RAPID COMMUNICATION
Safety of Belatacept Bridging Immunosuppression in Hepatitis CYPositive Liver Transplant Recipients With Renal Dysfunction John C. LaMattina,1,3 Mihaela P. Jason,1 Steven I. Hanish,1 Shane E. Ottmann,1 David K. Klassen,2 Darryn Potosky,2 William R. Hutson,2 and Rolf N. Barth1 Background. Perioperative renal dysfunction in liver transplant recipients complicates maintenance immunosuppressive therapy, particularly in patients with hepatitis C. Calcineurin inhibitors exacerbate renal dysfunction and mammalian target-of-rapamycin inhibitors are generally avoided because of perceived perioperative risks. The authors’ experience with seven liver transplant patients who received belatacept and mycophenolic acid maintenance immunosuppression is reported. Methods. A retrospective review of adult liver transplant recipients with hepatitis C receiving belatacept was conducted under Institutional Review Board approval. All patients were Epstein-Barr virus IgG seropositive. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. Results. Between December 19, 2011 and January 25, 2013, seven liver transplant recipients with hepatitis C received belatacept immunosuppression in the perioperative period. The primary indication for belatacept was perioperative renal dysfunction. Belatacept was initiated between 2 and 90 days posttransplant and the duration of belatacept therapy ranged from 19 to 89 days. Patients were transitioned onto calcineurin inhibitor therapy when they reached chronic kidney disease stage 2 or better. Six-month patient and graft survival was 86%. There was one episode of graft rejection on belatacept therapy in a patient who had also had early rejection before initiation of belatacept. Conclusions. The results in this initial group of patients suggest that belatacept with mycophenolic acid may be a safe maintenance immunosuppression regimen in hepatitis CYpositive liver transplant recipients with renal dysfunction, and that this regimen can serve as an effective bridge to calcineurin inhibitor therapy. Keywords: Costimulatory blockade, Chronic kidney disease. (Transplantation 2014;97: 133Y137)
elatacept is a first-in-class immunosuppressant that interferes with T-cell activation via blockade of the CD80/ 86 molecules on antigen-presenting cells. It was approved for use in renal transplantation in June 2011. Because of unfavorable results obtained in phase II trials, its use has not been expanded to liver transplantation. While the long-term
B
The authors declare no funding or conflicts of interest. 1 Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD. 2 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. 3 Address correspondence to: John C. LaMattina, M.D., Division of Transplantation, University of Maryland School of Medicine 29 South Greene Street, Suite 200 Baltimore, MD 21201. E-mail: [email protected] J.C.L. participated in making the concept and design, analyzing and interpreting the data and statistics, and drafting the article. M.P.J. participated in making the concept and design, collecting the data, and performing a critical revision of the article. S.I.H. participated in performing a critical revision of the article. S.E.O. participated in performing a critical revision of article. D.K.K. participated in making the concept and design, and analyzing and
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nephrotoxicity of present alternative immunosuppressive agents is widely reported (1, 2), the 3-year follow-up of renal transplant patients on de novo belatacept therapy in combination with mycophenolate mofetil and initial steroids has shown favorable renal function over time (3). Additionally, improvement in renal function has been noted when patients were switched from a calcineurin inhibitorYbased regimen to belatacept (4). As surgical technique and intensive care capabilities continue to improve perioperative outcomes, increasing focus
interpreting the data and statistics. D.P. participated in performing a critical revision of the article. W.R.H. participated in making the concept and design, and performing a critical revision of the article. R.N.B. participated in making the concept and design, analyzing and interpreting the data and statistics, and performing a critical revision of the article. Received 20 August 2013. Revision requested 9 September 2013. Accepted 17 October 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9702-133 DOI: 10.1097/01.TP.0000438635.44461.2e
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is being directed towards long-term outcomes. Numerous groups have reported pretransplant native renal function and its impact on long-term patient survival (5). Furthermore, it is clear that perioperative renal dysfunction is predictive of future chronic kidney disease (6Y8). Following the introduction of the MELD allocation system, an increasing number of liver transplant patients have a component of acute or chronic kidney disease at the time of liver transplantation (9). The nephrotoxicity profile of available agents complicates the selection of immunosuppressants in liver transplant recipients. Mammalian target-of-rapamycin inhibitors are generally avoided in the perioperative period secondary to complications with wound healing, thrombocytopenia, and the theoretical risk of hepatic artery thrombosis. This is compounded in patients with hepatitis C, in whom many centers attempt to minimize steroid use because of the risk of recurrent hepatitis C in the allograft despite disparate results in randomized trials (10, 11). As the number of patients undergoing liver transplantation for hepatitis C at the center now exceeds 50%, and there have been increasing degrees of renal dysfunction in the patients, this study sought to develop an immunosuppressive strategy that would minimize nephrotoxicity without a dependence on steroid use. There are presently no published studies regarding the use of belatacept in liver transplantation.
