Transplant Immunology 32 (2015) 35–39
Contents lists available at ScienceDirect
Transplant Immunology journal homepage: www.elsevier.com/locate/trim
Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: A proof-of-concept study Federico Cicora a,b,1, Fernando Mos a,2, Jorgelina Petroni a,2, Matías Casanova a,2, Liliana Reniero a,2, Javier Roberti b,⁎,3 a b
Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina Foundation for Research and Assistance of Kidney Disease (FINAER), Buenos Aires, Argentina
a r t i c l e
i n f o
Article history: Received 21 August 2014 Received in revised form 5 October 2014 Accepted 6 October 2014 Available online 20 October 2014 Keywords: Belatacept Antithymocyte globulin-Fresenius Induction Steroid Mycophenolate Renal transplantation
a b s t r a c t Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged ≥18 years, Epstein–Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5 h. Mean serum creatinine levels at 1, 3 and 6 months were 1.76 ± 0.59, 1.55 ± 0.60 and 1.49 ± 0.60 mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Kidney transplantation is the preferred treatment for end-stage renal disease, and the preservation of renal function in transplant recipients is crucial to prevent all-cause mortality and major adverse events [1,2]. One of the main reasons for diminished graft function may be the toxicities associated with calcineurin inhibitors (CNIs), which are the cornerstone of immunosuppression after kidney transplantation [1,2]. Moreover, in those patients who receive extended Abbreviations: ATGF, rabbit anti-thymocyte globulin Fresenius; CMV, cytomegalovirus; CNI,calcineurin inhibitors; DGF,delayed graft function;DSA,donor-specific antibodies;EBV, Epstein–Barr virus; IgG, immunoglobulin; KPC, Klebsiella pneumoniae carbapenemase; MMA, mycophenolic acid; NODAT, new-onset diabetes after transplantation; POD, post-operative day; PTLD, post-transplant lymphoproliferative disorder; rATG, rabbit anti-thymocyte globulin; WBC, white blood cells. ⁎ Corresponding author at: Austria 2381, 5D, 1425 Buenos Aires, Argentina. Tel./fax: + 54 11 48027423. E-mail address: [email protected] (J. Roberti). 1 FC Participated in research design, performance of the research, and interpretation of data. 2 FM, JP, MC, LR participated in data collection, interpretation of data, and review of paper. 3 JR participated in research design, literature search, performance of the research, and writing of the paper.
http://dx.doi.org/10.1016/j.trim.2014.10.002 0966-3274/© 2014 Elsevier B.V. All rights reserved.
criteria donor kidneys, which are becoming more common due to the limited availability of standard criteria donor organs, this problem is augmented [3]. It has been demonstrated that belatacept, a first-in-class selective costimulation blocker that inhibits the interaction between CD80/ CD86 and CD28 and prevents T cell activation, provides effective immunosuppression while avoiding the nephrotoxicities associated with CNIs [4–7]. Phase III trials comparing belatacept to cyclosporin in patients receiving a kidney transplant from either living, standard criteria deceased donors or extended criteria deceased donors demonstrated that belatacept was well-tolerated and offered better renal function and similar immunosuppressive efficacy with an improved cardiovascular risk profile [5,7,8]. However, these trials showed that belatacept patients experienced higher rates of acute rejection episodes within six months post-transplantation [5,7–9], and these acute rejection episodes were not typically associated with donorspecific antibodies (DSA) [8]. T cell mediated rejection episodes may increase interstitial fibrosis, tubular atrophy, and global glomerulosclerosis [10]. Indeed, any type of acute cellular rejection is associated with graft dysfunction over time [11]. Therefore, patients could benefit even more if the early acute cellular rejection rate is decreased. Rabbit anti-thymocyte globulin (rATG)-Fresenius (ATGF) is a purified, pasteurized preparation of polyclonal gamma immunoglobulins
36
F. Cicora et al. / Transplant Immunology 32 (2015) 35–39
raised in rabbits against human thymocytes and used for the prevention and treatment of acute graft rejection in renal transplant patients [12–15]. It has been shown that induction therapy with antithymocyte globulin reduced the acute graft rejection risk in renal transplant recipients [16,17]. Moreover, thymoglobulin has been used in two belatacept-based regimens (belatacept and mycophenolate mofetil or belatacept with sirolimus) compared to a tacrolimus-based, steroid avoiding regimen; results showed better renal function in the belatacept groups and suggested that this agent could be combined with thymoglobulin induction [18]. Our rationale was to use a combination of immunosuppressive agents that was as similar as possible to the regimen used in the BENEFIT and BENEFIT EXT trials on account of their strong empirical support. We hypothesized that by using an immunosuppressive regimen combining maintenance therapy with belatacept, MMA, and steroids (like in the BENEFIT and BENEFIT EXT trials) but adding induction therapy with ATGF instead of basiliximab, the good results obtained from these studies could be improved by decreasing the early acute rejection rate. Herein, we describe the results of a proof-of-concept prospective study using this new regimen. This prospective, single center, proof-of-concept study included males and females aged 18 years and older who were Epstein–Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft, similarly to BENEFIT and BENEFIT EXT. Only patients with a calculated panel reactive antibody score of 0% were included. Patients with a history of immunosuppression within 1 year before transplant surgery, previous lymphodepletion, immune deficiency, coagulopathy, malignancy, or glomerulopathy with potential for recurrence or those patients with potential for infections were excluded. From 42 patients who underwent single kidney transplantation at Hospital Alemán (Buenos Aires, Argentina) between May of 2013 and December of 2013, we identified 12 patients (32%) who could be administered this regimen. The patients were treated with ATGF (Fresenius SE & Co. KGaA, Bad Homburg, Germany) at 2–5 mg/kg for 5 to 7 doses starting on the day of transplant surgery. When the platelet and white blood cell (WBC) counts dropped to 80,000 and 3000/mm3, respectively, the dose of ATGF was reduced by 50%. If the platelet or WBC count was below 50,000 or 2000/mm3, respectively, ATGF administration was discontinued. The maintenance immunosuppressive regimen consisted of triple therapy with belatacept (Nulojix; Bristol-Myers Squibb, Princeton, NJ, USA), MMA (Myfortic; Novartis, East Hanover, NJ, USA), and corticosteroids. Intravenous belatacept was used at 10 mg/kg on post-operative