The Pennsylvania State University. The Graduate School. College of Medicine THE INFLUENCE OF INDUCTION THERAPY AND DIABETES ON

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1 The Pennsylvania State University The Graduate School College of Medicine THE INFLUENCE OF INDUCTION THERAPY AND DIABETES ON GRAFT FAILURE AFTER KIDNEY TRANSPLANT A Thesis in Public Health Sciences by Hosam A. Farag 2016 Hosam A. Farag Submitted in Partial Fulfillment of the Requirements for the Degree Master of Science May 2016

2 ii The thesis of Hosam A. Farag was reviewed and approved* by the following: Nasrollah Ghahramani Associate Professor of Medicine and Public Health Sciences Thesis Co-Advisor Christopher S. Hollenbeak Professor of Surgery and Public Health Sciences Thesis Co-Advisor Kristen Kjerulff Professor of Public Health Sciences Director, Master of Science in Public Health Sciences Program * Signatures are on file in the Graduate School

3 iii ABSTRACT Background: Induction therapy plays a significant role in reducing the rate of acute rejection in kidney transplantation (KT). Understanding differences in outcomes associated with various induction agents may lead to improvement in long-term care. Our objective was to examine the association of various induction therapies and diabetes with the risk of graft failure and patient mortality after KT. Methods: We performed a retrospective cohort study using data from the United Network for Organ Sharing (UNOS) between 2000 and We included only kidney transplantation patients who were maintained only on tacrolimus, mycophenolate mofetil (MMF) and steroids. We had 92,829 patients who were categorized into four groups based on induction therapy: basiliximab (n=23,531), daclizumab (n=14,563), rabbit antithymocyte globulin (r-atg) (n=51,497) and alemtuzumab (n=3,238). All patients. The primary outcomes were graft failure and patient mortality. Cox proportional hazards models were used to model time to event after adjusting for patients and disease characteristics. Results: Graft failure was significantly higher in the r-atg group (HR=1.047; 95% CI, to 1.088; P= ) than the basiliximab group. However, the daclizumab group had lower risk for graft failure (HR=0.922; 95 % CI, to 0.968; P= ). Graft failure was non-significantly higher in alemtuzumab group (HR=1.099; 95% CI, to 1.216; P=0.0666). Patient death was significantly lower in the daclizumab group (HR=0.892; 95% CI, to 0.958; P=0.0018) than the basiliximab group, whereas, patient death was non-significantly higher in the r-atg group (HR=1.041; 95% CI, to 1.101; P=0.163) and the alemtuzumab group (HR=0.978; 95% CI, to 1.142; P= Diabetic status has a significant impact on graft failure and patient death. Graft failure was significantly higher in Type 2 diabetes than Type 1 and newonset diabetes while the patient death was significantly higher in Type1 diabetes than Type 2 and new-onset diabetes. Conclusion: Daclizumab has better long-term graft survival outcomes than basiliximab and antithymocyte globulin (r-atg). It also has better long-term patient survival outcomes than basiliximab. In general IL2-RA receptor antagonists group (Basiliximab and Daclizumab) have better long-term graft survival outcomes than antithymocyte globulin (r-atg) when tacrolimus, mycophenolate mofetil (MMF) and steroids were used as maintenance therapy. Type of diabetes has a significant impact on graft failure and patient death.

4 iv TABLE OF CONTENTS LIST OF TABLES...v LIST OF FIGURES...vi Chapter 1: INTRODUCTION..1 Background...1 Chapter 2: SIGNIFICANCE AND AIMS...4 Chapter 3: METHODS...5 Study Design...5 Outcomes. 6 Statistical Analysis... 7 Chapter 4: RESULTS...8 Characteristics of the Cohort Study Graft Failure.. 10 Patient Mortality...15 Chapter 5: DISCUSSION...20 REFERENCES...25

5 v LIST OF TABLES Table 1: Demographic and background characteristics of patients by Induction therapy groups Table 2: Risk of graft failure by induction therapy groups Table 3: Association of induction therapy groups, DM and patients characteristics with risk of graft failure Table 4: Risk of graft failure by diabetes status...14 Table 5: Risk of patient mortality by induction therapy groups 16 Table 6: Association of induction therapy groups, diabetes and patient characteristics with risk of patient mortality Table 7: Risk of patient mortality rate by diabetes status...19

