASEY A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF T HE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2012

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2 2012 Michael Jin Casey

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3 numerous late nights

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4 ACKNOWLEDGMENTS I would like to thank my mentor Dr. Herwig Ulf Meier Kriesche who fully supported my decision to enroll in the Advanced Postgraduate Program in Clinical Investigation. I would like to thank Dr. Juan Scornik and Dr. Mark Segal for their invaluable advice and Dr. David Nels on for chairing my thesis committee. I would like to express my gratitude to Xuerong Wen not only for her exceptional statistical support, but also for her countless hours of study collaboration. I would like to express my appreciation to Dr. Marian Limach er who granted me the opportunity to enroll in the Advanced Postgraduate Program in Clinical Investigation and Eve Johnson for always keeping me on task throughout my graduate studies. Finally, I would like to give special thanks my lovely wife Hana and my dear children Nayeon and Rowan for tolerating the numerous hours I have spent cloistered away in my office working towards my degree. This work supported in part by the NIH/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR 000064.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST OF FIGURES ................................ ................................ ................................ .......... 7 ABSTRACT ................................ ................................ ................................ ..................... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 10 2 METHODS ................................ ................................ ................................ .............. 12 Study Participants ................................ ................................ ................................ ... 12 Study Outcomes ................................ ................................ ................................ ..... 12 Statistic al Analysis ................................ ................................ ................................ .. 13 HLA Antibody Detection ................................ ................................ .......................... 14 3 RESULTS ................................ ................................ ................................ ............... 15 Efficacy Outcomes for Delayed Immunosuppressi on Withdrawal ........................... 15 Nonsensitization after Graft Failure ................................ ................................ .. 15 PRA after Graft Failure ................................ ................................ ..................... 16 Relisting and Retransplantation ................................ ................................ ........ 17 Safety Outcomes for D elayed Immunosuppression Withdrawal ............................. 17 Subjects Referred for Retransplantation (Main Study Group) .......................... 17 Subjects Not Referred for Retransplantation (Safety Analysis Only Group) ..... 18 All Subjects (Main Study Group and Safety Analysis Only Group) ................... 19 4 DISCUSSION AND CONCLUSION ................................ ................................ ........ 30 Efficacy of Delayed Immunosuppression Withdrawal ................................ ............. 30 Safety of Delayed Immunosuppression Withdrawal ................................ ................ 31 Generalizability ................................ ................................ ................................ ....... 33 Study Strengths ................................ ................................ ................................ ...... 34 Study Limitations ................................ ................................ ................................ .... 34 Conclusion ................................ ................................ ................................ .............. 35 L IST OF REFERENCES ................................ ................................ ............................... 36 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 39

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6 LIS T OF TABLES Table page 3 1 Baseline characteristics for subjects referred for retransplantation evaluation ... 20 3 2 Adju sted odds ratios for nonsensitization after transplant failure ........................ 21 3 3 ................................ ................................ ..... 21 3 4 Three year mortali ty stratified by immunosuppression withdrawal duration in the main study group ................................ ................................ .......................... 22 3 5 Baseline characteristics for all patients with kidney transplant failure ................. 22 3 6 Time dependent Cox model for 3 year mortality in subjects not referred for retransplantation ................................ ................................ ................................ 23 3 7 Time dependent Cox model for 3 year infection related mortality in subjects not referred for retransplantation ................................ ................................ ........ 23 3 8 Time dependent Cox model for 3 year mortality in all subjects .......................... 24 3 9 Time dependent Cox model for 3 year infection related mortality in all subjects ................................ ................................ ................................ .............. 25

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7 LIST OF FIGURES Figure page 3 1 Subject categorization. ................................ ................................ ....................... 26 3 2 Nonsensitization stratified by immunosuppression withdrawal duration ............. 27 3 3 Multivariate analysis of nonsensitization after transplant failure ......................... 27 3 4 Mean PRA stratified by immunosuppression withdrawal duration ...................... 28 3 5 Three year infection free surviva l stratified by immunosuppression withdrawal duration ................................ ................................ ................................ .............. 28 3 6 Three year survival in patients referred versus non referred for kidney retransplantation ................................ ................................ ................................ 29

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8 Abs tract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science DELAYED IMMUNOSUPPRESSION WITHDRAWAL PRESERVES NONSENSITIZATION STATUS AFTER KIDNE Y TRANSPLANT FAILURE By Michael Jin Casey December 2012 Chair: David R. Nelson Major: Master of Science Clinical and Translational Science When kidney transplants fail, transplant medications are stopped to reduce risks associated with immunosuppres sion. However, retransplantation candidates are at high risk for sensitization which delayed i mmunosuppression withdrawal may minimize. We hypothesize that for patients with graft failure referred for retransplantation, delayed immunosuppression withdrawal preserves nonsensitization (PRA 0%) better than early immunosuppression withdrawal. We retrospectively examined subjects transpla nted at a single center between Aug 1999 and Jan 2011 with non death related graft loss. Subjects were stratified by time t o immunosuppression withdrawal after graft loss: >3 months, 1 3 months, month. Retransplant candidates were eligible for the main study where the primary outcome was nonsensitization at retransplantation evaluation. Subjects not referred for retransplantation were included in the safety analysis. We found 102 patients with 49 eligible for the main study. Nonsensitization rates at retransplantation evaluation were 66%, 38%, and 25% for immunosuppression withdrawal >3 months, 1 3 months, p = 0.041 ) After

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9 adjusting for cofactors such as blood t ransfusion and allograft nephrectomy, immunosuppression withdrawal >3 months remained significant for nonsensitization ( adjusted odds ratio =5.09, 95% C.I. [1.09 23.72]). Mortality and infection related de ath were not associated with delayed immunosuppressi on withdrawal in the main study group or total study population. In this study, delayed immunosuppression withdrawal appears safe as a strategy to minimize sensitization in low risk retransplantation candidates. No adverse safety signals were seen, but fu rther investigation with larger sample size is needed.