days (PODs) 1, 5, 15, 28, 56, and 84 and 5 mg/kg every 28 days thereafter; MMA was administered at 720 mg twice daily. Methylprednisolone was used as follows: 500 mg perioperatively, 250 mg on POD 1, and 125 mg on POD 2. Oral meprednisone was used at 20 mg/day for the first month, 15 mg/day between weeks 5 and 6, and 10 mg/day between week 7 and month 6; thereafter, the dose was reduced to 4 mg/day (See Fig. 1). Cytomegalovirus (CMV) prophylaxis consisted of 900 mg/day of valganciclovir for three to six months according to each patient's pre-transplantation mismatch status. Pneumocystis pneumonia prophylaxis was applied on a regular basis for nine months with trimethoprim/ sulfamethoxazole (Bactrim Simple [80/400]). According to the protocol used at our center, borderline, Banff IA, and Banff IB cellular rejection episodes were treated with three pulses of methylprednisolone (500 mg each). Rejection episodes categorized ≥ Banff II were treated with thymoglobulin. According to our protocol, in cases of antibodymediated rejection, belatacept was discontinued, replaced with tacrolimus, and the patients received a combination therapy with intravenous immunoglobulin, bortezomib, and plasmapheresis. The three recipients of Trypanosoma cruzi-infected kidneys did not receive prophylactic treatment for Chagas disease. However, they were screened by PCR
once per week for the first three months post-transplantation, once per month until month 12, and once a year thereafter. In case of T. cruzi infection, treatment comprised benznidazole (5 mg/kg/day for 60–90 days). Transplantation was performed using standard surgical techniques. Biopsies were performed when the patient's serum creatinine level increased by 30%, as compared to the baseline level, and antibodies were measured only in those patients who underwent a biopsy for cause. In 10 patients, surveillance biopsies and DSA measurement were performed between months 3 and 6; in the remaining two patients, biopsies could not be performed due to health insurance problems. Our main objectives were to assess patient and graft survival, acute rejection of the graft, the estimated glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) Study Equation 4, adverse events, and infections. The results are given as frequencies, percentages, means ± SD, medians, and ranges as appropriate. Stata version 11.0 (StataCorp, College Station, TX, USA) was used in our investigation. Twelve patients were transplanted; of these, nine were male and all were Caucasian. The median age of the patients was 53.5 years (range, 27–73 years). In terms of etiology, unknown disease was the most frequent in 5/12 patients and hypertension prior to transplantation was a comorbidity in 8/12 patients. Eleven of twelve patients received a kidney from a deceased donor; one patient received a kidney from a living unrelated donor. The median age of the donors was 58.5 years (range, 2–66 years). Seven of eleven deceased donors met the expanded criteria according to UNOS and as used in BENEFIT EXT trial: donors ≥60 years old, or donors ≥50 years old and who had at least two other risk factors (cerebrovascular accident, hypertension or serum creatinine N1.5 mg/dL) or an anticipated cold ischemia time N 24 h [7]. One patient received en bloc pediatric kidneys. In patient 2, the donor had a Remuzzi score of 7. The mean number of HLA mismatches was 3.75 ± 1.48. Two of twelve (16.7%) patients presented with CMV IgG D/R mismatches. Of note, 3/12 donors were positive for Chagas disease. The median cold ischemia time for the transplant patients with a deceased donor was 21.5 h (range, 15.6–27.7 h). Seven of twelve (58.3%) patients presented with delayed graft function (DGF) and one of twelve presented with surgical complications (urinary fistula). Six of twelve (50%) patients had at least one infection and five of those patients were readmitted to the hospital for treatment. Patient 6, who had an augmented bladder and intermittent urethral catheterization, presented with seven urinary tract infections and two cutaneous mycoses; patient 7, a 71 year-old male, presented with five urinary tract infections, one catheter-related bacteremia, and two bouts of esophageal candidiasis. The other four patients had between one and five infection episodes each. All episodes were successfully treated. Of note, patient 1 had a Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter sp. infection, and patient 5 had a T. cruzi infection transmitted via the graft; both were successfully treated (with meropenem and colistin in the first case and benznidazole in the second). Table 1 shows characteristics of transplant receptors and donors. Table 2 shows post-transplant outcomes. The mean MDRD values for those patients who received a kidney from a deceased donor were as follows: 9.59 ± 4.69, 47.61 ± 24.08, 56.39 ± 26.90, and 56.00 ± 23.50 for week 1 and months 1, 3, and 6, respectively (Fig. 2). Mean serum creatinine levels for all patients at 1, 3 and 6 months were 1.76 ± 0.59, 1.55 ± 0.60 and 1.49 ± 0.60 mg/dl, respectively. Two of twelve (16.7%) patients experienced clinical, biopsyproven rejection (patient 1 with two cellular rejection Banff IA episodes at month 1 and at month 7, and patient 10 with one borderline cellular episode, at month 4). These rejection episodes were successfully treated with three pulses of methylprednisolone (500 mg each). Surveillance biopsies performed between 3 and 6 months post-transplant showed no indication of subclinical cellular or antibody mediated rejection. No BK virus infection was detected and no donor-specific antibodies were
F. Cicora et al. / Transplant Immunology 32 (2015) 35–39
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Table 1 Kidney recipient and donor characteristics. Recipient
Donor
Patient
Age
Genre
Initial nephropathy
Comorbidities
No. of HLA mismatches
Type of donor
Donor's age
Extended criteria
Igg CMV
Chagas
Cold ischemia time, min
1 2 3 4 5 6 7 8 9 10 11 12
52 40 44 67 43 27 64 54 53 54 73 56
Male Male Female Male Male Female Male Male Female Male Male Male
Diabetes Unknown Reflux Unknown Unknown Reflux Unknown Obstructive uropathy Unknown Unknown Nephroangiosclerosis Nephroangiosclerosis
Diabetes None Hypertension Hypertension Hypertension None Hypertension Hypertension None Hypertension Hypertension Hypertension
5 5 1 3 3 2 3 5 3 4 5 6
Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Living
54 54 43 2 59 51 59 58 60 59 66 62
Yes No No No Yes No Yes Yes Yes Yes Yes No
Positive Positive Positive Negative Positive Positive Positive Positive Positive Positive Positive Positive
Negative Positive Positive Negative Negative Negative Negative Negative Negative Negative Positive Negative
1660 1277 1078 1325 1040 1290 1560 1320 1290 1200 936 236
Abbreviations used: CMV, cytomegalovirus; and IgG, immunoglobulin.
