Induction type and outcomes for kidney graft and patient survival in recipients with prior lung transplantation in the United States

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Induction Type and Outcomes for Kidney Graft and Patient Survival in Recipients with Prior Lung Transplantation in the United States Samy Riad MD, MS , Umesh Goswami MD , Scott Jackson MS , Marshall Hertz MD , Arthur Matas MD PII: DOI: Reference:

S1053-2498(19)31765-6 https://doi.org/10.1016/j.healun.2019.11.013 HEALUN 7042

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Journal of Heart and Lung Transplantation

Please cite this article as: Samy Riad MD, MS , Umesh Goswami MD , Scott Jackson MS , Marshall Hertz MD , Arthur Matas MD , Induction Type and Outcomes for Kidney Graft and Patient Survival in Recipients with Prior Lung Transplantation in the United States, Journal of Heart and Lung Transplantation (2019), doi: https://doi.org/10.1016/j.healun.2019.11.013

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Induction Type and Outcomes for Kidney Graft and Patient Survival in Recipients with Prior Lung Transplantation in the United States Samy Riad, MD, MS1; Umesh Goswami, MD2; Scott Jackson, MS3; Marshall Hertz, MD2; Arthur Matas, MD4 1

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Division of Renal Diseases and Hypertension, Department of Medicine; Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine; 3 Fairview Health Services, Minneapolis, MN, USA; 4Division of Transplant Surgery, Department of Surgery, University of Minnesota Corresponding Author: Samy Riad, MD, MS, Division of Renal Diseases and Hypertension, 717 Delaware Street SE, #354, Minneapolis, MN, 55414, Phone: 612-626-7319, Fax 612-626-3840 Running title: Kidney Transplant Induction in Lung Transplant Recipients Author contributions: Samy M. Riad: Concept/design, Drafting article, Critical revision of article, Approval of article Umesh Goswami: Concept/design, Data analysis/interpretation, Critical revision of article, Approval of article Scott Jackson: Data analysis/interpretation, Critical revision of article, Approval of article Marshall I. Hertz: Critical revision of article, Approval of article Arthur J. Matas: Critical revision of article, Approval of article

Abbreviations: SRTR: Scientific Registry of Transplant Recipients CNI: Calcineurin inhibitors ESRD: End Stage Kidney Disease OPTN: Organ Procurement and Transplant Network m-TOR: Mammalian Target of Rapamycin KDIGO: Kidney Disease Improving Global Outcomes SAF: Standard Analysis File

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TRFs: Transplant Recipient Follow-up work sheets HLA: Human Leukocyte Antigen DGF: delayed graft function MMF: Mycophenolate Mofetil rATG: Rabbit Thymoglobulin IL-2: Interleukin 2 LOS: Length of stay

Abstract Background: Induction immunosuppression regimens for kidney transplant in lung transplant recipients vary widely. We studied the impact of induction types for kidney-after-lung transplant recipients. Methods: Using the SRTR database between 1994 and 2015, we studied outcomes of patients and kidney grafts for 330 kidney-after-lung transplant recipients for whom induction before kidney transplant included depletional (n=115), non-depletional (n=170) or no induction (steroids only) (n=45). We studied risk factors for recipient and graft survival using Cox proportional hazards model adjusted for kidney and lung induction, kidney donor type, dialysis status, recipient and donor ages, time from lung to kidney transplant, cause of lung disease, bilateral vs. single lung transplant, diabetes and HLA mismatches before kidney transplant, with transplant center as a random effect. Results: There was no difference between groups in patient survival or death-censored kidney allograft survival. The one-year kidney acute rejection rates were 15.5 %, 7.14 % and 0% in depletional, nondepletional and no induction groups, respectively. In the Cox model for patient survival, living kidney donor recipients and bilateral lung transplant recipients were favorable predictors. For death-censored graft survival, kidney induction type did not predict graft survival. Results did not change when models only included recipients on tacrolimus and mycophenolate based maintenance.

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Conclusion: Type of kidney induction did not influence patient or kidney graft survival following kidney transplant for those with previous lung transplants. No induction may be the preferred choice for kidneyafter-lung transplant due to the lack of benefits of biologic induction in this large cohort.