6 vi LIST OF FIGURES Figure 1: Immunosuppressive therapy classification...3 Figure 2: Study population for each induction therapy group...6 Figure 3: Kaplan-Meier curve for graft survival stratified by induction therapy groups..11 Figure 4: Kaplan-Meier curve for graft survival stratified by diabetes status...14 Figure 5: Kaplan-Meier curve for patient survival stratified by induction therapy groups...16 Figure 6: Kaplan-Meier curve for patient survival stratified by diabetes status...19

7 1 Chapter 1 INTRODUCTION Background Renal transplantation is the treatment of choice for most patients with end-stage renal disease. A successful kidney transplant offers significant improvements in quality of life and survival relative to long-term dialysis therapy. [1] Immunosuppressive therapy plays a significant role in kidney transplantation to reduce the rate of acute rejection, maintain graft function and prevent graft loss. Immunosuppressive therapy typically comprises multiple medications that act on different targets of the immune system but the optimal combinations of immunosuppressive therapy remains controversial. Immunosuppressive therapies are categorized as induction and maintenance therapies (Figure 1). Induction therapy is used perioperatively to prevent acute rejection, [2] which is a strong predictor of long-term graft survival after kidney transplantation. [3] Induction therapy may consist of lymphocyte-depleting antibodies such as (thymoglobin (r-atg) and alemtuzumab) and non-depleting antibodies (interleukin-2 receptor antagonists) such as (basiliximab and daclizumab). Maintenance therapy is used lifelong to maintain graft function and prevent graft loss. It may consist of calcineurin inhibitors (tacrolimus and cyclosporine), nucleotide synthesis inhibitors ( mycophenolate mofetil and azathioprine ), target-of-rapamycin inhibitors (sirolimus), and steroids.

8 2 Studying mechanisms, side effects, and outcomes of induction agents may lead to improvement in long-term care. Basiliximab and daclizumab are humanized monoclonal interleukin-2 receptor antagonists (IL2-RAs) (or anti-cd25). IL2-RAs bind to the alphachain of the interleukin-2 receptor (IL2 -R) and prevent the formation of the IL-2 binding site, which is important for T cell activation. [4, 5] Inhibition of T cells by IL2-RAs could interrupt the cascade of cell activation and proliferation. [6] IL2-RAs are safer than other available induction antibodies, [7, 8] but they still have some risk of adverse effects like hypersensitivity reactions, [7, 9] infections, [10] and malignancies. [11] Rabbit antithymocyte globulin (r-atg) is a polyclonal gamma immunoglobulin derived from the immunization of rabbits with human thymocytes. The main adverse side effects associated with r-atg are fever, chills, gastrointestinal distress, [10, 12] severe [12, 13] cytomegalovirus (CMV) infections, and serious reactions, such as cytokine release. [11] Alemtuzumab is a humanized monoclonal antibody against the kda cell surface glycoproteins CD52. [14] Main adverse side effects are anaphylactic shock, low incidence of malignancy, [15] infection, [16] and immune thrombocytopenia (ITP). [17]

9 3 Induction therapy Depleting antibodies Thymoglobulin (r-atg) Alemtuzumab (campath) Non-depleting antibodies (IL2-RA) Basiliximab (simulect ) Daclizumab (zenapax) Kidney Transplante Maintenance therapy Calcineurin inhibitors (tacrolimus and cyclosporine) Nucleotide inhibitors (MMF and azathioprine) Rapamycin (sirolimus) Glucorticorticoids Figure 1: Immunosuppressive therapy classification New-onset diabetes after transplantation (NODAT) is a frequent metabolic complication after renal transplantation. It occurs mainly during the first 6 months post transplantation, when patients are treated with high doses of immunosuppressive therapy. Calcineurin inhibitors CNIs (e.g. tacrolimus) are diabetogenic by inducing a defect in insulin secretion by interfering with the nuclear factor of activated T-cell signaling in pancreatic β-cells. [18] Hypomagnesaemia induced by CNIs was found to be an [19, 20] independent predictor of NODAT in renal transplant.