Table 2 Outcomes. Outcomes
n (%)
Surgical complications, n (%) DGF, n (%) Hospital readmission, n (%) Opportunistic infection, n (%) Rejection in first 6 months, n (%) Incidence of malignancy, n (%) Incidence of PTLD, n (%) Incidence of NODAT, n (%) Graft loss in first 6 months, n (%) Death in first 6 months, n (%)
1/12 (8.3) 7/12 (58.3) 5/12 (41.7) 6/12 (50) 2/12 (16.7) 0/12 (0) 0/12 (0) 1/11 (9) 0/12 (0) 0/12 (0)
Biochemical outcomes
Median ± SD
Serum creatinine, mg/dL 1 month 3 months 6 months Hemoglobin, d/dL 1 month 3 months 6 months Hematocrit, % 1 month 3 months 6 months White blood cell, mm3 Baseline 1 month 3 months 6 months Lymphocyte cell, total, mm3 1 week 1 month 3 months 6 months Platelet count, mm3 Baseline 1 week 1 month 3 months 6 months Fasting glucose level, mg/dL Baseline 1 month 3 months 6 months Total cholesterol, mg/dL Baseline 3 months 6 months
1.76 ± 0.59 1.55 ± 0.60 1.49 ± 0.45 9.74 ± 1.15 11.54 ± 1.74 11.67 ± 2.05 29.78 ± 3.32 35.75 ± 5.39 36.36 ± 5.16 9811 6526 4803 5764 246 559 627 574
± ± ± ±
± ± ± ±
3424 3074 2712 2518
142 292 387 292
203,000 122,333 249,833 243,750 221,363
± ± ± ± ±
53,846 77,015 95,471 49,184 52,688
108.42 ± 40.37 99.67 ± 15.05 99.00 ± 18.42 108.45 ± 24.31 161.83 ± 44.08 197.17 ± 57.93 192.45 ± 27.67
Abbreviations used: DGF, delayed graft function; PTLD, posttransplant lymphoproliferative disorder; and NODAT, new onset diabetes after transplantation.
identified during follow-up. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. This proof-of-concept study shows a regimen combining belatacept, MMA, steroids, and induction therapy with thymoglobulin provided good results in renal transplant patients. Beforehand, belatacept trials were undertaken given the need to develop agents of comparable efficacy to CNIs but without their toxicities [8,19]. In adults receiving a kidney from living or standard criteria deceased donors, belatacept was associated with superior renal function, similar patient and graft survival rates, and a higher rate of early acute rejection, as compared to cyclosporin [5]. In recipients of extended criteria donor kidneys, belatacept showed an acute rejection rate comparable to that of cyclosporin but an improved cardiovascular/metabolic profile and an increase in the number of cases of PTLD [7]. It has been demonstrated that belatacept offered similar patient and graft survival compared with CsA, with better renal function despite higher rates and higher grades of early acute rejection episodes, which did not tend to recur [4]. In the BENEFIT EXT trial, the incidence of acute rejection was similar between the belatacept and CsA groups at 1 year: 18% in the belatacept groups and 14% in CsA group; importantly, 81% rejection episodes occurred within the first 3 months [7]. Consistent with the favorable results of the BENEFIT and BENEFIT EXT trials [4–7], we observed a very good renal function over six months in all patients, which is especially important in those recipients of extended criteria donor kidneys. In an attempt to explain the rejection rate found in the belatacept groups, it has been suggested that memory cells are costimulatory blockade-resistant and that T cell activation occurs through other costimulatory pathways [20]. Our hypothesis was that a T celldepleting agent such as ATGF used in induction therapy could contribute to a decreased rejection rate through its action on other pathways. In the BENEFIT and BENEFIT EXT trials, acute rejections occurred early after transplantation [21]. To specifically address this point, we used ATGF, as it has been demonstrated that rATG significantly decreases the incidence of early acute rejection in patients at both low and high immunological risk [17]. Moreover, ATGF induction in combination with immunosuppressive therapy is more effective in preventing acute graft rejection than immunosuppressive therapy without induction [14]. We previously found that the incidences of DGF, acute cellular rejection, and antibody-mediated rejection were not significantly different in renal transplant recipients treated with thymoglobulin or ATGF [15]. ATFG is administered during 5–7 days in fixed doses, according to the manufacturer's instructions, but not based on the lymphocyte depletion [15]. The high incidence of DGF may be explained by the predominance of extended criteria donors, factors associated with the graft procurement process, as well as causes related to brain death and ischemic injury
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F. Cicora et al. / Transplant Immunology 32 (2015) 35–39
Fig. 1. Scheme of the immunosuppression regimen.