Introduction: End stage kidney disease is common after non-renal solid organ transplantation and has been attributed to CNI exposure [1, 2]. Ojo et al. estimated the incidence of end stage renal disease (ESRD) at 1-1.5% per year following non-renal solid organ transplantation [1]. As survival after non-renal solid organ transplantation continues to improve, the rates of ESRD are likely to increase. The incidence of ESRD after non-renal solid organ transplantation necessitating listing for kidney transplant tripled between 1997 and 2008 [3]. Lung transplantation is a lifesaving procedure for those who are afflicted with end-stage lung disease. Renal dysfunction after lung transplant is very common, with a rate exceeding 50% by 5-years from engraftment; including nearly 4% requiring renal replacement therapy in the form of dialysis or transplant [4]. As the survival of lung transplant recipients continues to improve [5], the need for kidney transplantation in lung transplant recipients will continue to rise; and the question of best induction practice in this unique immunosuppressed cohort becomes particularly important. According to 2016 annual data report of the United States Organ Procurement and Transplant Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR)[6], 75% of lung transplant alone recipients received induction immunosuppression in the last decade. Non-depletional induction with an interleukin-2 receptor antagonist accounted for greater than 60% of induction therapy used; while T cell depleting agents were used in nearly 15% of the cases. Maintenance immunosuppression regimens after engraftment typically consist of tacrolimus, mycophenolate and steroids in over 90% of the recipients. Over the last decade, the use of cyclosporine, azathioprine and mammalian target of rapamycin (mTOR) inhibitors in lung transplantation has declined substantially. Thus, prior to kidney-after-lung

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transplantation, the majority of lung transplant recipients are maintained on triple therapy with tacrolimus, mycophenolic acid and corticosteroids. In the absence of data to inform the decision to use induction or the choice of induction regimen, the use of induction in kidney-after-lung transplant recipients varies widely between centers. The Kidney Disease Improving Global Outcome (KDIGO) guidelines recommend induction immunosuppression for de novo kidney transplant recipients [7]. However, the guidelines do not address those who are already receiving triple immunosuppression with or without previous induction. Using SRTR data, we studied outcomes of kidney induction use in lung transplant recipients on maintenance immunosuppression.

Materials and Methods: Data Source

This study used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the US, submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. All participating authors were included in the study plan and the data user agreement required by SRTR. Our institution has met all the SRTR/OPTN requirements to use the de-identified data in the standard analysis file (SAF). The transplant recipient registration (TRR) form was used to determine the immunosuppression maintenance after kidney transplantation. The six month and one-year transplant recipient follow-up worksheets (TRFs) were utilized to ascertain short-term outcomes such as length of stay, rejection and rehospitalization. Study Population

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Using the SAF file for all primary kidney transplant recipients between 1994 and 2015, we identified 429 recipients who received kidney-after-lung transplantation; recipients of other solid organs were excluded. We defined depletional induction as receiving alemtuzumab or anti-thymocyte globulin and non-depletional induction as receiving an interleukin-2 receptor blockade agent. No induction was defined as receiving steroids only without depletional or non-depletional agents. Of the 429 kidney-afterlung recipients, 29 subjects had received obsolete lung transplant procedures such as en-bloc transplant or living lobar transplant and were excluded from the analysis. Additionally, excluded were 72 subjects who received discontinued depletional agents such as Minnesota Anti-Lymphocyte Globulin (ALG) or OKT3, and unconventional induction combinations such as the use of both depletional and non-depletional or two different depletional induction agents. With the overlap between the two exclusion events, a total of 99 subjects were excluded from the analysis (Figure 1). The remaining 330 recipients were further grouped based on the type of kidney induction regimens used as depletional (n=115), non-depletional (n=170), and no induction (steroids only) (n=45) (Table 1). Also, we considered analyzing a subset of recipients (n=195) who were maintained on the contemporary regimen with tacrolimus and mycophenolate (Figure 1). Outcomes of Interest The primary outcomes of interest were patient and graft survival. Secondary outcomes were delayed graft function, one-year acute rejection, length of stay and rehospitalization. For the one-year binary outcomes of DGF, acute rejection and hospitalization, the six month and one-year transplant recipient follow-up worksheets (TRFs) were utilized. Patients were considered to have the event if either form listed “yes” to the relevant question. Patients were considered not to have the event if both forms listed “no”. In the case that both forms had a missing value, or there was one missing value and one no value, the data was considered to be missing. Statistical Analyses Patient characteristics, as well as non-survival outcomes, were compared between the three kidney induction groups using a Wilcoxon test for continuous variables, and a Chi-squared or Fisher test