RESULTS Recipient Demographics Recipient demographics are presented in Table 1. Indications for Belatacept Belatacept was initiated in all patients because of perioperative renal dysfunction manifested by perioperative dialysis dependence (n=3) or posttransplant oliguria with
TABLE 1.
Demographics
Age, yr Male gender (n, %) Race (n, %) African-American Caucasian BMI, kg/m2 Physiologic MELD Pretransplant diabetes (n, %) Pretransplant HTN (n, %) EBV seropositive (n, %) Indication for transplant (n, %) Hepatitis C Alcoholic liver disease and hepatitis C Simultaneous liver-kidney (n, %) Donor type Donation after brain death donor (n, %) Living donor (n, %) Donor age, yr
55.3T6.4 5 (71%) 1 (14%) 6 (86%) 28.2T4.3 22T11 2 (29%) 3 (43%) 7 (100%) 5 (71%) 2 (29%) 1 (14%) 6 (86%) 1 (14%) 50.0T20.7
BMI, body mass index; EBV, Epstein-Barr virus; HTN, hypertension; MELD, model for end-stage liver disease.
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decreasing creatinine clearance (n=4). Hepatitis C provided a relative contraindication to steroid therapy in these patients. Belatacept was typically started within the first 2 weeks postoperatively (POD 8T5), with the exception of one outlier that was started on POD 90 after failing multiple attempts at low-dose tacrolimus and cyclosporine regimens. Renal Function at Initiation of Belatacept Three patients were on renal replacement therapy at the time of belatacept initiation. The average dialysis time was 9.0T6.7 days. The calculated creatinine clearance was 27T5 mL/min/1.73 m2 in the remaining four patients. The timing of initiation and cessation of belatacept therapy is outlined in Table 2. Recovery of Renal Function All patients recovered renal function. All patients were transitioned to calcineurin inhibitorYbased maintenance immunosuppressive therapy once they approached chronic kidney disease (CKD) stages 1 to 2. Of patients who were on dialysis at the time of belatacept initiation (n=3), the average time on dialysis after belatacept initiation was 5.3T2.9 days. The mean calculated GFR upon transition to calcineurin inhibitors was 86T23 mL/min/1.73 m2, an improvement of 59T28 mL/min/1.73 m2 as compared to before the initiation of belatacept. Patients were maintained on belatacept for 63T21 days. Liver Allograft Rejection One biopsy-proven episode of rejection occurred in a patient on belatacept therapy. This patient had also experienced Banff 5 to 6 rejection before the initiation of belatacept therapy while on low-dose tacrolimus and mycophenolic acid. The rejection episode on belatacept was graded as Banff 4. Patient and Graft Survival All patients and allografts survived for the duration of belatacept therapy. Six-month patient and graft survival was 86%. One patient died of metastatic cholangiocarcinoma. Preoperative imaging had demonstrated a 3-cm lesion thought to be hepatocellular carcinoma. However, on final explant pathology, the mass was consistent with an intrahepatic cholangiocarcinoma greater than 3 cm.
DISCUSSION Although belatacept is presently approved for use in renal transplantation, there is a warning advising against its use in liver transplantation: ‘‘Use of NULOJIX in liver transplant patients is not recommended. In a clinical trial of liver transplant patients, use of NULOJIX regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms.’’ Clinicians have been appropriately cautious in expanding the use of belatacept to liver transplant recipients in the context of such a warning. The data upon which the recommendation was made was published in abstract form (12). It is notable that in this study, 250 liver transplant patients were randomized to receive either tacrolimus with mycophenolate mofetil, tacrolimus alone, more intense
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
TABLE 2.
Belatacept and renal function
Patient Gender 1 2 3 4 5 6 7
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Ethnicity
Male Caucasian Male Caucasian Female Caucasian Male Caucasian Male Caucasian Male African-American Female Caucasian
Days on dialysis CrCl at True Pre-tx Belatacept CrCl at after Days on transition, MELD Pre-tx days on initiated initiation, Age score dialysis dialysis (POD) mL/min/1.73 m2 initiation belatacept mL/min/1.73 m2 45 60 54 61 47 62 58
31 36 30 9 5 26 15
Yes Yes Yes No No No No
7 2 18 None None None None
8 2 3 10 16 11 90
32 On dialysis On dialysis On dialysis 29 28 18
None 9 2 5 None None None
80 57 57 89 71 19 69
76 58 85 114 93 57 120
Marked improvement in creatinine clearance was noted in each patient undergoing belatacept immunosuppression. Pre-tx, pre-transplant; MELD, model for end-stage liver disease; POD, postoperative day; CrCl, creatinine clearance.