[22]. In our study, two patients experienced rejection episodes but, importantly, they occurred after immunosuppression had been reduced as a result of infection episodes that were successfully treated. Ferguson et al. [18] conducted the first clinical study of belatacept with thymoglobulin induction and used a mammalian target of rapamycin inhibitor in a comparison of two belatacept-based regimens with a tacrolimus-based, steroid-avoiding regimen and obtained acceptable rates of acute rejection and improved renal function in the belatacept groups. Recently, Kirk et al. [23] investigated a belataceptbased CNI- and steroid-free regimen in recipients of live donor kidneys using alemtuzumab induction and sirolimus and obtained good results with induction therapy. Our results are in accordance with these studies and support the concept of combining a belatacept-based regimen and depletional induction to reduce early belatacept-resistant rejection. PTLD may develop as a side effect of thymoglobulin usage; moreover, in the BENEFIT trials the incidence of PTLD was increased in the belatacept group [5,7,24]. None of the patients presented with PTLD during follow-up, and although all of the recipients in our study were
EBV-positive, close screening should be done. Also in the belatacept trials, more fungal infections were observed in the belatacept group; however, most cases were not serious and were typically mucocutaneous [3,4,25]. Our results coincide with these reports. A double-J stent, a predisposing factor for infection, was used in all of our patients; in addition, the patient with the most infection episodes had an augmented bladder. Therefore, we can only speculate that reducing the use of stents could help decrease the infection rate. In addition, this infection rate could be a result of the potent immunosuppressive therapy: relatively high doses of steroids given the depleting antibody induction and triple maintenance immunosuppression; so, a regimen with a reduced dose of ATGF warrants further investigation. Other side effects of rATG such as thrombocytopenia and anemia [26] were not observed in our study. Three transplant patients received kidneys from T. cruzi-seropositive donors, and a reactivation rate of 8.3–17% has been reported with standard immunosuppression, mainly within the first year or after an increase in immunosuppression [27]. We could not find any studies describing the use of belatacept in this context. The recipients did not receive prophylactic therapy but we performed strict monitoring for the early detection and treatment of reactivation, including weekly PCR tests for two months post-transplantation, every two weeks for the third month, monthly until month 12, and once a year thereafter. One patient showed positive results but was successfully treated with benznidazole. Despite being a proof-of-concept study, we clearly acknowledge the limitations of our work—mainly its short follow-up, a small number of patients and lack of a comparison group. Chagas disease and a KPCproducing bacteria case prove to be a challenge for the regimen. In conclusion, our experience shows that this belatacept-based regimen with ATGF induction therapy provided good renal function, was especially important in recipients with extended criteria donor kidneys, and led to acceptable rejection and infection rates. Notably, the regimen proved efficacious in a challenging context; so, the potential of this approach makes it worthy of further investigation. Disclosure
Fig. 2. Estimated graft filtration rate (calculated using the MDRD formula 4) for 12 patients at baseline, postoperative day 3, week 1, months 1 and 6 of follow-up.
The authors have no conflict of interest in relation to funding of this work.
F. Cicora et al. / Transplant Immunology 32 (2015) 35–39
Conflict of interest FM, JP, MC, LR have received scholarships from Gador Argentina. JP has received speaker fee from Bristol Myers Squibb Argentina. FC and JR declare no conflict of interests. References [1] Fellström B, Jardine AG, Soveri I, et al. Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation. Am J Transplant 2005;5:1986–91. [2] Soveri I, Holdaas H, Jardine A, Gimpelewicz C, Staffler B, Fellström B. Renal transplant dysfunction—importance quantified in comparison with traditional risk factors for cardiovascular disease and mortality. Nephrol Dial Transplant 2006;21:2282–9. [3] Charpentier B, Medina Pestana JO, Del C, Rial M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys. Am J Transplant 2013; 13:2884–91. [4] Rostaing L, Vincenti F, Grinyó J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant 2013;13:2875–83. [5] Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belataceptbased immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010;10:535–46. [6] Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant 2012;12:210–7. [7] Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant 2010;10:547–57. [8] Leibler C, Matignon M, Pilon C, et al. Kidney transplant recipients treated with belatacept exhibit increased naïve and transitional B cells. Am J Transplant 2014; 14:1173–82. [9] Wojciechowski D, Vincenti F. Belatacept for prevention of acute rejection in adult patients who have had a kidney transplant: an update. Biol Targets Ther 2012;6: 385–93. [10] Halloran PF. T cell-mediated rejection of kidney transplants: a personal viewpoint. Am J Transplant 2010;10:1126–34. [11] Wu K, Budde K, Lu H, et al. The severity of acute cellular rejection defined by Banff classification is associated with kidney allograft outcomes. Transplantation 2014; 97:1146–54.
