Single-dose thymoglobulin induction in living-donor renal transplantation

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1 Ann Transplant, 2; (2): 5-58 Original Paper Received: Accepted: Published: 2..3 Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Single-dose thymoglobulin induction in living-donor renal transplantation Peter Schenker ABCDEFG, Arzu Öztürk BCDE, Oliver Vonend 2 CDE, Bernd Krüger 3 CDEF, Martin Jazra DE, Andreas Wunsch DE, Bernhard K. Krämer 3 DE, Richard Viebahn ADEG Department of Surgery, Knappschafts-Hospital, Ruhr-University Bochum, Bochum, Germany 2 Department of Nephrology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany 3 Department of Medicine, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany Summary Background: Material/Methods: Results: Conclusions: The use of Thymoglobulin induction therapy in living-donor renal transplantation remains controversial. We aimed to evaluate outcomes in living-related donor (LRD) and living unrelated donor (LURD) renal transplants with Thymoglobulin induction. We retrospectively analysed the outcome of all Thymoglobulin induced livingdonor renal transplants performed at our centre from 22 to 2. We reviewed living-donor renal transplants (LRD=; LURD=4) who received thymoglobulin induction (single dose,.5 mg/kg bodyweight) with a mean follow-up of 52.±3.9 months. Although baseline characteristics of the LRD and LURD groups were similar, differences were noted for recipient age, gender, and HLA-matching. Overall, the estimated 5-year patient survival was 92% and graft survival, 83%. The - and 5-year patient survival rates were 97.4% and 9.7% for LRD and 98.3% and 92.2% for LURD (P=.79), respectively. Cumulative graft survival (LRD vs. LURD) rates were 93% vs. 95% after year and 8% vs. 88% after 5 years (P=.53). Kidney graft function was comparable for both the groups. Acute rejection was observed in 7% LRD and 35% LURD patients (P=.35). Further, % of the patients experienced delayed graft function (LRD % vs. LURD 8%; P=). Rates of cytomegalovirus (CMV) infection (%), polyomavirus infection (5%), malignancy (4%), and lymphoproliferative disorder (%) were low, with no differences between the 2 groups. Single-dose thymoglobulin induction in living-donor renal transplantation was associated with high patient and graft survival without increasing the risk of infections or malignancy and without significant differences between LRD and LURD patients. disease Word count: 29 Tables: 2 Figures: 2 References: 39 Author s address: 5 Peter Schenker, Department of Surgery, Knappschafts-Hospital, Ruhr-University Bochum, In der Schornau 23-25, Bochum, Germany, peter.schenker@rub.de

2 Ann Transplant, 2; (2): 5-58 BACKGROUND Renal transplantation is the preferred treatment in patients with end-stage renal disease, and it has a significant survival advantage over dialysis []. Worldwide, organ shortages and the continuous increase in waiting time for deceased donor transplant recipients have made it necessary to search for alternative donor sources. Living-donors are an increasingly important source of kidneys for transplantation in Germany. In 29, approximately 2.% of all kidney grafts transplanted in Germany were living-donor transplants [2]. It is well established that renal transplants from living-related and living-unrelated donors have a superior graft survival to that of deceased donor grafts [3 5]. However, numerous studies have shown that living-donor kidney transplant recipients have a higher rate and severity of rejection and a shorter rejection-free period than deceased renal transplant recipients do [ 8]. In general, standard immunosuppressive regimens consist of calcineurin inhibitors (e.g. tacrolimus or cyclosporine), anti-proliferative agents (e.g. mycophenolate mofetil [MMF]) and corticosteroids to prevent graft rejection along with high-dose corticosteroids, or polyclonal or monoclonal antibodies to treat rejection [9,]. Induction regimens for preventing early acute rejection have become increasingly common in recent years [9, 4]. The induction agent of choice, as well as the dose and duration, remain controversial, centre-specific, and are often based on limited clinical data. Thymoglobulin induction therapy has been demonstrated to reduce the incidence of acute rejection episodes following kidney transplantation in high-risk patients as compared with no antibody induction or the usage of interleukin-2 (IL-2) receptor antagonists [5 7]. These findings are consistent with the recent recommendation from the KDIGO clinical practice guidelines [8]. Delayed