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10 CHAPTER 1 INTRODUCTION It is well known that kidney transplantation is life sparing for patients with end stage kidney disease (ESRD) who are on the waiting list 1 3 Projected lifetime almost doubles after deceased donor kidney transplantation compared with remaining on the waitlist. 4 rises again. 5 6 In addition, an increased risk of sepsis and infection related deaths are seen after transplant failure compared to patients who retain transplant function 5,7 Yet, retransplantation with a subsequent kidney transplant is associated with a significant reduction in mortality when compared with their wait listed counterparts w ith pri or transplant failure 8 A growing number of patients with a failed kidney transplant are relisted for a subsequent kidney transplant. United States registry data show that approximately 20% of all ESRD patients on the kidney transplant waiting list have a prior failed transplant. 9 However, transplanting these patients in a timely manner is challenging because prior solid organ transplantation is a risk factor for human leukocyte antigen (HLA) sensitization which may limit the availability of compati ble organs and prolong transplant waitlist time. 10 Prior studies have shown that transplant nephrectomy is a risk factor for sensitization 11 13 In fact, kidney transplant failure itself carries a high risk of sensitization and is probably related to sever al factors such as sudden immunosuppression cessation, transplant nephrectomies, and blood transfusions. 14 When kidney transplants fail, transplant medications are commonly stopped to reduce the risks associated with immunosuppression, namely infection an d premature death. 15 16 However, when to withdraw immunosuppression is still an unanswered

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11 question. Potential benefits of delayed immu nosuppression withdrawal include rejection risk reduction, allograft nephrectomy risk reduction, and preserva tion of re sidual renal function 17 18 but another more intriguing benefit may be minimizing the risk of sensitization that may occur soon after kidney transplant failure 14 By minimizing the risk of sensitization, patients with a failed kidney transplant may have a greater chance at receiving a subsequent life sparing kidney transplant. We hypothesize that in patients with kidney transplant failure who were referre d for retransplantation, delaying the withdrawal of immunosuppression medications reduces the risk of se nsitization compared to early immunosuppression withdrawal. In addition, we evaluate whether delayed immunosuppression withdrawal is associated with significant a dditional risk compared to early immunosuppression withdrawal especially in potential retrans plant candidates.

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12 CHAPTER 2 METHODS The study utilized data from the Organ Transplant Tracking Record (OTTR) and the electronic medical record system at the Shands Transplant Center at the University of Florida. The OTTR database was developed to docume nt and store patient demographic and clinical characteristics, laboratory test results, status of referral, listing, transplant, complications, graft failure, and death. The study protocol was approved by the University of Florida Institutional Review Boar d. Study Participants A retrospective cohort study was conducted. The study participants consisted of adult kidney transplant recipients transplanted between August 1999 and January 2011 who experienced non death related graft failure. Subjects were analy zed by time to immunosuppression withdrawal after kidney transplant failure and they were divided into 3 months, and >3 months. Immunosuppression withdrawal was defined as the point when all noncorticosteroid immunosuppressan t drugs were stopped. Subjects who were subsequently evaluated for kidney retransplantation were eligible for the main study group. Subjects not evaluated for subsequent kidney retransplantation were analyzed only for safety endpoints. Study Outcome s The primary outcome was rate of nonsensitization among subjects evaluated for retransplantation (main study group) Nonsensitization was defined as a panel reactive antibody (PRA) level of 0%. We chose to study nonsensitization (PRA = 0%) because it wa s an un ambiguous endpoint where there wa s a clear distinction between subjects with and without HLA alloantibodies. This simplified endpoint removed any speculation

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13 associated with trying to assign relative importance to different degrees of PRA change. Also the outcome of nonsensitization was probably less biased by the different lab techniques used to determine PRA over time. Prior to primary transplant, the peak PRA was used to determine whether a patient was nonsensitized (PRA=0%) or sensitized (PRA>0%). After graft failure, the PRA at the time of retransplant evaluation was used. Secondary outco mes from the main study group were PRA level at the time of evaluation for retransplantation, 3 year relisting rate, and 3 year retransplantation rate All sub jects whether evaluated or not evaluated for retransplantation were studied for the safety outcomes 3 year mortality 3 year infection related mortality and 3 year infection free survival (time to first infection). Date of graft failure served as the star ting point for all reported 3 year outcomes. Potential covariates for nonsensitization include donor type (deceased v. living donor), recipient age at the time of graft failure, black race, gender, diabetes as cause of end stage renal disease, nonsensitiz ation status prior to primary kidney transplant, HLA mismatch, induction with a lymphocyte depleting agent, acute rejection, primary graft survival length, duration from graft failure to re evaluation PRA, transplant nephrectomy, and blood transfusion Acu te rejection was defined as a biopsy confirmed cellular rejection Banff 1A or higher or biopsy confirmed antibody mediated rejection. Statistical Analysis Continuous variables were compared using F test for more than two comparison groups. Categorical var iables were analyzed using chi sq uare test or Fisher Exact Test Multivariate logistic regression analysis was employed to identify the significant risk factors for nonsensitization at the time of evaluation for retransplantation. Multivariate time depende nt Cox model was utilized to assess time to events adjusting for