10 4 Chapter 2 SIGNIFICANCE AND AIMS Understanding differences in outcomes associated with various induction agents may lead to improvement in long-term care. Our objectives were to examine the association of various induction therapies and diabetes with the risk of graft failure and patient mortality after kidney transplant (KT).

11 5 Chapter 3 METHODS Study Design The study was a retrospective cohort study using data from the United Network for Organ Sharing (UNOS) between 2000 and Inclusion criteria were as follows: (1) only kidney transplant patients; (2) patients maintained only on combination of tacrolimus, mycophenolate mofetil (MMF) and steroids for lifelong use; (3) recipients of basiliximab, daclizumab, antithymocyte globulins (r-atg) or alemtuzumab as induction therapy. A total of 92,829 patients were included in the final analysis. The study population was divided into four groups based on the induction therapy (Figure 2): Group (1) received basiliximab, tacrolimus, mycophenolate mofetil (MMF) and steroids (n=23,531); Group (2) received daclizumab, tacrolimus, mycophenolate mofetil (MMF) and steroids (n=14,563); Group (3) received antithymocyte globulins (r- ATG), tacrolimus, mycophenolate mofetil (MMF) and steroids (n=51,497); Group (4) received alemtuzumab, tacrolimus, mycophenolate mofetil (MMF) and steroids (n=3,238).

12 6 Outcomes The main outcomes were the risk of graft failure and patient mortality. Graft failure was defined as a re-transplant, dialysis or death following a transplant. New-onset of diabetes after transplant (NODAT) was defined as having random glucose levels greater than 200 mg/dl, fasting glucose levels greater than 140 mg/dl, or the need for insulin or oral hypoglycemic agents in the post-transplant period. Figure 2: Study population for each induction therapy group

13 7 Statistical Analysis Survival rates were estimated using the Kaplan-Meier curve. Log-rank tests were used to compare unadjusted survival curves. Cox proportional hazards models were used to estimate the hazard ratio for induction therapy groups after controlling for recipient demographics. P values <0.05 were considered statistically significant. Analyses were performed using SAS version 9.3.

14 8 Chapter 4 RESULTS Characteristics of the Cohort Study Patients characteristics stratified by induction therapy groups are presented in Table 1. IL2-RAs groups (basiliximab and daclizumab) were used more in low risk patients; no diabetes, no and low HLA mismatch, no and low peak reactive antibodies (PRA), no pre-transplant dialysis and normal BMI while the lymphocyte depleting groups (r-atg and alemtuzumab) were used in high risk patients. The recipients of Alemtuzumab were more likely to have Type 1 (>29%) and Type 2 (46%) diabetes, were more likely to develop new- onset diabetes (>12%), were more likely to be sensitized (PRA >22%), and were more likely to be obese (>29%) compared with the other three induction groups. The recipients of r-atg were more likely to receive higher HLA- mismatch kidneys (medium > 48% and high >13%) and were more likely to have pretransplantation dialysis (>83%) compared with the other three induction groups.