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[12] Ducloux D, Kazory A, Challier B, et al. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study. Transplantation 2004;77:1029–33. [13] Ciancio G, Burke GW, Miller J. Induction therapy in renal transplantation: an overview of current developments. Drugs 2007;67:2667–80. [14] Deeks ED, Keating GM. Rabbit antithymocyte globulin (thymoglobulin): a review of its use in the prevention and treatment of acute renal allograft rejection. Drugs 2009;69:1483–512. [15] Cicora F, Mos F, Paz M, Roberti J. Clinical experience with thymoglobulin and antithymocyte globulin-Fresenius as induction therapy in renal transplant patients: a retrospective study. Exp Clin Transplant 2013;11:418–22. [16] Woodle ES, Alloway RR, Buell JF, et al. Multivariate analysis of risk factors for acute rejection in early corticosteroid cessation regimens under modern immunosuppression. Am J Transplant 2005;5:2740–4. [17] Mourad G, Morelon E, Noël C, Glotz D, Lebranchu Y. The role of thymoglobulin induction in kidney transplantation: an update. Clin Transplant 2012;26:E450–64. [18] Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant 2011;11:66–76. [19] Webber A, Hirose R, Vincenti F. Novel strategies in immunosuppression: issues in perspective. Transplantation 2011;91:1057–64. [20] Wojciechowski D, Vincenti F. Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation. Semin Immunol 2011;23: 157–64. [21] Vincenti F, Dritselis A, Kirkpatrick P. Belatacept. Nat Rev Drug Discov 2011;10:655–6. [22] Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant 2011;11:2279–96. [23] Kirk AD, Guasch A, Xu H, et al. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant 2014;1142–51. [24] Thiyagarajan UM, Ponnuswamy A, Bagul A. Thymoglobulin and its use in renal transplantation: a review. Am J Nephrol 2013;37:586–601. [25] Grinyo J, Alberu J, Contieri FLC, et al. Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study. Transpl Int 2012;25:1059–64. [26] Aboujaoude M. Intraoperative anti-thymocyte globulin-Fresenius (ATG-F) administration as induction immunosuppressive therapy in kidney transplantation. Mol Immunol 2003;39:1089–94. [27] Chin-Hong PV, Schwartz BS, Bern C, et al. Screening and treatment of chagas disease in organ transplant recipients in the United States: recommendations from the chagas in transplant working group. Am J Transplant 2011;11:672–80.
Contents lists available at ScienceDirect
Transplant Immunology journal homepage: www.elsevier.com/locate/trim
Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: A proof-of-concept study Federico Cicora a,b,1, Fernando Mos a,2, Jorgelina Petroni a,2, Matías Casanova a,2, Liliana Reniero a,2, Javier Roberti b,⁎,3 a b
Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina Foundation for Research and Assistance of Kidney Disease (FINAER), Buenos Aires, Argentina
a r t i c l e
i n f o
Article history: Received 21 August 2014 Received in revised form 5 October 2014 Accepted 6 October 2014 Available online 20 October 2014 Keywords: Belatacept Antithymocyte globulin-Fresenius Induction Steroid Mycophenolate Renal transplantation
a b s t r a c t Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged ≥18 years, Epstein–Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5 h. Mean serum creatinine levels at 1, 3 and 6 months were 1.76 ± 0.59, 1.55 ± 0.60 and 1.49 ± 0.60 mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Kidney transplantation is the preferred treatment for end-stage renal disease, and the preservation of renal function in transplant recipients is crucial to prevent all-cause mortality and major adverse events [1,2]. One of the main reasons for diminished graft function may be the toxicities associated with calcineurin inhibitors (CNIs), which are the cornerstone of immunosuppression after kidney transplantation [1,2]. Moreover, in those patients who receive extended Abbreviations: ATGF, rabbit anti-thymocyte globulin Fresenius; CMV, cytomegalovirus; CNI,calcineurin inhibitors; DGF,delayed graft function;DSA,donor-specific antibodies;EBV, Epstein–Barr virus; IgG, immunoglobulin; KPC, Klebsiella pneumoniae carbapenemase; MMA, mycophenolic acid; NODAT, new-onset diabetes after transplantation; POD, post-operative day; PTLD, post-transplant lymphoproliferative disorder; rATG, rabbit anti-thymocyte globulin; WBC, white blood cells. ⁎ Corresponding author at: Austria 2381, 5D, 1425 Buenos Aires, Argentina. Tel./fax: + 54 11 48027423. E-mail address: [email protected] (J. Roberti). 1 FC Participated in research design, performance of the research, and interpretation of data. 2 FM, JP, MC, LR participated in data collection, interpretation of data, and review of paper. 3 JR participated in research design, literature search, performance of the research, and writing of the paper.
http://dx.doi.org/10.1016/j.trim.2014.10.002 0966-3274/© 2014 Elsevier B.V. All rights reserved.