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14 immunosuppression withdrawal time. In the multivariate models, rates of event occurrence in the patients with immunosuppression withdrawal >3 months and 1 3 months were compared with those of <1 month (baseline), respectively. All statistical analyses were conducted with SAS 9.2 (Cary, NC). H LA Antibody Detection Throughout the entire study, HLA antibodies were screened (antibody positive or negative) by solid phase assay (ELISA, Luminex scre en and/or Flow PRA). PRA was determined by cytotoxicity (years 1999 2006) or by calculated PRA using single antigen beads (years 2006 2012). All antibody tests were performed by solid phase assays using commercial reagents for enzyme immunoassay and flow c ytometry. The tests used to measure HLA antibodies were enzyme immunoassay (GTI, Waukesha, WI), Luminex screen, Flow PRA and single antigen beads (One Lambda, Canoga Park, CA). For the latter test, raw median fluorescence intensity values > 1,000 were cons idered positive and values of 1,000 to 3,000 were considered positive but acceptable for potential donors carrying the target antigen. Donor specificity was assigned for antibodies to HLA A, B, C, DR, and DQ.

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15 CHAPTER 3 RESULTS Out of 1651 kidney tran splants performed between August 1999 and January 2011, 102 subjects were identified as having non death related graft failure. Forty nine subjects were subsequently evaluated for kidney retransplantation and eligible for the main study group. Of the main study participants, 12, 8, and 29 subjects had their immunosuppression withdrawn after graft failure 3 months, and > 3 months respectively (Figure 3 1). Delayed immunosuppression withdrawal after graft failure was seen in subjects with resi dual renal function and those with an anticipated short waitlist time. In the >3 months immunosuppression withdrawal group, the median duration of prolonged immunosuppression was 11.9 months [range 3.8 49.7] after graft failure. Five patients (17%) in the > 3 months immunosuppression withdrawal group maintained their immunosuppression due to a functioning non renal solid org an transplant Baseline char acteristics including blood transfusion, allograft nephrectomy, and acute rejection were statistically simi lar among all three immunosuppression withdrawal groups (Table 3 1). Early graft losses made up a substantial portion of the main study group such that the median duration of primary graft survival was 19 months with no significant differences between the immunosuppression withdrawal groups (Table 3 1). Efficacy Outcomes for Delayed Immunosuppression Withdrawal Nonsensitization after Graft Failure Prior to initial kidney transplantation, similar rates of nonsensitized subjects were observed in the three i mmunosuppression withdrawal groups. However after transplant failure, notable reductions in nonsensitized subjects (increased sensitization rates) were

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16 3 months immunosuppression withdrawal groups, while only a mild reduction w as seen in the > 3 month immunosuppression withdrawal group. Consequently, a statistically significant separation in nonsensitization rates after transplant failure developed between these groups, p = 0.041 (Figure 3 2). Of subjects who converted from nons ensitized prior to primary graft placement to sensitized, 20% had testing for HLA antibodies at the time of graft failure and none had detectable antibodies at that time. After adjusting for covariates including nonsensitization prior to kidney transpla ntation, the multivariate logistic regression model showed that the > 3 months immunosuppression withdrawal group continued to have better preservation of group (adjusted odds r atio [aOR]=5.09 [95% C.I. 1.09 23.72]). No benefit was seen in the 1 immunosuppression withdrawal group (aOR=0.58 [95% C.I. 0.07 4.99]). None of the other model covariates such as blood transfusion or graft nephrectomy were significantly associated with nonsensitization after transplant failure (Figure 3 3, Table 3 2 ). PRA after Graft Failure PRA values (meanstandard deviation) at the time of retransplant evaluation in 3 months, and > 3 months immunosuppression withdrawal groups were 39 10 45 17, and 175 respectively ( p = 0.045), and the change in mean PRA respectively (Figure 3 4). A mu ltivariate linear regression model showed that the >3 month immunosuppression withdrawal group had a smaller rise in to

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17 p = 0.056 3 months immunosup pression withdrawal groups ( p = 0.36). Other model covariates recipient gender, induction with a lymphocyte depleting agent, acute rejection, graft nephrectomy, and blood transfusion were not sign ificantly associated 3). Relisting and R etransplantation 3 months, and > 3 months immunosuppression withdrawal groups were 75%, 25%, and 76% respectively. 3 months, and > 3 months immuno suppression withdrawal groups were 25%, 0%, and 48% respectively. The 1 3 months immunosuppression withdrawal group had a significantly smaller rate of relisted subjects ( p = 0.031) and no subjects were retransplanted. After excluding the 1 3 month immunosu ppression group, a trend toward more retransplantations was seen with the > immunosuppression withdrawal group ( p = 0.17). Similar rates of retransplantation with living donor kidneys wer e seen 33% versus 29% months immunosuppression withdrawal groups, respectively. Safety Outcomes for Delayed Immunosuppression Withdrawal Subjects Referred for Retransplantation (Main Study Group) In subjects referred for retr ansplantation, the 3 year mortality rate in the main 3 months, and > 3 months immunosuppression withdrawal groups, were 1 (8.3%), 4 (50%), and 2 (6.9%) respectively (Table 3 4) Only one subject died from an infection related cause and another subject died from malignancy (chronic myelogenous