15 9 Patients Characteristics Group 1 Basiliximab + Tacrolimus MMF Steroids Group 2 Daclizumab + Tacrolimus MMF Steroids Group 3 r-atg + Tacrolimus MMF Steroids Group 4 Alemtuzumab + Tacrolimus MMF Steroids Diabetes Non-diabetic 75.13% 79.50% 73.22% 11.24% status Type 1 DM 3.99% 4.02% 4.81% 29.77% Type 2 DM 15.55% 12.08% 16.87% 46.20% New-onset DM 5.34% 4.40% 5.09% 12.79% HLA No mismatch 9.64% 9.65% 9.12% 11.24% Mismatch Low 33.77% 33.94% 28.31% 29.77% Medium 44.06% 43.82% 48.70% 46.20% High 12.53% 12.59% 13.87% 12.79% Peak No PRA 57.31% 59.08% 41.78% 29.93% Reactive Low 25.66% 21.97% 20.02% 18.56% Antibody Medium 12.29% 12.57% 22% 28.94% (PRA) High 4.75% 6.39% 16.20% 22.58% Pre-transplant No Dialysis 20.59% 20.07% 16.32% 18.10% dialysis Dialysis 79.41% 79.93% 83.68% 81.90% BMI Normal weight 42.58% 46.34% 38.66% 40.74% Overweight 30.59% 30.67% 32.40% 28.63% Obesity 25.47% 22.01% 27.10% 29.15% Extreme obesity 1.36% 0.99% 1.84% 1.48% Sex Female 36.93% 38.55% 43.21% 47.16% Male 63.07% 61.45% 56.79% 52.84% Race White 55.49% 52.72% 50.16% 49.04% African American 19.69% 22.80% 29.54% 28.78% Hispanic 17.58% 15.97% 13.10% 16.15% Asian 5.14% 5.77% 5.45% 4.35% Indian/Alaska 0.92% 1.36% 0.79% 1.20% Other 1.18% 1.37% 0.97% 0.46% Age <18 years old 11.16% 11.22% 4.20% 2.87% years old 24.11% 27.08% 26.05% 28.72% years old 42.32% 44.16% 49.85% 50.49% >60 years old 22.41% 17.54% 19.91% 17.91% Table 1: Demographic and background characteristics of patients by induction therapy groups.

16 10 Graft Failure Induction Therapy Kaplan-Meier curves for graft survival were significantly different across induction therapies (Figure 3). Overall graft failure risk was statistically significantly higher with r-atg, but no difference with alemtuzumab and significantly lower with daclizumab compared to basiliximab group. The risk of graft failure by induction therapy groups is presented in Table 2. Recipients who received the r-atg therapy had a significantly higher rate of graft failure (HR=1.05; 95% CI, to 1.088; P= ) compared with the basiliximab group while the recipients who received daclizumab therapy had a significantly lower rate of graft failure (HR=0.92; 95 % CI, to 0.968; P= ) compared with the basiliximab group. There was no significant difference between alemtuzumab group (HR=1.10; 95% CI, to 1.216; P=0.0666) and the basiliximab group Table 3. African American race, male sex, obesity, older age (>60 years old), younger age (<18 years old), pre-transplant dialysis, high HLA mismatch and high peak reactive antibodies were significant risk factors for graft failure in patients after kidney transplant, independent of induction therapy.

17 11 Figure 3: Kaplan-Meir curve for graft survival stratified by induction therapy groups Years Group (1) Group (2) Group (3) Group (4) Basiliximab Daclizumab r-atg Alemtuzumab % 4% 6.50% 7.30% % 1.70% 2.60% 3.20% % 4% 5.10% 6% % 7% 8.60% 9.70% % 10.80% 12.50% 12.30% Table 2: Risk of graft failure by induction therapy groups

18 12 Parameter Class Pr > Chi Hazard 95% Hazard Ratio Confidence Sq Ratio Limits Group 2 Daclizumab (Tacrolimus+MMF+Steroids) Group 3 Antithymocyte globulin (Tacrolimus+MMF+Steroids) Group 4 Alemtuzumab (Tacrolimus+MMF+Steroids) Diabetes Type 1 DM < status Type 2 DM < New-onset DM < HLA Low Mismatch Medium < High < Panel Low Reactive Medium < Antibodies High < Dialysis Pre-transplant dialysis < BMI Overweight Obesity < Extreme Obesity Sex Female < Race African American < Hispanic < Asian < America Indian/Alaska Other Age <18 years old < years old < >60 years old < Table 3: Association of induction therapy groups, DM and patients characteristics with risk of graft failure.

19 13 Diabetes Kaplan-Meier curves for graft survival were significantly different by diabetes status (Figure 4). Overall graft failure risk was statistically significantly higher with Type 2 and type 1 diabetes and new-onset of diabetes compared to non-diabetes status. The risk of graft failure by diabetes status is presented in Table 4. Diabetic status of kidney transplant patients was a significant risk factor for graft loss. Type 2 diabetes patients (HR=1.48; 95% CI, to 1.545; P< ), Type 1 diabetes patients (HR=1.42; 95% CI, to 1.527; P< ) and patients with newonset diabetes (HR=1.16; 95% CI, to 1.232; P< ) had a significantly higher rate of graft failure compared to non-diabetes patients Table 3.