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for categorical variables, when appropriate. Patient and graft survival following kidney transplant was analyzed using Kaplan-Meier curves. Cox proportional hazards regression was used for both patient survival (Table 3) and death censored kidney graft survival (Table 4) modeling with the transplant center as a random effect. We considered two sets of models for patient survival and death censored graft survival. The first set used the entire cohort while the second set was restricted to recipients who were maintained on tacrolimus and mycophenolate immunosuppression or the contemporary maintenance cohort. The models were adjusted for induction received before both kidney and lung transplant, recipient age, gender, HLA mismatches, kidney donor type, lung transplant type, DM, payor status, time from lung transplant and dialysis status. All survival outcomes were censored at ten years post-kidney transplant. Statistical analyses were performed in R, ver. 3.5.2.

Results: Baseline Characteristics of the Study Cohort The volume of transplants per year increased over time from fewer than ten per year in the 1990s to twenty or more after 2000 and remained steady thereafter. Our final cohort consisted of 330 adult primary kidney recipients with a kidney-after-lung transplant without other solid organ transplants such as pancreas, liver or heart. Of these, 115 (34.8%) received depletional induction, 170 (51.5%) received nondepletional induction, and 45 (13.6%) received no induction. The use of no induction treatment declined over the years and non-depletional induction use slightly increased over time. The use of depletional induction regimens fluctuated and did not show a definite trend (Figure 2). Recipient characteristics for the three groups are shown in (Table 1). Individuals in the no induction group were slightly younger, with a median age of 43.9 IQR [32.2- 55.3] P. value <0.001. Over 90% of recipients were Caucasians, which were equally distributed among the three groups.

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Living kidney donor transplants were less frequent in the depletional group 59.1%; compared to 72.9% and 75.6% among non-depletional and no induction groups, respectively p-value 0.026. Similarly, bilateral lung transplant procedure was observed less in the depletional group at 61.7% vs. 75.3% and 73.3% in non-depletional and no induction groups respectively p-value 0.044. Over 80% of the no induction group had not received induction before lung engraftment as compared to 69.6% and 66.5% of the depletional and non-depletional induction groups. Cystic fibrosis and emphysema accounted for the majority of lung transplantation indications. Proportion on dialysis, cold ischemia time, PRA, HLA mismatches and proportion covered by public payor were similar among all three groups (Table 1). There was no difference in patient survival by induction type (Figure 3) log rank p= 0.808. The one-year survival rate for depletional induction was 90.4% CI (85.1-95.9); non-depletional, 95.9 % CI (92.9-98.9); no induction, 95.6 % CI (89.7-100). The three-year survival rate for depletional induction was 82.3% CI (75.6-89.7); non-depletional, 82.7% CI (77.2-88.6); no induction, 84.4% CI (74.5-95.7). Death censored graft survival was also similar between groups (Figure 4) log rank p=0.653. The one-year graft survival rate for depletional group was 96.5% CI (93.1-99.9); non depletional 97.6% CI (95.3-100); no induction 97.8% CI (93.6-100). The three-year survival rate for depletional group was 92.3 % (87.2- 97.6); non-depletional 93.4% CI (89.4-97.4); no induction 95.3% CI (89.1-100). Delayed graft function occurred in (6.1%) among those who were in the depletional group; 2.4% in the non-depletional group; and 2.2% in the no induction group. The median length of hospital stay after kidney engraftment was slightly longer in the no induction group (6 days as compared to 5 days in the depletional and non-depletional induction groups p-value 0.031). Median creatinine at one year was 1.2 mg/dL and was similar in all three groups. One year after renal engraftment, acute rejection was observed in 15.5% in the depletional group, 7.14% in the non-depletional group and 0% in the no induction group, however, these differences did not reach statistical significance (Table 2). Rehospitalization during the first year was similar among all three groups.