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18 leukemia) B oth subjects were from the 1 3 months immunosuppression withdrawal group. Cardiovascular events were the most common cause of death occurring in 3 out of 7 subjects. Due to the low number of death events, no meaningful statistical conclusion was derived from mortality and delayed immunosuppression withdrawal. However, a multivariate time dependent Cox model found no difference i n infection free patient survival (time to first infection) between all three immunosuppression withdrawal groups, p = 0.61 (Figure 3 5). Excluding nonmelanoma skin cancers, only one malignancy was diagnosed and was mentioned previously. Subjects Not Refe rred for Retransplantation (Safety Analysis Only Group) The 53 subjects who were not referred for retransplantation (safety analysis only) were an average of nine years older th an the main study group (Table 3 5 ). The 3 year mortality rate was 51% (27/53 s ubjects) with a majority of deaths occurring within a year after graft failure. Half of these deaths (13/27 subjects) were infection related. In this group, both patient mortality and infection related mortality were significantly higher compared to the ma in study group (Figure 3 6). In subjects not referred for retransplantation, there were 16, 16, and 21 subjects in 3 months, and > 3 months immunosuppression withdrawal groups respectively. Multivariate time dependent Cox models showed that the 1 3 months and > 3 months immunosuppression withdrawal groups were not associate d with increased death ( p = 0.60 and p = 0.84 respectively) or i nfection related death ( p = 0.57 and p = 0.31 respectively) compared to the < 1 month immunosuppression withdrawal group (Tables 3 6 and 3 7) Also, delayed immunosuppression withdrawal was not associated with shorter t ime to first infection. Excluding subjects with nonmelanoma skin cancers, three subjects were diagnosed with malignancies (renal cell carcinoma, melanoma, and

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19 subjects with mal ignancy were in the > 3 months immunosuppression withdrawal group. All Subjects (Main Study Group and Safety Analysis Only Group) Similarly, a combined safety analysis was performed for all 102 subjects who were evaluated for retransplantation (main study group) and not evaluated for retransplantation (safety analysis only group) For the combined safety analysis, m ultivariate time d ependent Cox models showed that the 1 3 months and >3 months delayed immunosuppression withdrawal groups were not associated with increased death ( p = 0.27 and p = 0.58 respectively) or infection related death ( p = 0.53 and p = 0.26 respectively) when compared to the group (Table s 3 8 and 3 9). Not surprisingly, subjects not referred for ret ransplantation were at greater risk for death (aOR=2.9, 95% C.I. [1.16 7.48]) and infection related death (aOR=10.3, 95% C.I. [1.23 85.7]). Comparable to earlier results, delayed immunosuppression withdrawal was not associated with a shorter time to first infection in the combined safety analysis.

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20 Table 3 1 Baseline c haracteristics for s ubjects r eferred for r etransplantation e valuation Baseline c haracteristics All p atients n = 49 IS w ithdrawal n = 12 IS w ithdrawal 1~3 months n = 8 IS w ithdrawal > 3 months n = 29 p v alue Age at g raft f ailure, y.o., m ean SD 43 14 43 13 42 10 43 15 0.9931 Female g ender, n (%) 20 (41) 8 (67) 3 (38) 9 (31) 0.1203 Black r ace, n (%) 15 (31) 3 (25) 3 (38) 9 (31) 0.9419 ESRD d iabetes, n (%) 6 (16) 3 (27) 1 (20) 2 (10) 0.3688 Deceased d onor, n (%) 41 (84) 9 (75) 8 (100) 24 (83) 0.4118 Nonsensitized p rior to 1 o g raft, n (%) 35 (71) 7 (58) 5 (63) 23 (79) 0.3305 m ismatches, n (%) 33 (77) 9 (82) 6 (75) 18 (75) >0.999 Induction m edicine lymphocyte d epleting a gent, n (%) 12 (24) 5 (42) 1 (13) 6 (21) 0.3342 Acute r ejection, n (%) 14 (29) 3 (25) 2 (25) 9 (31) >0.999 1 o Graft s urvival, months, m edian [25%, 75% q uartil e ] 19 [5, 49] 19 [7, 51] 26 [9, 46] 14 [3, 49] 0.3546 Blood t ransfusion r ecipient, n (%) 17 (35) 4 (33) 5 (63) 8 (28) 0.1789 N ephrectomy after graft f ailure, n (%) 18 (49) 4 (36) 3 (60) 11 (52) 0.6465 IS=immuno suppression. HLA= h uman leukoc yte ant igen

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21 Table 3 2 Adjusted o dds r atios for n onsensitization after t ransplant f ailure Effect Adjusted o dds r atio 95% c onfidence l imit p value Lower limit Upper limit IS w ithdrawal, 1 0.58 0.067 4.989 0.618 IS w ithdrawal, > 5.09 1.090 23.719 0.038* Induction, LDA v o ther 0.19 0.028 1.336 0.095 Female r ecipient 0.29 0.064 1.307 0.107 PRA prior to 1 o g raft, PRA=0 v PRA>0 1.37 0.331 5.666 0.665 Acute r ejection 0.30 0.056 1.611 0.160 Allograft n ephrect omy 0.57 0.124 2.631 0.473 Blood t ransfusion 2.83 0.499 16.058 0.240 IS= i mmunosuppression. LDA= l ymphocyte depleting agent. PRA= p anel r eactive a ntibody p value < 0.05 Table 3 3. Linear r egression m Parameter e stimate Standard e rror p v alue IS w ithdrawal 1~3 m m onth n/a n/a 0.358 IS w ithdrawal >3 m m onth n/a n/a 0.056 Induction, LDA v o ther 17.4 12.3 0.165 Female r ecipient 6.2 11 0 0.574 Acute r ejection 13. 2 10.9 0.235 Allograft n ephrectomy 2. 4 10.2 0.817 Blood t ransfusion 15.1 11.0 0.17 7 o graft to after graft failure IS= i mmunosuppression. LDA= l ymphocyte depleting agent. n/a=not applicable