graft function (DGF) in live and deceased donor allograft recipients has been associated with inferior long-term outcomes [9 2]. Thymoglobulin-initiated pre-reperfusion has been shown to decrease the incidence of DGF in deceased donor kidney transplantation [22,23]. Although DGF is less frequent in livingdonor recipients, it still occurs in 5 % of cases [2,24,25]. Whether the use of pre-reperfusion Thymoglobulin in living-donor recipients Schenker P et al Single-dose thymoglobulin induction in living-donor will decrease the incidence of DGF or have any beneficial effects on long-term outcomes remains unclear. The routine use of induction agents in live-donor kidney transplant recipients remains a controversial topic. Any beneficial influence of such agents on DGF or acute rejection, which are related to long-term outcomes, remains unproven. Despite the many potential benefits of antibody induction therapy, these agents are associated with increased short-term financial costs and have a potential for adverse events, including a presumed greater risk of infection and development of malignancy [2,27]. Therefore, many centres are cautious about using antibody induction therapy routinely in living-donor recipients. However, at our institution, we have routinely used Thymoglobulin as an induction agent in living-donor recipients since 22. The purpose of this study was to describe the effects of single-dose Thymoglobulin induction in living-donor kidney transplantation on graft and patient outcomes, with an emphasis on the differences between living-related donors (LRD) and living-unrelated donors (LURD). MATERIAL AND METHODS We retrospectively analysed the outcomes of all adult, living-donor renal transplant patients receiving single-dose Thymoglobulin induction therapy at the Department of Surgery, Knappschafts- Hospital, Ruhr-University of Bochum, Germany. Between January 22 and December 2, 22 patients underwent living-donor renal transplantation at our centre. Of these, (82%) received a single dose of Thymoglobulin (.5 mg/kg). Only patients with a negative pre-operative crossmatch were transplanted. Donor and recipient characteristics, operative variables and post-transplantation characteristics were evaluated. The outcomes were analysed for short- and longterm graft and patient survival, DGF, rejection rate, malignancy, and infectious complications. DGF was defined as the need for dialysis within the first week after transplantation. Protocol biopsies were not performed. Rejection episodes were diagnosed by renal biopsy or were characterised by an increase in serum creatinine levels by 3% or more from the baseline, which was not attributable to other causes, with subsequent return to baseline levels after treatment. Treatment strategies were related to the severity of acute rejection episodes, i.e. mild-to-moderate rejection 5

3 Original Paper Ann Transplant, 2; (2): 5-58 episodes were treated with a steroid bolus for 3 days, whereas severe rejection episodes were treated with a 7- to -day course of Thymoglobulin, rituximab, and/or plasmapheresis. Immunosuppressive Regimens All patients received a quadruple immunosuppression regimen comprising induction with single-dose Thymoglobulin followed by triple immunosuppressive therapy as detailed below. Thymoglobulin (Genzyme; Neu-Isenburg, Germany) infusion was administered in the operating room at a dosage of.5 mg/kg bodyweight before reperfusion of the graft. Premedication consisted of 25 mg prednisolone (Solu-Decortin H; Merck Pharma, Darmstadt, Germany), 3 mg ranitidine, and 4 mg dimethindene maleate, followed by further 25 mg of prednisolone pre-reperfusion. Maintenance immunosuppression consisted of tacrolimus (Prograf; Astellas, München, Germany), mycophenolate mofetil (CellCept; Roche, Grenzach-Wyhlen, Germany), and lowdose corticosteroids. Tacrolimus was started 3 5 days before transplantation at a dosage of.5 mg/kg body weight per day, divided into 2 doses. Dosages were adjusted to achieve whole blood trough concentrations of 8 2 ng/ml for the first 2 months and 5 8 ng/ml thereafter. MMF was given orally from post-operative day in a dose of 2 g/day. Tacrolimus trough levels were measured by immunoassay (IMX; Abbott Laboratories, IL, USA). A low-dose steroid regimen consisting of 25 mg prednisolone was administered on day. Thereafter, steroids were to be steadily tapered from 2 mg on day 2 to 5 mg by day. Surgical procedure For all patients, open donor nephrectomy was performed using an anterior vertical mini-incision lateral to the rectus muscle, and the left kidney was procured in 