Risk Factors for Patient Survival.

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Compared to no induction, neither depletional induction [HR 0.729, 95%CI (0.428, 1.244), P 0.246] nor non-depletional induction [HR 0.966, 95%CI (0.584, 1.596), P 0.892] was a predictor of mortality (Table 3). The results were consistent in both the full cohort and the contemporary maintenance cohort models. Living kidney donation, compared to deceased donation, was associated with a 34% lower risk of mortality [HR 0.66, 95%CI (0.459, 0.951), P 0.026]. This association remained statistically significant in the contemporary maintenance cohort model [HR 0.57, 95%CI (0.344, 0.959), P 0.034]. Similarly, bilateral lung transplant, as compared to single lung transplant, conferred a continued survival advantage following kidney transplant [HR 0.62, 95%CI (0.407, 0.948), P 0.027] in the full model, with similar association [HR 0.54, 95%CI (0.303, 0.95), P 0.033] in the contemporary maintenance cohort model. Older recipient age was associated with modestly increased risk of mortality [HR 1.03, 95% CI (1.009, 1.053) p =0.006] in the full cohort model and [HR 1.032, 95% CI (1.003, 1.062) p =0.033] in the contemporary maintenance cohort model. Longer time from lung engraftment to kidney transplantation was associated with slightly improved survival in the full cohort model [HR 0.947, 95% CI (0.898, 0.999) p =0.046] but not in the contemporary maintenance cohort model. Lung induction regimen, indication for a lung transplant, kidney HLA-mismatches, pretransplant dialysis status, public payor status, and recipients DM status were not predictors of patient survival in either of the models.

Risk factors for Death Censored Kidney Graft Survival Kidney induction type did not influence death censored graft survival (Table 4). The lack of influence was consistent in the full cohort model as well as the contemporary maintenance model. On the other hand, depletional induction used prior to lung engraftment was associated with better kidney graft survival [HR 0.189, 95% CI (0.044, 0.816), p 0.026] although this association was not significant in the contemporary maintenance cohort model [HR 0.159, 95% CI (0.019, 1.307), p 0.087]. Each HLA mismatch was associated with a 23% increased risk of death-censored graft loss [HR 1.23, 95% CI (1.014, 1.486), p 0.035]. This association remained significant in the contemporary maintenance cohort

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model. Being on dialysis before transplantation, living donor status, bilateral lung transplant, public payor, lung transplant indication, and recipient DM status were not predictors of death-censored kidney graft survival in either of the models.

Discussion: As the survival of lung transplant recipients continues to improve, the incidence of end stage renal disease requiring dialysis or renal transplantation continues to rise [8]. For non-renal transplant recipients who need renal replacement therapy, a kidney transplant is associated with better survival than dialysis. Cassuto and colleagues reported that kidney transplant after lung was associated with a

53% lower mortality as compared to remaining on the waitlist [9]. When lung transplant recipients present for kidney transplants, they are already on maintenance immunosuppressive therapy and typically with functioning allografts. The vast majority of lung transplant recipients are maintained on triple therapy with tacrolimus, mycophenolic acid and prednisone. Being on triple immunosuppression maintenance modulates the T-cell responses to antigen presentation, as evidenced by the functioning lung allograft and the majority of recipients having a PRA of zero percent (Table 1). KDIGO recommendations [7] do not address induction for kidney transplants in recipients with functioning non-renal solid organ transplants. Previous analyses from smaller retrospective cohorts [10, 11] of single-center experience, as well as earlier OPTN database analysis [12] have indicated no prominent role or possibly worse outcome associated with kidney induction in non-renal transplant recipients. However, these analyses did not focus on determinants of outcome in kidney-after-lung transplant recipients. We found that when compared with no induction at the time of kidney transplant, induction therapy with either depletional or non-depletional induction agents did not improve patient or kidney graft survival. Besides, there was no difference between groups in delayed graft function, acute rejection rate, and 1-year median creatinine value. Although rejection was not observed in the no induction group, the difference did not reach