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22 Table 3 4 Three y ear m ortality s tratified by i mmunosuppression w ithdrawal d uration in the m ain s tudy g roup IS w ithdrawal g roup Number of d eaths Cause of d eath m onth ( n =1 2) 1 CVD 1~3 m onths ( n = 8) 4 CVD (2 subjects) CML s epsis >3 m onths ( n = 29) 2 Abdominal b leed r enal f ailure IS= i mmunosuppression. CVD= c ardi ovascular disease. CML= c hronic m yelogenous l eukemia Table 3 5 Baseline c haracteristics for a ll p atients with k idney t ransplant f ailure Characteristics All p atients ( n = 102) Referred for RTX ( n = 49) Not r eferred for RTX ( n = 53) p value Age at g raft f ailure, m ean Yrs SD 47 14 43 14 52 14 0.0012 Female g ender, n (%) 39 (39) 20 (41) 19 (38) 0.7743 Black r ace, n (%) 35 (35) 15 (31) 20 (40) 0.5449 Diabetes as 1 o c ause of ESRD, n (%) 8 (10) 6 (16) 2 (5) 0.1376 No nsensitized p rior to 1 o g raft, n (%) 73 (72) 35 (71) 38 (72) 0.9759 Deceased d onor, n (%) 83 (84) 41 (84) 42 (84) 0.9648 Induction t herapy l ymphocyte d epleting a gent, n (%) 26 (26) 12 (24) 14 (27) 0.7358 Acute r ejection, n (%) 34 (33) 14 (29) 20 (38) 0.3266 CMV i nfection, n (% ) 10 (10) 6 (12) 4 (8) 0.4254 BKV i nfection, n (%) 4 (4) 1 (2) 3 (6) 0.6187 1 o Graft n ephrectomy, n (%) 39 (49) 18 (49) 21 (50) 0.9046 RTX= r etransplantation

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23 Table 3 6 Time d ependent Cox m odel for 3 y ear m ortality in s ubjects n ot r eferred for r etranspl antation Parameter Adjusted o dds r atio 95% confidence i nterval p v alue Lower limit Upper limit IS w ithdrawal, 1 month 1.342 0.448 4.016 0.5991 IS w 1.138 0.319 4.060 0.8419 Diabetes as 1 o c ause of ESRD 0.504 0.059 4.337 0.5325 Allograft n ephrectomy 0.604 0.224 1.628 0.3188 Induction, LDA v o ther 2.268 0.696 7.391 0.1742 Black r ace r ecipient 4.934 0.410 59.323 0.2084 Acute r ejection 1.463 0.526 4.073 0.4661 Female r ecipient 1.030 0.368 2.884 0.9546 Deceased d onor 0.501 0.123 2.036 0.3338 Nonsensitized prior to 1 o g raft 1.997 0.694 5.744 0.1996 IS= i mmunosuppression. ESRD= e nd s tage r enal d isease. LDA= lymphocyte depleting agent Table 3 7 Time d ependent Cox m odel for 3 y ear infection r elated m ortal ity in s ubjects n ot r eferred for r etransplantation Parameter Adjusted o dds r atio 95% c onfidence i nterval p v alue Lower limit Upper limit IS w ithdrawal, 1 1.554 0.335 7.203 0.5732 IS w 0.348 0.046 2.644 0.3075 Diabetes as 1 o c ause of ESRD 0.203 0.015 2.803 0.2342 Allograft n ephrectomy 1.731 0.427 7.012 0.4422 Induction, LDA v o ther 2.776 0.470 16.391 0.2598 Black r ace r ecipient n/a n/a n/a 0.9983 Acute r ejection 4.010 0.909 17.702 0.0667 Fema le r ecipient 0.717 0.139 3.705 0.6918 Deceased d onor 0.697 0.128 3.800 0.6763 Nonsensitized prior to 1 o g raft n/a n/a n/a 0.9951 IS= i mmunosuppression. ESRD= e nd s tage r enal d isease. LDA= l ymphocyte depl eting agent. n/a=not applicable

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24 Table 3 8 Time d epe ndent Cox m odel for 3 y ear m ortality in a ll s ubjects Parameter Adjusted o dds r atio 95% c onfidence i nterval p v alue Lower limit Upper limit IS w ithdrawal, 1 month 1.768 0.643 4.859 0.2695 IS w month 1.361 0.458 4.042 0.5793 Not r eferred for r etransplantation 2.944 1.159 7.476 0.0231 Diabetes as 1 o c ause of ESRD 1.300 0.355 4.766 0.6920 Allograft n ephrectomy 0.524 0.226 1.217 0.1327 Induction, LDA v o ther 1.902 0.749 4.832 0.1763 Black r ace r ecipient 2.302 0.955 5.549 0.0634 Acute r ejection 1.406 0.640 3.087 0.3964 Female r ecipient 1.419 0.620 3.247 0.4073 Deceased d onor 0.555 0.145 2.134 0.3918 Nonsensitized prior to 1 o g raft 1.695 0.685 4.192 0.2535 IS=i mmunosuppression. ESRD= e nd s tage r enal disease. LDA=lymphocyte depleting agent p value < 0.05

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25 Table 3 9. Time d ependent C ox m odel for 3 year i nfection r elated m ortality in a ll s ubjects Parameter Adjusted o dds r atio 95% confidence i nterval p v alue Lower limit Upper limit IS w ithdrawal, 1 3 months v month 1.560 0.395 6.167 0.5260 IS w month 0.343 0.053 2.243 0.2644 Not r eferred for r etransplantation 10.272 1.231 85.714 0.0314 Diabetes as 1 o c ause of ESRD 0.648 0.101 4.156 0.6469 Allograft n ephrectomy 1.489 0.444 4.9 91 0.5193 Induction, LDA v o ther 1.796 0.397 8.127 0.4470 Black r ace r ecipient 1.449 0.397 5.287 0.5747 Acute r ejection 2.754 0.754 10.054 0.1253 Female r ecipient 1.011 0.262 3.898 0.9876 Deceased d onor 0.778 0.150 4.046 0.7651 Nonsensitized prior t o 1 o g raft n/a n/a n/a 0.9923 IS= i mmunosuppression. ESRD= e nd s tage r enal d isease. LDA= l ymphocyte depleting agent. n/a=not applicable p value < 0.05