7% of cases. Antimicrobial and viral prophylaxis All patients received perioperative antimicrobial prophylaxis with ceftriaxone. Prophylactic treatment for Pneumocystis jiroveci pneumonia consisting of trimethoprim-sulfamethoxazole was given thrice weekly for 3 months post-transplantation. Cytomegalovirus (CMV) antiviral prophylaxis was administered using i.v. ganciclovir followed by oral ganciclovir/valganciclovir for 3 months after transplantation to recipients with positive serologies for CMV and those who received organs from donors with positive CMV serologies. Statistical analyses For statistical analysis, the chi-square test and Fisher s exact test were used to compare categorical variables, while the Mann-Whitney U test was used to compare continuous variables. Patient and graft survivals were calculated using the Kaplan Meier method, including the logrank test. A P-value below.5 was considered statistically significant. All these analyses were performed using SPSS software (Chicago, IL, USA). RESULTS A total of 22 patients underwent living-donor renal transplantation at our institution during the 8-year study period. Of these patients, (82%) received single-dose Thymoglobulin induction therapy. The remaining 22 patients were excluded because they received another lymphocyte depleting antibody (ATG-Fresenius), IL-2 receptor antagonists, or no induction therapy, because of participation in other studies/protocols (e.g. ABO-incompatible renal transplantation). Induction therapy with Thymoglobulin was well tolerated by all the patients. There were no serious side-effects related to single-dose Thymoglobulin in our study population. Transient leucopenia and thrombocytopenia were frequently observed within the first postoperative days. However, these changes were moderate and needed no specific therapy. For the patients, kidneys (%) were obtained from living-related donors (LRD), and 4 (4%) were obtained from living-unrelated donors (LURD). The mean recipient age was 45.8±3.3 years. The LRD transplant patients were significantly younger than the LURD patients (P<.) Glomerulonephritis (29%), polycystic kidney disease (9%), IgA-nephropathy (%), and hypertension (%) were the most common indications for transplantation in our patients. Sixteen (%) patients underwent pre-emptive transplantation before the initiation of dialysis therapy. On comparing the mean duration of dialysis therapy 52

4 Ann Transplant, 2; (2): 5-58 Schenker P et al Single-dose thymoglobulin induction in living-donor Table. Recipient and donor characteristics. Values are given as mean ±SD or n (% of group). Characteristics Live-donor Related Unrelated P value N 4 Recipient age (years) 45.8± ± ±9. P <. Recipient gender Female n (%) Male n (%) (35) 39 (5) 24 () (4) Recipient BMI (kg/m²) 25.± ± ±3. Cause of ESRD n (%) Glomerulonephritis Polycystic kidney disease IgA-nephropathy Hypertension Alport Syndrome Others (25) 8 (3) 2 (2) () 2 (3) 7 (28) 4 (35) (28) 4 () 4 () 2 (5) 5 (2) Pre-emptive transplantation n (%) 8 (3) 8 (2) Dialysis modality HD CAPD 73 4 (77) () 27 (8) 5 (2) Duration of dialysis (months) 23.8± ±2. 2.8±2.4 P =.4 HLA mismatch 3.±.7 2.4±.5 4.2±. P <. Ischemia time (min) 99±43 25±42 9±45 Previous renal transplants n (%) 2 (3) 4 () Donor age (years) 5.4±.3 5.±2.4 5.±9.3 Donor gender Female n (%) Male n (%) Donor BMI (kg/m²) 25.9± ± ±4. Relationships Parents Siblings Spouses Others CMV serostatus (D/R) Positive/Positive Positive/Negative Negative/Positive Negative/Negative ESRD end-stage renal disease; HD haemodialysis; CAPD continuous ambulatory peritoneal dialysis; HLA human leukocyte antigen; CMV cytomegalovirus; D donor; R recipient; BMI body mass index before transplantation, no difference was noted between the LRD and LURD groups. LRD recipients had significantly better HLAmatching results as compared to the LURD recipients (2.4±.5 vs. 4.2±.; P<.). Of the patients, had received a previous transplant, while 5 others had panel-reactive antibodies greater than 2%. The mean donor age was 5.4±.3 years. There were no significant differences between the 2 groups with respect to donor gender and donor age. The characteristics of the donor and recipient groups are shown in Table. Patient and graft survival The mean duration of follow-up was 52.±3.9 months. The Kaplan Meier estimate for overall 53