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statistical significance. Nonetheless, this finding is thought-provoking. It is possible that induction use associated complications, such as infections and cytopenia, can lead to immunosuppression reduction resulting in rejection. Similar to primary kidney transplants in the general population[13], we found that the use of living donor kidneys in kidney-after-lung transplant recipients was associated with significantly improved survival when compared with deceased donor kidneys. This association remained significant even after adjusting for being on dialysis status; also remained consistent in both multivariate models. As compared to single lung transplants, bilateral lung transplants have been associated with better long-term survival[14, 15]. This association continued after a kidney transplant. Whether to decide on bilateral vs. single in anticipation of needing a subsequent kidney transplant is beyond the scope of our analysis. Lung depletional induction effect on death censored kidney graft survival is intriguing. Especially, with the median time for receiving a kidney after lung was around seven years. However, the association did not hold in those who were maintained on contemporary immunosuppression regimen with mycophenolate and tacrolimus. The impact of depletional induction in lung alone transplants is controversial. Hachem et al. had found improved survival of bilateral lung transplant recipients but more incidence of bronchiolitis obliterans in association with depletional induction as compared to no induction[16]. In our study, whether those who received lung depletional induction had a more balanced post lung engraftment course positioning them for better outcomes after kidney transplant versus being healthier candidates to start with, is not apparent in our data. Comparable to HLA mismatched in kidney transplant alone[17], each kidney HLA mismatch in kidney-after-lung transplant recipients was associated with a 23% increased risk for allograft loss. Waiting for a better kidney match may be justifiable; although we were not able to assess the impact of dialysis duration on kidney or patient survival, which is a limitation in this study. Biologic induction is expensive. James and Mannon have summarized the cost of different biologic induction therapies [18]. They reported that the wholesale price for a depletional induction

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course (6mg/kg) of rabbit Thymoglobulin in a 70 kg individual is ~ US$13,756, whereas the cost of nondepletional induction with basiliximab is ~ US$6500. In comparison, the cost of 1 gram of solumedrol is ~US$60. In addition to increased cost, all biologic inductions have been associated with an increased risk of opportunistic fungal and viral infections after transplantation[19, 20]. Polyclonal depletional induction agents have been linked to PTLD more than non-depletional agents [21, 22]. In the light of the seemingly non-influential role of biologic induction, prior to kidney transplant, on kidney allografts and recipient’s survival in kidney-after-lung transplant recipients, providers should reconsider the use of biologic induction in this particular group due to the unnecessary increased risks of infections, possibly PTLD and the unjustifiable cost associated with biologic induction. Strength and Limitation: To date, this is the largest study of primary kidney transplants after lung transplantation. However, our study is affected by several limitations: Unmeasured confounders could not be fully accounted for due to the retrospective nature of this study. Also, there was variability in center reporting patterns leading to missing induction, immunosuppression maintenance and rejection data. The lack of granular follow-up data on infection and post-transplant lymphoproliferative disorders did not allow us to include these outcomes in our analysis. The untracked immunosuppression level of exposure data (i.e., measured drug levels) restricted the analysis to account for maintenance immunosuppression intensity. Additionally, the data file only includes medication regimens at the time of discharge; therefore, subsequent medication changes cannot be accounted for in our analysis. Finally, given the number of recipients in each group, we may not have enough power to detect a significant difference in outcomes of patient or graft survival.

Conclusions: In this cohort of kidney-after-lung transplant recipients, induction therapy did not influence the outcome of patients or allograft survival. Kidney transplants from living donors portend survival benefits in lung transplant recipients as compared to deceased donors. Transplant providers are encouraged to

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balance the risks of infection, malignancies and cost against the lack of benefits of biologic inductions in this unique population on maintenance immunosuppression. Disclosure Statement: The authors have no conflict of interest to disclose. Acknowledgments: We want to acknowledge both the University of Minnesota department of medicine for providing the funds to acquire the SRTR standard analysis file and the Fairview Health Services for providing the statistical support needed for this project. Special thanks to Alyson Coleman, a project specialist at the division of nephrology and hypertension for her editorial support. Disclaimer: The data reported here have been supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government.