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26 Figure 3 1 Subject categorization IS=immunosuppression

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27 Figure 3 2 Non sensitization s tratified by i mmunosuppression w ithdrawal d uration IS= i mmunosuppression Figure 3 3. Multivariate a nalysis of n onsensitization after t ransplant f ailure IS= i mmunosuppression. LDA= l ymphocyte depleting agent

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28 Fi gure 3 4. Mean PRA stratified by i mmunosuppression w ithdrawal d uration IS= i mmunosuppression Figure 3 5 Three year i nfection f ree s urvival stratified by i mmuno suppression withdrawal duration (d eath censored )

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29 Figure 3 6. Three y ear s urvival in p atients r eferred versus n on referred for k idney r etransplantation A) Overall p atient s urviva l, B) Survival from i nfection related death A. B.

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30 CHAPTER 4 DISCUSSION AND CONCLUSION E fficacy of Delayed Immunosuppression Withdrawal Our study address es the question of whether a strategy of delayed nonsensitization status. We chose to study nonsensitizatio n (PRA = 0%) as the primary outcome because it is an unambiguous endpoint where there is a clear distinction between subjects with and without HLA alloantibodies. Since less sensitized patients are more likely to be transplanted sooner 10,19 preserving a status is a crucial component of care for those who hope to be retransplanted in the future. In addition, nonsensitized patients have the clinical advantages of decreased risk for acute rejection, better graft function, and incre ased patient and graft survival compared to sensitized patients 20 21 In stepwise fashion, our study found that longer durations of immunosuppression withdrawal were associated with greater nonsensitization preservation after graft failure. After adjusting for other potential risk factors in the multivariate model, this phenomenon persisted in the > 3 months immunosuppression withdrawal group compared to the rapid immunosuppression withdrawal group. Our results are consistent with recent single center studies that have suggested that immunosuppression withdrawal after transplant failure may be a risk factor for the emergence of HLA antibodies and sensitiz ation 14,22 In a previous small study from our transplant center 14 23% of patients who did not undergo transplant nephrectomy developed antibodies, and 39% of patients who were not transfused became sensitized. However, 11 patients continued on immunosup pression and remained nonsensitized

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31 despite 7 who underwent transplant nephrectomy o r were transfused 14 In a single center study by Augustine and colleagues 22 24 subjects who continued their immunosuppression after kidney graft failure (mainly due to a functioning pancreas transplant) were compared with subjects who had their immunosuppression weaned after graft failure. They observed that weaning of immunosuppression was associated with sensitization independent of transplant nephrectomy, but their stud y was limited by the absence of blood transfusion data a significant risk factor for sensitization and the absence of safety data on infection related outcomes 22 Similar to first time kidney transplant recipients, retransplantation confers a significant survival benefit to patients who returned to dialysis after primary graft failure 3,8 In our study, we identified a trend towards more retransplantations in the > 3 group warr anting further investigation with larger samples. However, it is important to note that retransplantation rates observed in our single center study may not be generalizable due to the varied waiting times in regional retransplantation rates. In our 1 3 mon ths immunosuppression withdrawal group, no retransplantations were observed probably because this group was less healthy than the other groups, as evidenced by a significantly lower percentage of relisted subjects. Safety of Delayed Immunosuppression With drawal After transplant failure, infection is the second leading cause of death 23 and the risks of sepsis and infection related death are significantly higher compared to subjects with a functioning transplant 5,7 Prior authors have suggested that signif icant risk was associated with continuing immunosuppression after transplant failure and that immunosuppression should be tapered off as quickly as feasible 15,24 O ther authors

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32 have a dvocated a more gradual withdrawal to immunosuppression after noting few infection rela ted complications 17 In other words, there is no consensus on the optimal duration of immunosuppression withdrawal after graft failure 16,25 A unique feature of this study is that we independently studied subjects with graft failure who were subsequently evaluated for retransplantation (main study group). This is an important distinction from prior studies because we selected a cohort that was probably healthier and better suited to handle the additional risks of prolonged immunosuppression c ompared to the general dialysis population with transplant failure. It is easy to understand why many clinicians are wary of delaying immunosuppression withdrawal when rates of death and infection related complications are high after transplant failure 5,7 ,15 However, our study showed lower rates of death and infection related death in the main study group when compared to subjects not referred for retransplantation. Therefore not all patients with graft failure may be equally susceptible to the risks of de layed immunosuppression withdrawal and further exploration of this subgroup is needed. The other aim of this study wa s to examine the risk associated with delayed immunosuppression withdrawal that could impact patient survival. In our study, no obvious sa fety signals were observed in the main study group to suggest that delayed immunosuppression withdrawal was overtly hazardous, but we were unable to draw any conclusions about patient death and infection related death due to few event numbers. W e were how ever, able to study time to first infection (infection free survival) and found no difference between the three immunosuppression withdrawal groups in patients referred for retransplantation.