criteria donor kidneys, which are becoming more common due to the limited availability of standard criteria donor organs, this problem is augmented [3]. It has been demonstrated that belatacept, a first-in-class selective costimulation blocker that inhibits the interaction between CD80/ CD86 and CD28 and prevents T cell activation, provides effective immunosuppression while avoiding the nephrotoxicities associated with CNIs [4–7]. Phase III trials comparing belatacept to cyclosporin in patients receiving a kidney transplant from either living, standard criteria deceased donors or extended criteria deceased donors demonstrated that belatacept was well-tolerated and offered better renal function and similar immunosuppressive efficacy with an improved cardiovascular risk profile [5,7,8]. However, these trials showed that belatacept patients experienced higher rates of acute rejection episodes within six months post-transplantation [5,7–9], and these acute rejection episodes were not typically associated with donorspecific antibodies (DSA) [8]. T cell mediated rejection episodes may increase interstitial fibrosis, tubular atrophy, and global glomerulosclerosis [10]. Indeed, any type of acute cellular rejection is associated with graft dysfunction over time [11]. Therefore, patients could benefit even more if the early acute cellular rejection rate is decreased. Rabbit anti-thymocyte globulin (rATG)-Fresenius (ATGF) is a purified, pasteurized preparation of polyclonal gamma immunoglobulins
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raised in rabbits against human thymocytes and used for the prevention and treatment of acute graft rejection in renal transplant patients [12–15]. It has been shown that induction therapy with antithymocyte globulin reduced the acute graft rejection risk in renal transplant recipients [16,17]. Moreover, thymoglobulin has been used in two belatacept-based regimens (belatacept and mycophenolate mofetil or belatacept with sirolimus) compared to a tacrolimus-based, steroid avoiding regimen; results showed better renal function in the belatacept groups and suggested that this agent could be combined with thymoglobulin induction [18]. Our rationale was to use a combination of immunosuppressive agents that was as similar as possible to the regimen used in the BENEFIT and BENEFIT EXT trials on account of their strong empirical support. We hypothesized that by using an immunosuppressive regimen combining maintenance therapy with belatacept, MMA, and steroids (like in the BENEFIT and BENEFIT EXT trials) but adding induction therapy with ATGF instead of basiliximab, the good results obtained from these studies could be improved by decreasing the early acute rejection rate. Herein, we describe the results of a proof-of-concept prospective study using this new regimen. This prospective, single center, proof-of-concept study included males and females aged 18 years and older who were Epstein–Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft, similarly to BENEFIT and BENEFIT EXT. Only patients with a calculated panel reactive antibody score of 0% were included. Patients with a history of immunosuppression within 1 year before transplant surgery, previous lymphodepletion, immune deficiency, coagulopathy, malignancy, or glomerulopathy with potential for recurrence or those patients with potential for infections were excluded. From 42 patients who underwent single kidney transplantation at Hospital Alemán (Buenos Aires, Argentina) between May of 2013 and December of 2013, we identified 12 patients (32%) who could be administered this regimen. The patients were treated with ATGF (Fresenius SE & Co. KGaA, Bad Homburg, Germany) at 2–5 mg/kg for 5 to 7 doses starting on the day of transplant surgery. When the platelet and white blood cell (WBC) counts dropped to 80,000 and 3000/mm3, respectively, the dose of ATGF was reduced by 50%. If the platelet or WBC count was below 50,000 or 2000/mm3, respectively, ATGF administration was discontinued. The maintenance immunosuppressive regimen consisted of triple therapy with belatacept (Nulojix; Bristol-Myers Squibb, Princeton, NJ, USA), MMA (Myfortic; Novartis, East Hanover, NJ, USA), and corticosteroids. Intravenous belatacept was used at 10 mg/kg on post-operative days (PODs) 1, 5, 15, 28, 56, and 84 and 5 mg/kg every 28 days thereafter; MMA was administered at 720 mg twice daily. Methylprednisolone was used as follows: 500 mg perioperatively, 250 mg on POD 1, and 125 mg on POD 2. Oral meprednisone was used at 20 mg/day for the first month, 15 mg/day between weeks 5 and 6, and 10 mg/day between week 7 and month 6; thereafter, the dose was reduced to 4 mg/day (See Fig. 1). Cytomegalovirus (CMV) prophylaxis consisted of 900 mg/day of valganciclovir for three to six months according to each patient's pre-transplantation mismatch status. Pneumocystis pneumonia prophylaxis was applied on a regular basis for nine months with trimethoprim/ sulfamethoxazole (Bactrim Simple [80/400]). According to the protocol used at our center, borderline, Banff IA, and Banff IB cellular rejection episodes were treated with three pulses of methylprednisolone (500 mg each). Rejection episodes categorized ≥ Banff II were treated with thymoglobulin. According to our protocol, in cases of antibodymediated rejection, belatacept was discontinued, replaced with tacrolimus, and the patients received a combination therapy with intravenous immunoglobulin, bortezomib, and plasmapheresis. The three recipients of Trypanosoma cruzi-infected kidneys did not receive prophylactic treatment for Chagas disease. However, they were screened by PCR