20 14 Figure 4: Kaplan-Meier curve for graft survival stratified by diabetes status Years Non-diabetes Type 1 DM Type 2 DM New-onset DM % 8.40% 8.60% 6.30% % 2.90% 3% 2.70% % 5.60% 6% 5.70% % 8.90% 10.60% 9.10% 5 11% 12.90% 16.50% 13.40% Table 4: Risk of graft failure by diabetes status

21 15 Patient Mortality Induction Therapy Kaplan-Meier curves for patient survival were significantly different across induction therapies (Figure 5). The patient survival curves were significantly different across induction therapies. Overall the risk of mortality rate was statistically significantly lower with daclizumab, but no difference between alemtuzumab group and r-atg group when they were compared to basiliximab group. The risk of mortality rate by induction therapy groups is presented in Table 5. Recipients who received daclizumab therapy had a significantly lower mortality rate (HR=0.89; 95% CI, to 0.958; P= ) compared with the basiliximab group. The r- ATG group (HR=1.041; 95% CI, to 1.101; P= ) and alemtuzumab group (HR=0.978; 95% CI, to 1.142; P= ) were not risk factors for patient death Table 6. White race, male gender, obesity, older age (>60 years old), younger age (<18 years old), pre-transplant dialysis, high HLA mismatch and high peak reactive antibodies were significant risk factors for patient death after kidney transplant, independent of induction therapy.

22 16 Figure 5: Kaplan-Meier curve for patient survival stratified by induction therapy groups Years Group (1) Group (2) Group (3) Group (4) Basiliximab Daclizumab r-atg Alemtuzumab % 0.14% 0.21% 0.10% % 0.77% 1.08% 1.05% % 1.70% 2.30% 2.60% % 2.90% 4% 4.20% % 4.80% 5.70% 5.63% Table 5: Risk of patient mortality by induction therapy groups

23 17 Parameter Class Pr > Chi Hazard 95% Hazard Ratio Confidence Sq Ratio Limits Daclizumab Group 2 (Tacrolimus+MMF+Steroids) Antithymocyte globulin Group 3 (Tacrolimus+MMF+Steroids) Alemtuzumab Group 4 (Tacrolimus+MMF+Steroids) Diabetes Type 1 DM < status Type 2 DM < New-onset DM < HLA Low Mismatch Medium High Panel Low Reactive Medium < Antibodies High < Dialysis Pre-transplant dialysis < BMI Overweight Obesity Extreme Obesity Sex Female < Race African American Hispanic < Asian < America Indian/Alaska Other Age <18 years old < years old < >60 years old < Table 6: Association of induction therapy groups, DM and patients characteristics with risk of patient mortality.

24 18 Diabetes Kaplan Meier curves for patient survival were significantly different by diabetes status (Figure 6). Overall the risk of mortality rate was statistically significantly higher with Type 1 and Type 2 diabetes and new-onset of diabetes compared to non-diabetes status. The risk of mortality rate by diabetic status is presented in Table 7. Diabetic status of kidney transplant patients was a significant risk factor for patient death. Type 1 diabetes patients (HR=2.20; 95% CI, to 2.419; P< ), Type 2 diabetes patients (HR=1.87; 95% CI, to 1.978; P< ) and patients with new-onset diabetes (HR=1.34; 95% CI, to 1.457; P< ) had a significantly higher risk of mortality rate compared to non-diabetes patients Table 6.

25 19 Figure 6: Kaplan-Meier curve for patient survival stratified by diabetes status Years Non-diabetes Type 1 DM Type 2 DM New-onset DM % 0.33% 0.40% 0.26% % 1.90% 1.86% 1.53% % 3.80% 4% 2.80% % 6% 7.30% 4.30% 5 4% 8.30% 11.60% 6.70% Table 7: Risk of patient mortality by diabetes status