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33 The safety analysis for the subjects not referred for retranspl antation showed higher rates of patient death and infection related death compared to the main study group. These findings were not surprising since these subjects were older and probably less healthy. Interestingly, our multivariate models did not show th at delayed immunosuppression withdrawal was associated with patient death or infection related death in subjects not referred for transplantation (safety analysis only group) and in the total study population (main study group + safety analysis only group) Our results differ from the study results of Smak Gregoor and colleagues who saw increased mortality er graft failure. 15 However, our study was adjusted for time bias using a time dep endent Cox model. Yet Given the known risks of increased mortality and infection after transplant failure 5,7 it would be premature to declare that delayed immunosuppressio n withdrawal is uniformly safe so further investigation with larger sample size is warranted. inception, a prospective study of this nature would not have been ethical because we knew that prolonged immunosuppression can be harm ful and there was scant evidence for benefit. However, with these and other data, a prospective trial may be more realistic in the future. Generalizability In our single center study, generalizability is an important issue and our mortality rates appeared to be in line with other publications. In subjects not referred for retransplantation (safety analysis only), the 51% three year mortality rate was almost identical to the mortality rate in incident United States dialysis patients 26 Also, mortality rate s in the main study group, safety analysis only group, and the combined groups

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34 (102 subjects) were comparable to those seen in a prior large United States registry study of patients with failed kidney transplants 8 Study Strengths There are several streng ths to our study which also address some of the shortcomings from prior studies. First, our study has the largest cohort of patients on prolonged immunosuppression after transplant failure available for PRA analysis (29 subjects) and safety analysis (50 su bjects). Second, it is a clinica l based observational study where outcome, exposure, and covariates were ascertained using medical records. Third, unlike prior studies, we address the issue of optimal timing for immunosuppression withdrawal by comparing ef ficacy and safety outcomes across different durations of immunosuppression withd rawal after graft failure. Fourth important potential confounders in the PRA analysis such as acute rejection 27 induction medication 28 HLA matching 10,29 graft nephrectomy 11,30 and blood transfusions 31 35 are analyzed and controlled for in the multivar iate models. Finally, we provide a more detailed safety analysis of delayed immunosuppression withdrawal including infection related outcomes when compared to prior studies. We believe these strengths allow for the most wide ranging analysis of the risks and benefits of delayed immunosuppression withdrawal to date. Study Limitations Our study is subjected to the inherent limitations of a retrospective cohort study design whe re associations can be made but causality cannot be assigned However as mentioned previously, a prospective study would have not been ethical due to the lack of prior safety data for delayed immunosuppression withdrawal. Limited sample size may cause insu fficient power and an inconclusive death analysis in this study h owever

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35 significant differences in nonsensitization rates among different immunosuppression withdrawal groups were identified out of the small study cohort, which drives the results more cons ervative. Residual confounders may exist from unmeasurable events such as community instead of the hospital lab and may not have been captured by the study. Finally, we were no t able to investigate the effects of different immunosuppression regimens or the order of drug withdrawal. C onclusion In this study, the strategy of delayed immunosuppression withdrawal appears to preserve nonsensitization status in patients with renal graft failure referred for retransplantation. In addition, we observed other potential benefits with this strategy such a s lower mean PRA scores and a trend toward more retransplantations. Patient death, infection related death, and other safety signals were not associated delayed immunosuppression withdrawal in subjects referred for retransplantation (main study group) as w ell as subjects not referred for retransplantation (safety analysis only group) and the combined study population. However, further investigation with larger sample size is required for further verification. In summary, delayed immunosuppression withdrawa l appears safe as a strategy to minimize sensitization in low risk retransplantation candidates such as those who anticipate a short stay on the waitlist or those with live donors.

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36 L IST OF REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341(23):1725 30. 2. Ojo AO, Hanson JA, Meier Kriesche H, Okechukwu CN, Wolfe RA, Leichtman AB, Agodoa LY, Kaplan B, Port FK. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait li sted transplant candidates. J Am Soc Nephrol. 2001; 12:589 97 3. Meier Kriesche HU, Sc hold JD, Srinivas TR, Reed A, Kaplan B. Kidney transplantation halts cardiovascular disease progression in patients with end stage renal disease. Am J Transplant 2004;4:1662 1668. 4. Danovitch, GM ed. Handbook of Kidney Transplantation. 4 th ed. Philadelphi a, PA, USA: Lippincott Williams & Wilkins;2005, pp 19 20. 5. Kaplan B, Meier Kriesche HU. Death after graft loss: an important late study endpoint in kidney transplantation. Am J Transplant. 2002; 2: 970 974 6. Knoll G, Muirhead N, Trpeski L, Zhu N, Bado vinac K. Patient survival following renal transplant failure in Canada. Am J Transplant. 2005; 5(7): 1719 1724. 7. Johnston O, Zalunardo N, Rose C, Gill JS. Prevention of Sepsis during the Transition to Dialysis May Improve the Survival of Transplant Fail ure Patients. J Am Soc Nephrol 18: 1331 1337, 2007. 8. Ojo A, Wolfe RA, Agodoa LY, Held PJ, Port FK, Leavey SF, Callard SE, Dickinson DM, Schmouder RL, Leichtman AB. Prognosis after primary renal transplant failure and the beneficial effects of repeat tran splantation: multivariate analyses from the United States Renal Data System. Transplantation 1998;66(12):1651 9. 9. U.S. Renal Data System, USRDS 2011 Annual Data Report: Atlas of End Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2011. Table E.3. 10. Meier Kriesche HU, Scornik JC, Susskind B, Rehman S, Schold JD. A lifetime versus a graft life approach redefines the importance of HLA matching in kidne y transplant patients. Transplantation. 2009;88(1):23 9. 11. Adeyi OA, Girnita AL, Howe J, Marrari M, Awadalla Y, Askar M, Martell J, Zeevi A, Shapiro R, Nalesnik M, Randhawa P, Demetris AJ, Duquesnoy RJ. Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches. Transpl Immunol. 2005;14(1):53 62.