once per week for the first three months post-transplantation, once per month until month 12, and once a year thereafter. In case of T. cruzi infection, treatment comprised benznidazole (5 mg/kg/day for 60–90 days). Transplantation was performed using standard surgical techniques. Biopsies were performed when the patient's serum creatinine level increased by 30%, as compared to the baseline level, and antibodies were measured only in those patients who underwent a biopsy for cause. In 10 patients, surveillance biopsies and DSA measurement were performed between months 3 and 6; in the remaining two patients, biopsies could not be performed due to health insurance problems. Our main objectives were to assess patient and graft survival, acute rejection of the graft, the estimated glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) Study Equation 4, adverse events, and infections. The results are given as frequencies, percentages, means ± SD, medians, and ranges as appropriate. Stata version 11.0 (StataCorp, College Station, TX, USA) was used in our investigation. Twelve patients were transplanted; of these, nine were male and all were Caucasian. The median age of the patients was 53.5 years (range, 27–73 years). In terms of etiology, unknown disease was the most frequent in 5/12 patients and hypertension prior to transplantation was a comorbidity in 8/12 patients. Eleven of twelve patients received a kidney from a deceased donor; one patient received a kidney from a living unrelated donor. The median age of the donors was 58.5 years (range, 2–66 years). Seven of eleven deceased donors met the expanded criteria according to UNOS and as used in BENEFIT EXT trial: donors ≥60 years old, or donors ≥50 years old and who had at least two other risk factors (cerebrovascular accident, hypertension or serum creatinine N1.5 mg/dL) or an anticipated cold ischemia time N 24 h [7]. One patient received en bloc pediatric kidneys. In patient 2, the donor had a Remuzzi score of 7. The mean number of HLA mismatches was 3.75 ± 1.48. Two of twelve (16.7%) patients presented with CMV IgG D/R mismatches. Of note, 3/12 donors were positive for Chagas disease. The median cold ischemia time for the transplant patients with a deceased donor was 21.5 h (range, 15.6–27.7 h). Seven of twelve (58.3%) patients presented with delayed graft function (DGF) and one of twelve presented with surgical complications (urinary fistula). Six of twelve (50%) patients had at least one infection and five of those patients were readmitted to the hospital for treatment. Patient 6, who had an augmented bladder and intermittent urethral catheterization, presented with seven urinary tract infections and two cutaneous mycoses; patient 7, a 71 year-old male, presented with five urinary tract infections, one catheter-related bacteremia, and two bouts of esophageal candidiasis. The other four patients had between one and five infection episodes each. All episodes were successfully treated. Of note, patient 1 had a Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter sp. infection, and patient 5 had a T. cruzi infection transmitted via the graft; both were successfully treated (with meropenem and colistin in the first case and benznidazole in the second). Table 1 shows characteristics of transplant receptors and donors. Table 2 shows post-transplant outcomes. The mean MDRD values for those patients who received a kidney from a deceased donor were as follows: 9.59 ± 4.69, 47.61 ± 24.08, 56.39 ± 26.90, and 56.00 ± 23.50 for week 1 and months 1, 3, and 6, respectively (Fig. 2). Mean serum creatinine levels for all patients at 1, 3 and 6 months were 1.76 ± 0.59, 1.55 ± 0.60 and 1.49 ± 0.60 mg/dl, respectively. Two of twelve (16.7%) patients experienced clinical, biopsyproven rejection (patient 1 with two cellular rejection Banff IA episodes at month 1 and at month 7, and patient 10 with one borderline cellular episode, at month 4). These rejection episodes were successfully treated with three pulses of methylprednisolone (500 mg each). Surveillance biopsies performed between 3 and 6 months post-transplant showed no indication of subclinical cellular or antibody mediated rejection. No BK virus infection was detected and no donor-specific antibodies were
F. Cicora et al. / Transplant Immunology 32 (2015) 35–39
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Table 1 Kidney recipient and donor characteristics. Recipient
Donor
Patient
Age
Genre
Initial nephropathy
Comorbidities
No. of HLA mismatches
Type of donor
Donor's age
Extended criteria
Igg CMV
Chagas
Cold ischemia time, min
1 2 3 4 5 6 7 8 9 10 11 12
52 40 44 67 43 27 64 54 53 54 73 56
Male Male Female Male Male Female Male Male Female Male Male Male
Diabetes Unknown Reflux Unknown Unknown Reflux Unknown Obstructive uropathy Unknown Unknown Nephroangiosclerosis Nephroangiosclerosis
Diabetes None Hypertension Hypertension Hypertension None Hypertension Hypertension None Hypertension Hypertension Hypertension
5 5 1 3 3 2 3 5 3 4 5 6
Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Living
54 54 43 2 59 51 59 58 60 59 66 62
Yes No No No Yes No Yes Yes Yes Yes Yes No
Positive Positive Positive Negative Positive Positive Positive Positive Positive Positive Positive Positive
Negative Positive Positive Negative Negative Negative Negative Negative Negative Negative Positive Negative
1660 1277 1078 1325 1040 1290 1560 1320 1290 1200 936 236
Abbreviations used: CMV, cytomegalovirus; and IgG, immunoglobulin.
Table 2 Outcomes. Outcomes
n (%)
Surgical complications, n (%) DGF, n (%) Hospital readmission, n (%) Opportunistic infection, n (%) Rejection in first 6 months, n (%) Incidence of malignancy, n (%) Incidence of PTLD, n (%) Incidence of NODAT, n (%) Graft loss in first 6 months, n (%) Death in first 6 months, n (%)
1/12 (8.3) 7/12 (58.3) 5/12 (41.7) 6/12 (50) 2/12 (16.7) 0/12 (0) 0/12 (0) 1/11 (9) 0/12 (0) 0/12 (0)
Biochemical outcomes
Median ± SD
Serum creatinine, mg/dL 1 month 3 months 6 months Hemoglobin, d/dL 1 month 3 months 6 months Hematocrit, % 1 month 3 months 6 months White blood cell, mm3 Baseline 1 month 3 months 6 months Lymphocyte cell, total, mm3 1 week 1 month 3 months 6 months Platelet count, mm3 Baseline 1 week 1 month 3 months 6 months Fasting glucose level, mg/dL Baseline 1 month 3 months 6 months Total cholesterol, mg/dL Baseline 3 months 6 months
1.76 ± 0.59 1.55 ± 0.60 1.49 ± 0.45 9.74 ± 1.15 11.54 ± 1.74 11.67 ± 2.05 29.78 ± 3.32 35.75 ± 5.39 36.36 ± 5.16 9811 6526 4803 5764 246 559 627 574
± ± ± ±
± ± ± ±
3424 3074 2712 2518
142 292 387 292
203,000 122,333 249,833 243,750 221,363
± ± ± ± ±
53,846 77,015 95,471 49,184 52,688
108.42 ± 40.37 99.67 ± 15.05 99.00 ± 18.42 108.45 ± 24.31 161.83 ± 44.08 197.17 ± 57.93 192.45 ± 27.67
Abbreviations used: DGF, delayed graft function; PTLD, posttransplant lymphoproliferative disorder; and NODAT, new onset diabetes after transplantation.