26 20 Chapter 5 DISCUSSION The study compares the association of IL2-RA group (basiliximab and daclizumab) and lymphocyte depleting antibodies group (r-atg and alemtuzumab ) with five-year graft failure and patient mortality when used in conjunction with triple maintenance therapy comprising tacrolimus, mycophenolate mofetil and steroids. Kaplan Meier curves for graft survival by induction therapy show that daclizumab group has highest graft survival while alemtuzumab group has lowest graft survival (Figure 3). Kaplan Meier curves for patient survival by induction therapy show that daclizumab group and basiliximab group have higher patient survival than alemtuzumab group and r-atg group (Figure 6). The results support that the IL2-RA group have better long-term graft and patient survival outcomes. However, characteristics of the patients by induction therapy groups in Table 1 showed that IL2-RA group was used more frequently in low-risk patients to reduce the incidence of acute rejection without much adverse effects while lymphocyte depleting group was used more frequently in high-risk patients, although it increases the risk of infection and malignancy. We need to differentiate between the effect of IL2-RA group on the graft failure and the frequency of using IL2-RA in low risk patients.

27 21 Mourad et al. performed a randomized clinical trial [21] to compare antithymocyte globulin r-atg to basiliximab in low immunologic risk kidney transplant patients receiving cyclosporine, mycophenolate mofetil and steroids. Graft survival and patient survival were similar in r-atg and basiliximab groups. This trial also reported significantly higher rates of cytomegalovirus infection with r-atg compared with IL2- RA. Induction therapy with a lymphocyte-depleting antibody group increased the risk of infections and malignancies compared to the IL2-RA group. IL2- RAs are safer than [7, 8] other available induction antibodies. Brennan et al. performed a randomized clinical trial, [22] of antithymocyte globulin r- ATG compared with basiliximab in high immunologic risk kidney transplant patients receiving cyclosporine, mycophenolate mofetil and steroids. The antithymocyte globulin group, as compared with the basiliximab group, had lower incidences of acute rejection. The antithymocyte globulin group and the basiliximab group had similar incidences of graft loss and death. Patients receiving antithymocyte globulin had a greater incidence of infection. Noel et al. performed a randomized clinical trial [23] comparing antithymocyte globulin r-atg with daclizumab in high immunologic risk kidney transplant patients receiving tacrolimus, mycophenolate mofetil and steroids. Antithymocyte globulin r- ATG was superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.

28 22 Alemtuzumab group has smallest sample size (n=3,238) compared to the other [16, 17] groups because it has more side effects, has higher graft failure, [24] used more in high risk patients Table 1. Long-term outcomes might be inferior with alemtuzumab compared with conventional induction treatment. [24] Clinical use of alemtuzumab might be severely limited. The recipients of Alemtuzumab were more likely to develop new-onset diabetes compared to the other groups Table 1 although the four groups received tacrolimus and steroids which are considered to be diabetogenic maintenance therapy. [24, 25] Types of diabetes have significant impacts on graft failure after kidney transplantation. Type 2 diabetes (48%), Type 1 diabetes (42%) and new-onset diabetes (16%) have higher risk for graft failure compared to non-diabetes status Table 3. Kaplan Meier curves for graft survival by diabetes status shows that Type 2 diabetes has lowest graft survival (Figure 4). Types of diabetes have significant impacts on patient death after kidney transplantation. Type 1 diabetes (more than two times), Type 1 diabetes (42%) and newonset diabetes (16%) have higher risk for patient death compared to non-diabetes status Table 6. Kaplan Meier curves for patient survival by diabetes status shows that Type 1 diabetes has lowest patient survival (Figure 6).

29 23 The strength of this study includes the large sample size to detect small differences in the outcome. Multiple transplantation centers potentially make the data more generalizable. Minimizing the differences in the groups by having the same lifelong maintenance therapy powers our study. Limitations of study are inherent to retrospective studies using registry data including coding and typing errors, lack of data and underreporting new events like new-onset diabetes. Lack of maintenance therapy doses and through levels in UNOS database may produce bias.

30 24 CONCLUSION In this study, the IL2-RA group had better long-term graft survival and patient survival compared to lymphocyte depleting antibodies group. Using IL2-RA group in low risk patients might play a significant role to have better long-term graft survival and patient survival outcomes. The chances of a favorable balance between benefits and harm could be maximized by limiting the use of lymphocyte depleting agents to patients at increased risk for acute rejection. Type of diabetes has a significant impact on graft failure and patient death.

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