5 Original Paper Ann Transplant, 2; (2): 5-58 A B Figure. Kaplan-Meier patient (A) and graft (B) survival curves for the related und unrelated groups. The difference between the 2 groups was not statistically significant (log-rank test: patient survival, P=.79; graft survival, P=.53). patient survival rate was 98% after year and 92% after 5 years. Seven patients died during the follow-up period (mean time, 3.7±2.2 months); these deaths were attributed to infection (n=3) and cardiac disease (n=4). Of these 7 patients, 5 had a functioning allograft at the time of death. Patient survival rates at and 5 years were 97.4% and 9.7% in the LRD group as compared to 98.3% and 92.2% in the LURD group (P=.79; log-rank test, Figure ). Kaplan Meier estimates of overall kidney graft survival rates at and 5 years were 94% and 83%, respectively. Further, - and 5-year graft survival rates were 93% and 8% for LRD as compared to 95% and 88% for LURD, respectively. No significant difference was noted in the - and 5-year kidney graft survival rates between the 2 groups (P=.53; log-rank test, Figure ). During the study period, 3 (3%) patients suffered graft failure, i.e. 9/ (5%) patients from the LRD group and 4/4 (%) patients from the LURD group experienced graft failure. The causes of graft failure included death with functioning graft (n=5), technical complications (n=3), incompliance (n=2), acute rejection (n=), infection (n=), and renal disease recurrence (n=). Acute rejection and delayed graft function The overall acute rejection rate within the first post-operative year, as diagnosed either by clinical signs or biopsy-proven, was 24%. Of the patients who received LRD, (7%) patients experienced acute rejection, as compared with 4 of 4 patients (35%) in the LURD group. As expected, the rejection rate was significantly higher in the LURD group (P=.35). More than 5% of the rejections in each group occurred during the first 2 weeks post-transplantation. The majority of these rejections were classified as Banff IA and responded well to steroid pulse therapy. There was a single event of grade III severity that occurred in the LURD group. This graft was lost because of acute graft rejection. As shown in Table 2, no statistically significant differences were noted between the 2 groups concerning the histological classification of biopsy-proven rejection. Further, the incidence of DGF was similar between the LRD and LURD groups (% vs. 8%, respectively). Renal function The overall mean serum creatinine concentration after a mean follow-up of 54.2±3. months in the remaining 87 patients with a functioning allograft was.5±. mg/dl. The mean serum creatinine concentrations were similar in the LRD and LURD groups after months (.5±.5 mg/dl vs..49±.7 mg/dl; P=.54), 2 months (.5±.5 mg/dl vs..4±. mg/dl; P=.44), and 3 months post-transplantation, respectively (.59±.7 mg/dl vs..43±.5 mg/dl; P=.44; Figure 2). Malignancy and infectious complications Four patients (4%) experienced cancer after transplantation. Malignancies were observed in 54

6 Ann Transplant, 2; (2): 5-58 Schenker P et al Single-dose thymoglobulin induction in living-donor Table 2. Living-donor renal transplantation outcomes for the LRD and LURD groups. Values are given as mean ±SD or n (% of group). Rejection n (%) Biopsy-proven Clinically suspected Banff grade IA IB IIA IIB III Live-donor (n=) 24 (24) 22 (22) 2 (2) 9 Related (n=) (7) (7) Unrelated (n=4) 4 (35) 2 (3) 2 (5) Time to first rejection (months).3±2..5±2..±2.7 Delayed graft function n (%) () 7 () 3 (8) Malignancy 4 (4) 2 (3) 2 (5) PTLD Infection Cytomegalovirus n (%) Polyomavirus n (%) Patient survival -year 5-year Graft survival -year 5-year Cause of death Cardiac n (%) Infection n (%) () 5 (5) (4) 3 (3) Graft failure n (%) 3 (3) 9 (5) 4 () PTLD post-transplant lymphoproliferative disorder. 3 5 (8) 2 (3) (5) (2) 5 5 (2) 3 (8) (3) 2 (5) P value P=.35 2 patients in the LRD group, including basal cell carcinoma of the nose in recipient and prostate cancer in another. In the LURD group, malignancies included basal cell carcinoma of the brow (n=) and vulvar carcinoma (n=). At the time of analysis, no patient had died because of malignancy. None of the subjects in either group experienced post-transplant lymphoproliferative disorder. Overall, no statistically significant difference in infection rates was observed between the 2 groups. The incidence of CMV and polyomavirus infection was 8% and 3% in the LRD group and 2% and 8% in the LURD group, respectively. DISCUSSION Living-donor renal transplantation is becoming increasingly popular because of better quality organs and excellent outcomes as compared to deceased donor transplantation, which entails issues such as organ shortage and long waiting times. In this study, we analysed the outcomes of livingdonor renal transplant recipients who received single-dose