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Reference: 1.

Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10):931-940.

2.

Moreno JM, Cuervas-Mons V, Rubio E, et al. Chronic renal dysfunction after liver transplantation in adult patients: prevalence, risk factors, and impact on mortality. Transplant Proc. 2003;35(5):1907-1908.

3.

Srinivas TR, Stephany BR, Budev M, et al. An emerging population: kidney transplant candidates who are placed on the waiting list after liver, heart, and lung transplantation. Clin J Am Soc Nephrol. 2010;5(10):1881-1886.

4.

Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Official Adult Heart Transplant Report--2013; focus theme: age. J Heart Lung Transplant. 2013;32(10):951-964.

5.

Thabut G, Mal H. Outcomes after lung transplantation. J Thorac Dis. 2017;9(8):2684-2691.

6.

Valapour M, Lehr CJ, Skeans MA, et al. OPTN/SRTR 2016 Annual Data Report: Lung. Am J Transplant. 2018;18 Suppl 1:363-433.

7.

Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299-311.

8.

Lonze BE, Warren DS, Stewart ZA, et al. Kidney transplantation in previous heart or lung recipients. Am J Transplant. 2009;9(3):578-585.

9.

Cassuto JR, Reese PP, Sonnad S, et al. Wait list death and survival benefit of kidney transplantation among nonrenal transplant recipients. Am J Transplant. 2010;10(11):2502-2511.

10.

Sood P, Gao X, Mehta R, et al. Kidney Transplant Outcomes After Primary, Repeat and Kidney After Nonrenal Solid Organ Transplantation: A Single-Center Experience. Transplantation direct. 2016;2(6):e75.

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11.

Mai HL, Treilhaud M, Ben-Arye SL, et al. Poor Patient and Graft Outcome After Induction Treatment by Antithymocyte Globulin in Recipients of a Kidney Graft After Nonrenal Organ Transplantation. Transplantation direct. 2018;4(4):e357.

12.

Cassuto JR, Levine MH, Reese PP, et al. The influence of induction therapy for kidney transplantation after a non-renal transplant. Clin J Am Soc Nephrol. 2012;7(1):158-166.

13.

Matas AJ, Payne WD, Sutherland DE, et al. 2,500 living donor kidney transplants: a single-center experience. Ann Surg. 2001;234(2):149-164.

14.

Puri V, Patterson GA, Meyers BF. Single versus bilateral lung transplantation: do guidelines exist? Thorac Surg Clin. 2015;25(1):47-54.

15.

Chambers DC, Yusen RD, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant. 2017;36(10):1047-1059.

16.

Hachem RR, Edwards LB, Yusen RD, Chakinala MM, Alexander Patterson G, Trulock EP. The impact of induction on survival after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry. Clin Transplant. 2008;22(5):603-608.

17.

Wissing KM, Fomegne G, Broeders N, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with antiinterleukin-2 receptor antibodies. Transplantation. 2008;85(3):411-416.

18.

James A, Mannon RB. The Cost of Transplant Immunosuppressant Therapy: Is This Sustainable? Curr Transplant Rep. 2015;2(2):113-121.

19.

Thomusch O, Wiesener M, Opgenoorth M, et al. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. Lancet. 2016;388(10063):3006-3016.

20.

Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909-1919.

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21.

Opelz G, Naujokat C, Daniel V, Terness P, Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation. 2006;81(9):1227-1233.

22.

Kirk AD, Cherikh WS, Ring M, et al. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant. 2007;7(11):2619-2625.

Figure Legends: Table 1. Baseline Characteristics by Induction Received (N (%) or Median [IQR]) Table 2. Univariate Outcomes by Induction Type (N (%) or Median [IQR] Table 3. Multivariate Cox Proportional Hazards for Survival Table 4. Multivariate Cox Proportional Hazards for Death Censored Kidney Graft Survival Figure 1. Study Population Figure 2. Volumes of Kidneys after Lung and Inductions Pattern Figure 3. Patient Survival by Kidney Induction Type Figure 4. Kidney Death Censored Graft Survival by Kidney Induction Type

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Figure 1. Study Population

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Figure 2. Volumes of Kidneys after Lung and Inductions Pattern