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37 12. Sumrani N, Delaney V, Hong JH, Daskalakis P, Sommer BG. The influence of nephrectomy of the primary allograft on retranspl ant graft outcome in the cyclosporine era. Transplantation 1992;53(1):52 5. 13. Khakhar AK, Shahinian VB, House AA, Muirhead N, Hollomby DJ, Leckie SH, McAlister VC, Chin JL, Jevnikar AM, Luke PP. The impact of allograft nephrectomy on percent panel reacti ve antibody and clinical outcome. Transplant Proc. 2003;35(2):862 3. 14. Scornik, JC; Meier Kriesche, H U. Human leukocyte antigen sensitization after transplant loss: timing of antibody detection and implications for prevention. Human Immunology 2011;72:3 98 401. 15. Smak Gregoor PJH, Zietse R, van Saase JLCM, op de Hoek CT, IJzermans JNM, Lavrijssen ATJ, de Jong GMTh, Kramer P, Weimar W. Immunosuppression should be stopped in patients with renal allograft failure. Clin Transplant 2001: 15: 397 401. 16. Ke ndrick EA, Davis CL. Managing the failing allograft. Semin Dial. 2005 Nov Dec;18(6):529 39. 17. Morales A, Gavela E, Kanter J, Beltrn S Sancho A, Escudero V, Crespo J, Pallard LM. Treatment of Renal Transplant Failure. Transplantation Proceedings 2008; 40, 2909 2911. 18. Jassal SV, Lok CE, Walele A, Bargman JM. Continued transplant immunosuppression may prolong survival after return to peritoneal dialysis: results of a decision analysis. Am J Kidney Dis. 2002;40(1):178 83. 19. Organ Procurement and Tran splantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN / SRTR 2010 Annual Data Report. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Divisi on of Transplantation; 2011: Table 5.2. 20. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL, Bray RA, Gebel HM, Matas AJ. Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant. 2011;1 1(10):2132 43. 21. Barama A, Oza U, Panek R, Belitsky P, MacDonald AS, Lawen J, McAlister V, Kiberd B. Effect of recipient sensitization (peak PRA) on graft outcome in haploidentical living related kidney transplants. Clin Transplant. 2000;14(3):212 7. 22. Augustine JJ, Woodside KJ, Padiyar A, Sanchez EQ, Hricik DE, Schulak JA. Independent of nephrectomy, weaning of immunosuppression leads to late sensitization after kidney transplant failure. Transplantation 2012 Sep 5. [Epub ahead of print]

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38 23. Gill JS, A bichandani R, Kausz AT, Pereira BJ. Mortality after kidney transplant failure: the impact of non immunologic factors. Kidney Int. 2002 Nov;62(5):1875 83. 24. Vanrenterghem Y, Khamis S. The management of the failed renal allograft. Nephrol Dial Transplant. 1996;11(6):955 7. 25. Bennett WM. The failed renal transplant: in or out? Semin Dial. 2005 May Jun;18(3):188 9. 26. U.S. Renal Data System, USRDS 2011 Annual Data Report: Atlas of End Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2011. Volume 2, Table 5a. 27. Katznelson S, Bhaduri S, Cecka JM. Clinical aspects of sensitization. Clin Transpl. 1997:285 96. 28. Dawson KL, Patel SJ, Xu J, Knight RJ, Gaber AO. Effect of immunosuppression for first kidney or kidney/pancreas transplant on sensitization at the time of second transplant. Transplantation. 2011 Apr 15;91(7):751 6. 29. Sanfilippo F, Goeken N, Niblack G, Scornik J, Vaughn WK. The effect of first cad aver renal transplant HLA A, B match on sensitization levels and re transplant rates following graft failure. Transplantation 1987;43:240 4. 30. Billen EVA, Christians MHL, Lee J, van den Berg Loonen EM. Donor directed HLA antibodies before and after trans plantectomy detected by the Luminex single antigen assay. Transplantation 2009;87:563 9. 31. Fuller TC, Delmonico FL, Cosimi B, Huggins CE, King M, Russell PS. Impact of blood transfusion on renal transplantation. Ann Surg. 1978 Feb;187(2):211 8. 32. Scorn ik JC, Ireland J, Howard RJ, Pfaff WW, Fennell RS 3rd. Sensitization by blood transfusions in previously transplanted patients. Transplantation 1983;35:505 6. 33. Hyun J, Park KD, Yoo Y, Lee B, Han BY, Song EY, Park MH. Effects of different sensitization e vents on HLA alloimmunization in solid organ transplantation patients. Transplant Proc. 2012 Jan;44(1):222 5. 34. Scornik JC, Schold JD, Bucci M, Meier Kriesche HU. Effects of blood transfusions given after renal transplantation. Transplantation 2009;87:13 81 6. 35. Scornik JC, Brunson ME, Howard RJ, Pfaff WW. Alloimmunization, memory, and the interpretation of crossmatch results for renal transplantation. Transplantation 1992;54:389 94.

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39 BIOGRAPHICAL SKETCH Michael Casey is an assistant professor of medici College of Medicine, Department of Medicine. After completing medical school at the University of North Carolina in 2001, he trained in internal medicine at California Pacific Medical Center in San Francisco, California. S ubsequently, he completed a nephrology fellowship at Stanford University and a transplant nephrology fellowship at California Pacific Medical Center. In 2008, he joined the University of Florida as a transplant nephrologist in the Division of Nephrology, H ypertension, and Renal Transplantation. Dr. Casey has a strong interest in clinical transplant research and has presented his work at several national conferences as well as served as a co investigator on many clinical trials. In 2012, he completed a Maste r of Science in Clinical and Translational Research while a scholar in the University of Florida Program in Clinical Investigation.