Thymoglobulin induction using a dose of.5 mg/kg body- weight between 22 and 2 in our institution. Consistent with other reports [28 3], our results confirmed that renal transplant recipients of LRD and LURD groups had similar graft and patient survivals. Recipients of renal allografts from LURD had a higher risk of developing rejection by year; however, this did not translate to a reduction in graft survival. Excellent patient and graft survival were observed after living-donor renal transplantation at our centre. One- and 5-year patient survival estimates were 97.4% and 9.7% for LRD, and 98.3% and 92.2% for LURD, respectively. Patient survival in similar other case series ranges from 94% to % after year, and from 83% to 9% after 5 years [4,2,29]. 55

7 Original Paper Ann Transplant, 2; (2): 5-58 rejection rates of 3% in LURD and 8.5% in LRD. Voiculescu et al. [34] found much higher rejection rates 54.2% in LURD and 52.5% in LRD, using T-cell depleting antibodies in 75% of LURD patients. Campbell et al. [] reported 44% acute rejections in living donors vs. 28% in cadaveric donors with the use of more frequent antibody induction in the latter (2% vs. 8%). Figure 2. Renal function (serum creatinine concentration in mg/dl) at, 2, and 3 months after transplantation in the LRD and LURD groups. No significant difference was noted in the mean serum creatinine values between the 2 groups at any time point (P=). In this study, overall kidney graft survival rates at and 5 years were 94% and 83%, respectively. According to the most current US Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Network data, the overall unadjusted graft survival rates for recipients of living donor renal transplantations at and 5 years are 9.3% and 8.4%, respectively [3]. Despite a markedly higher donor age in our study population (5.4 years vs. 4.4 years), survival rates at our centre were comparable with the results of living-donor renal transplants in the United States. HLA matches are known to have an important effect on the outcome of graft survival [32]. However, many recent single-centre studies have reported similar graft survival rates with LRD and LURD in spite of greater HLA mismatches in LURD [29,3]. In our study, although LURD had significantly higher HLA mismatches than LRD (P<.), this did not have any adverse effect on the outcomes. However, HLA mismatches might have contributed to some early rejections observed in the LURD group. In our study, the overall acute rejection rate was 24% within the first year (LRD 7% vs. LURD 35%, P=.5). Rejection rates have varied widely in recent series that have compared LRD and LURD due to discrepancies in rejection criteria and differences in immunosuppression protocols. Fuller et al. [33] reported -year acute In another study by Ahmad and co-workers [3], acute rejection occurred in 4% (LRD) and 35% (LURD) of patients using basiliximab induction in 29% of patients. In a registry analysis, Lim et al. reported a 5% reduction in the incidence of acute rejection (9% rejection rate at months) in living-donor renal transplant recipients received IL-2 receptor antagonist induction [35]. These rates are definitely higher as compared with the 5% rate noted in another study that used Thymoglobulin for induction therapy in 24 live-donor recipients [3]. Ciancio and co-workers [37] reported a rejection rate of % after 3 years in a small group of 3 living-donor transplant recipients using 7 doses of Thymoglobulin ( mg/kg/day), which were in sharp contrast to the results of Tan et al. [38], who reported a rejection rate of 29.2% in living-donor renal transplants after a single dose of 5 mg/kg Thymoglobulin in a steroid-free immunosuppressive regimen with a follow-up period of 4 days. Our present data confirm the results reported by Hardinger et al. [3], i.e. living-donor transplant recipients have excellent outcomes and minimal additional risks with the routine use of Thymoglobulin induction. In this study by Hardinger et al. [3], Thymoglobulin induction was associated with an absence of delayed graft function. In the present study the incidence of DGF was %. We believe that the older donor age (38 vs. 5 years) in our study is in part responsible for the higher rate of poor initial graft function. To the best of our knowledge, only limited data are available reporting the outcomes of livingdonor renal transplant patients receiving single-dose Thymoglobulin induction therapy with.5 mg/kg bodyweight. Despite the widespread use of Thymoglobulin for induction therapy in the US, this drug has not received FDA approval for use in induction therapy [39]. The fact that Thymoglobulin has not been approved for this indication has hindered the development of large clinical induction trials in the US. 5