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Figure 3. Patient Survival by Kidney Induction Type

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Figure 4. Kidney Death Censored Graft Survival by Kidney Induction Type

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Table 1. Baseline Characteristics by Induction Received (N (%) or Median [IQR]) Depletional n=115

Non-Depletional n=170

No Induction n=45

p.Value

56.8 [43.2;63.0]

52.2 [37.8;61.7]

43.9 [32.2;55.3]

0.001

Recipient Gender Female

67 (58.3%)

99 (58.2%)

25 (55.6%)

0.944

White Race

107 (93.0%)

162 (95.3%)

43 (95.6%)

0.707

Diabetes Mellitus

33 (29.5%)

60 (35.5%)

13 (29.5%)

0.513

7.36 [5.28;10.3]

7.26 [5.50;10.3]

6.26 [3.99;8.41]

0.042

Pre-transplant Dialysis

72 (63.2%)

105 (61.8%)

31 (70.5%)

0.565

Living Kidney Donor

68 (59.1%)

124 (72.9%)

34 (75.6%)

0.026

Cold Ischemia Time (hours)

17.2 [10.0;24.4]

18.9 [13.7;24.0]

22.0 [17.8;27.0]

0.229

Peak PRA prior to Kidney

0.00 [0.00;6.25]

0.00 [0.00;7.25]

2.00 [0.00;5.00]

0.681

HLA Mismatches

3.00 [2.00;5.00]

3.00 [2.00;5.00]

3.00 [2.00;4.00]

0.271

Recipient Age

Time from lung engraftment in years

Lung Transplant Indication

0.099

Cystic Fibrosis

32 (27.8%)

71 (41.8%)

23 (51.1%)

Emphysema

46 (40.0%)

53 (31.2%)

9 (20.0%)

ILD

20 (17.4%)

26 (15.3%)

7 (15.6%)

Other

17 (14.8%)

20 (11.8%)

6 (13.3%)

71 (61.7%)

128 (75.3%)

33 (73.3%)

Bilateral Lung Transplant Lung induction type

0.044 0.002

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None

80 (69.6%)

113 (66.5%)

36 (80.0%)

Depletional

27 (23.5%)

22 (12.9%)

6 (13.3%)

Non-Depletional

8 (6.96%)

35 (20.6%)

3 (6.67%)

59 (51.8%)

72 (42.4%)

22 (48.9%)

Private Payer

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0.280

Table 2. Univariate Outcomes by Induction Type (N (%) or Median [IQR]) Depletional n=115

Non-Depletional n=170

No Induction n=45

p.Value

Delayed Renal Graft Function

7 (6.09%)

4 (2.35%)

1 (2.22%)

0.221

One-year Creatinine (mg/dL)

1.20 [1.00;1.48]

1.20 [1.00;1.41]

1.20 [1.00;1.40]

0.984

Years after Kidney Transplant

5.40 [3.00;8.95]

5.03 [2.99;7.96]

6.44 [3.58;9.85]

0.202

Acute Rejection by 6 months

10 (11.0%)

5 (4.13%)

0 (0.00%)

0.111

Acute Rejection by 1 Year

13 (15.5%)

8 (7.14%)

0 (0.00%)

0.101

LOS after kidney transplant

5.00 [4.00;6.50]

5.00 [4.00;6.75]

6.00 [5.00;8.00]

0.031

56 (56.0%)

77 (51.3%)

18 (48.6%)

0.673

One-year Hospitalization

22

Table 3. Multivariate Cox Proportional Hazards for Survival Entire Cohort n= 330

Contemporary Maintenance Cohort N=195

HR (95% C. I.) p-Value

HR (95% C. I.) p-Value

Kidney Induction No Induction

Ref

Ref

Depletional

0.729

(0.428, 1.244)

0.246

0.644

(0.306, 1.356)

0.246

Non-Depletional

0.966

(0.584, 1.596)

0.892

1.330

(0.651, 2.717)

0.434

Lung Induction No Induction

Ref

Ref

Depletional

0.770

(0.46, 1.289)

0.320

0.672

(0.344, 1.313)