identified during follow-up. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. This proof-of-concept study shows a regimen combining belatacept, MMA, steroids, and induction therapy with thymoglobulin provided good results in renal transplant patients. Beforehand, belatacept trials were undertaken given the need to develop agents of comparable efficacy to CNIs but without their toxicities [8,19]. In adults receiving a kidney from living or standard criteria deceased donors, belatacept was associated with superior renal function, similar patient and graft survival rates, and a higher rate of early acute rejection, as compared to cyclosporin [5]. In recipients of extended criteria donor kidneys, belatacept showed an acute rejection rate comparable to that of cyclosporin but an improved cardiovascular/metabolic profile and an increase in the number of cases of PTLD [7]. It has been demonstrated that belatacept offered similar patient and graft survival compared with CsA, with better renal function despite higher rates and higher grades of early acute rejection episodes, which did not tend to recur [4]. In the BENEFIT EXT trial, the incidence of acute rejection was similar between the belatacept and CsA groups at 1 year: 18% in the belatacept groups and 14% in CsA group; importantly, 81% rejection episodes occurred within the first 3 months [7]. Consistent with the favorable results of the BENEFIT and BENEFIT EXT trials [4–7], we observed a very good renal function over six months in all patients, which is especially important in those recipients of extended criteria donor kidneys. In an attempt to explain the rejection rate found in the belatacept groups, it has been suggested that memory cells are costimulatory blockade-resistant and that T cell activation occurs through other costimulatory pathways [20]. Our hypothesis was that a T celldepleting agent such as ATGF used in induction therapy could contribute to a decreased rejection rate through its action on other pathways. In the BENEFIT and BENEFIT EXT trials, acute rejections occurred early after transplantation [21]. To specifically address this point, we used ATGF, as it has been demonstrated that rATG significantly decreases the incidence of early acute rejection in patients at both low and high immunological risk [17]. Moreover, ATGF induction in combination with immunosuppressive therapy is more effective in preventing acute graft rejection than immunosuppressive therapy without induction [14]. We previously found that the incidences of DGF, acute cellular rejection, and antibody-mediated rejection were not significantly different in renal transplant recipients treated with thymoglobulin or ATGF [15]. ATFG is administered during 5–7 days in fixed doses, according to the manufacturer's instructions, but not based on the lymphocyte depletion [15]. The high incidence of DGF may be explained by the predominance of extended criteria donors, factors associated with the graft procurement process, as well as causes related to brain death and ischemic injury
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Fig. 1. Scheme of the immunosuppression regimen.
[22]. In our study, two patients experienced rejection episodes but, importantly, they occurred after immunosuppression had been reduced as a result of infection episodes that were successfully treated. Ferguson et al. [18] conducted the first clinical study of belatacept with thymoglobulin induction and used a mammalian target of rapamycin inhibitor in a comparison of two belatacept-based regimens with a tacrolimus-based, steroid-avoiding regimen and obtained acceptable rates of acute rejection and improved renal function in the belatacept groups. Recently, Kirk et al. [23] investigated a belataceptbased CNI- and steroid-free regimen in recipients of live donor kidneys using alemtuzumab induction and sirolimus and obtained good results with induction therapy. Our results are in accordance with these studies and support the concept of combining a belatacept-based regimen and depletional induction to reduce early belatacept-resistant rejection. PTLD may develop as a side effect of thymoglobulin usage; moreover, in the BENEFIT trials the incidence of PTLD was increased in the belatacept group [5,7,24]. None of the patients presented with PTLD during follow-up, and although all of the recipients in our study were
EBV-positive, close screening should be done. Also in the belatacept trials, more fungal infections were observed in the belatacept group; however, most cases were not serious and were typically mucocutaneous [3,4,25]. Our results coincide with these reports. A double-J stent, a predisposing factor for infection, was used in all of our patients; in addition, the patient with the most infection episodes had an augmented bladder. Therefore, we can only speculate that reducing the use of stents could help decrease the infection rate. In addition, this infection rate could be a result of the potent immunosuppressive therapy: relatively high doses of steroids given the depleting antibody induction and triple maintenance immunosuppression; so, a regimen with a reduced dose of ATGF warrants further investigation. Other side effects of rATG such as thrombocytopenia and anemia [26] were not observed in our study. Three transplant patients received kidneys from T. cruzi-seropositive donors, and a reactivation rate of 8.3–17% has been reported with standard immunosuppression, mainly within the first year or after an increase in immunosuppression [27]. We could not find any studies describing the use of belatacept in this context. The recipients did not receive prophylactic therapy but we performed strict monitoring for the early detection and treatment of reactivation, including weekly PCR tests for two months post-transplantation, every two weeks for the third month, monthly until month 12, and once a year thereafter. One patient showed positive results but was successfully treated with benznidazole. Despite being a proof-of-concept study, we clearly acknowledge the limitations of our work—mainly its short follow-up, a small number of patients and lack of a comparison group. Chagas disease and a KPCproducing bacteria case prove to be a challenge for the regimen. In conclusion, our experience shows that this belatacept-based regimen with ATGF induction therapy provided good renal function, was especially important in recipients with extended criteria donor kidneys, and led to acceptable rejection and infection rates. Notably, the regimen proved efficacious in a challenging context; so, the potential of this approach makes it worthy of further investigation. Disclosure
Fig. 2. Estimated graft filtration rate (calculated using the MDRD formula 4) for 12 patients at baseline, postoperative day 3, week 1, months 1 and 6 of follow-up.
The authors have no conflict of interest in relation to funding of this work.
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