8 Ann Transplant, 2; (2): 5-58 With the development of more sophisticated immunosuppression regimens in the calcineurininhibitor era, and because of the potential side effects of lymphocyte-depleting antibodies, the need for anti-lymphocyte globulins, particularly for use as induction treatment, has been questioned [,27]. Moreover, immunosuppression management of the living-donor kidney recipient has changed dramatically over the past decade in the United States. The use of at least induction regimen has increased between 999 and 28, from 42% of transplants to 8% in this period. The most frequently used agents in 999 were IL-2 receptor antagonists, which were used in 3% of patients overall. In 28, 4% of patients received rabbit anti-thymocyte globulin (Thymoglobulin), while 3% received an IL-2 receptor antagonist and 2% were treated with alemtuzumab (Campath) [2]. Nevertheless, improving clinical outcomes requires a sensitive balance between achieving efficacious rejection prophylaxis and avoiding complications such as infections or malignancy that impact morbidity and mortality. One known side effect of anti-thymocyte induction agents is the higher risk of cancer, in particular, lymphoproliferative diseases. Opelz et al. [2] showed that the risk of non-hodgkin lymphoma is markedly higher with murine anti-cd3 monoclonal antibody (OKT3), horse anti-thymocyte globulin (ATGAM) and Thymoglobulin, whereas there is no increase in lymphoma risk with IL-2 receptor antagonists or ATG-F. According to our present results from the living-donor transplant population, no post-transplant lymphoproliferative disorder was detected during the follow-up period. This low incidence of PTLD is consistent with the overall experience at our institution, wherein the intensive use of Thymoglobulin has not resulted in an increased risk of malignancy. CONCLUSIO In summary, despite the limitations of a retrospective study, our results indicate that singledose Thymoglobulin induction therapy in living-donor renal transplants was associated with excellent patient and graft survival. Low levels of relevant complications were observed, particularly with regard to malignancy and infection rates over a mean follow-up period of 4.5 years. Acknowledgements Schenker P et al Single-dose thymoglobulin induction in living-donor REFERENCES:. Wolfe RA, Ashby VB, Milford EL et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med, 999; 34: Eurotransplant International Foundation. Annual Report 29. Available at: org/files/annual_report/ar_29.pdf. Accessed on 7 December 2 3. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S: High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med, 995; 333: Matas AJ, Payne WD, Sutherland DE et al: 2,5 living donor kidney transplants: a single-center experience. Ann Surg, 2; 234: Gjertson DW, Cecka JM: Living unrelated donor kidney transplantation. Kidney Int, 2; 58: Campbell SB, Hothersall E, Preston J et al: Frequency and severity of acute rejection in live- versus cadaveric-donor renal transplants. Transplantation, 23; 7: Lim WH, Chang SH, Coates PT, McDonald SP: Parental donors in live-donor kidney transplantation associated with increased rejection rates and reduced glomerular filtration rates. Transplantation, 27; 84: Rosenberg JC, Jones B, Oh H: Accelerated rejection following offspring-to-mother and husband-towife transplants. Clin Transplant, 24; 8: Ciancio G, Burke GW, Miller J: Induction therapy in renal transplantation: an overview of current developments. Drugs, 27; 7: Knoll G: Trends in kidney transplantation over the past decade. Drugs, 28; 8(Suppl.): 3. Deeks ED, Keating GM: Rabbit antithymocyte globulin (thymoglobulin): a review of its use in the prevention and treatment of acute renal allograft rejection. Drugs, 29; 9: Axelrod DA, McCullough KP, Brewer ED et al: Kidney and pancreas transplantation in the United States, : the changing face of living donation. Am J Transplant, 2; : Mota C, Martins L, Costa T et al: Nineteen years of experience utilizing anti-t-lymphocyte globulin induction in pediatric kidney transplantation. Ann Transplant, 2; 5: Kaden J, May G, Volp A, Wesslau C: Improved longterm survival after intra-operative single high-dose ATG-Fresenius induction in renal transplantation: a single centre experience. Ann Transplant, 29; 4: 7 7 Genzyme provided support to P.S. for this project. 57

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