0.244

Non-Depletional

1.309

(0.759, 2.257)

0.332

0.839

(0.414, 1.697)

0.625

Recipient Age in years

1.030

(1.009, 1.053)

0.006

1.032

(1.003, 1.062)

0.033

Recipient Gender Male

1.146

(0.804, 1.632)

0.451

1.342

(0.813, 2.216)

0.249

Donor Age in years

1.002

(0.989, 1.015)

0.768

1.005

(0.989, 1.021)

0.563

0.947

(0.898, 0.999)

0.046

0.949

(0.884, 1.018)

0.144

Time from lung engraftment in years Lung Transplant Indication Cystic Fibrosis

Ref

Ref

Emphysema

1.081

(0.545, 2.144)

0.824

1.452

(0.605, 3.483)

0.404

ILD

1.053

(0.514, 2.158)

0.888

1.345

(0.521, 3.474)

0.540

Other

0.910

(0.446, 1.855)

0.795

1.005

(0.385, 2.622)

0.993

23

Bilateral Lung 0.621

(0.407, 0.948)

0.027

0.536

(0.303, 0.95)

0.033

Diabetes Mellitus

1.170

(0.762, 1.798)

0.472

0.965

(0.565, 1.649)

0.898

Living Donor

0.661

(0.459, 0.951)

0.026

0.574

(0.344, 0.959)

0.034

Public Payer Recipient

0.805

(0.552, 1.175)

0.261

0.762

(0.454, 1.28)

0.304

Pre-transplant Dialysis

1.066

(0.732, 1.553)

0.739

1.455

(0.853, 2.479)

0.168

HLA-Mismatches

1.017

(0.925, 1.117)

0.734

1.037

(0.902, 1.191)

0.611

Transplant

24

Table 4. Multivariate Cox Proportional Hazards for Death Censored Kidney Graft Survival Entire Cohort n= 330

Contemporary Maintenance Cohort N=195

HR (95% C. I.) p-Value

HR (95% C. I.) p-Value

Kidney Induction No Induction

Ref

Ref

Depletional

1.861

(0.592, 5.85)

0.288

1.758

(0.405, 7.637)

0.452

Non-Depletional

2.182

(0.725, 6.573)

0.165

1.252

(0.298, 5.266)

0.759

Lung Induction No Induction

Ref

Ref

Depletional

0.189

(0.044, 0.816)

0.026

0.159

(0.019, 1.307)

0.087

Non-Depletional

0.260

(0.058, 1.16)

0.078

0.532

(0.107, 2.648)

0.441

Recipient Age in years

1.037

(0.998, 1.078)

0.063

1.006

(0.951, 1.065)

0.822

Recipient Gender Male

1.081

(0.572, 2.042)

0.811

1.247

(0.457, 3.401)

0.666

Donor Age in years

1.012

(0.987, 1.037)

0.356

1.015

(0.983, 1.048)

0.357

0.921

(0.837, 1.014)

0.094

0.957

(0.836, 1.096)

0.526

Time from lung engraftment in years Lung Transplant Indication Cystic Fibrosis

Ref

Ref

Emphysema

0.493

(0.139, 1.753)

0.275

0.746

(0.106, 5.256)

0.768

ILD

0.539

(0.14, 2.072)

0.368

1.707

(0.252, 11.56)

0.584

Other

0.674

(0.205, 2.22)

0.517

0.285

(0.028, 2.865)

0.286

25

Bilateral Lung 0.718

(0.302, 1.706)

0.453

0.570

(0.144, 2.253)

0.423

Diabetes Mellitus

1.239

(0.577, 2.657)

0.583

2.051

(0.706, 5.957)

0.187

Living Donor

1.082

(0.519, 2.254)

0.833

0.961

(0.29, 3.189)

0.948

Public Payer Recipient

0.892

(0.444, 1.791)

0.748

0.869

(0.277, 2.728)

0.809

Pre-transplant Dialysis

1.649

(0.786, 3.46)

0.186

2.318

(0.671, 8.002)

0.184

HLA-Mismatches

1.228

(1.014, 1.486)

0.035

1.357

(1.013, 1.819)

0.041

Transplant

26