(MI) belatacept with mycophenolate mofetil, or less intense (LI) belatacept with mycophenolate mofetil. All patients received steroids for 3 months. In this study, the two belatacept dosing regimens (MI and LI) were similar to the dosing protocols used in the two large randomized trials of belatacept in renal transplantation (13, 14). However, patients in the liver study received one additional dose of belatacept on postoperative day 3. The Food and Drug Administration (FDA)-approved protocol for renal transplantation corresponded to the LI regimen in the renal trials, and it is this protocol that is utilized in our present study (Table 3b). In the phase II study of belatacept in liver transplantation, the primary endpoints of death, graft loss, and acute rejection were more common. In analysis and in consultation with the study authors (Klintmalm, personal communication), it appeared that the majority of deaths in the belatacept cohort were secondary to postoperative complications not directly attributable to belatacept therapy. While acute rejection was more common with belatacept therapy as compared to tacrolimus and mycophenolate mofetil, renal function was improved, and fewer episodes of neurotoxicity and hypertension were noted. As our center has a disproportionate number of recipients whose primary indication for transplantation is
hepatitis C, we have been increasingly faced with the challenges associated with immunosuppressive management in hepatitis CYpositive recipients with renal dysfunction. This population is poorly served by the presently available immunosuppressive regimens. After careful assessment of the phase II liver transplant report, available data regarding the use of belatacept in renal transplantation, and lengthy discussion regarding the risk-to-benefit ratio of its use in closely followed liver transplant recipients, we incorporated belatacept into the institutional immunosuppressive protocol in patients who did not tolerate our standard maintenance therapy of tacrolimus and mycophenolic acid. This was not used as de novo therapy, and patients were transitioned to a calcineurin inhibitorYbased regimen as renal function improved. To avoid the potential for posttransplant lymphoproliferative disorder, only recipients who were seropositive for Epstein-Barr virus were eligible for belatacept. Although a myriad of studies have demonstrated an association between the use of calcineurin inhibitors and the subsequent development of CKD, large single-center studies were unable to demonstrate that an improvement in renal function occurred with decreased dosing of calcineurin inhibitors (7) or that calcineurin inhibitor exposure independently predicted subsequent kidney disease (9). Nonetheless,
TABLE 3A. Standard regimen for hepatitis CYpositive patients with perioperative renal dysfunction undergoing liver transplantation POD 0
POD 1
POD 2
POD 3
With improving renal function
Induction Steroids
Basiliximab 20 mg Basiliximab 20 mg Methylprednisilone Methylprednisilone Methylprednisilone 250 mg 125 mg 65 mg Antimetabolite Mycophenolate Mycophenolate Mycophenolate mofetil Mycophenolate mofetil Mycophenolate mofetil mofetil mofetil 500 mg bid 500 mg bid 500 mg bid or 500 mg bid 500 mg bid mycophenolic acid 360 mg bid Calcineurin inhibitor Tacrolimus (goal 6Y8 ng/mL) Tacrolimus is introduced on postoperative day (POD) 1 in patients with normal renal function, but is generally held in patients with perioperative renal dysfunction. Basiliximab induction is not used in patients with normal renal function.
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TABLE 3B.
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Belatacept protocol
Belatacept dose Mycophenolic acid dose (daily)
Day 0
Day 4
Day 14
Day 28
Month 2
Month 3
Monthly
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
5 mg/kg 360 mg bid
Belatacept was used in patients with hepatitis C who experienced prolonged perioperative renal dysfunction or could not tolerate calcineurin inhibitor therapy. Such patients received induction, a 3-day rapid steroid taper as above, and were maintained on mycophenolic acid. Belatacept was initiated when it became evident that the patients would not be maintained on a calcineurin inhibitor.
the potential correlation between calcineurin inhibitor use and worsening renal function encouraged the authors to utilize belatacept in patients who were not good candidates for prolonged therapy with steroids and mycophenolic acid. It was hypothesized that this would lead to rapid cessation of renal replacement therapy and dialysis catheter removal, facilitating discharge and return to baseline function. While the time spent on dialysis posttransplant was indeed short, as one would expect with a component of hepatorenal syndrome resolving following liver transplantation, these patients continued to demonstrate renal dysfunction. The authors expected this dysfunction, manifested by a CKD stage 3 or greater, to be exacerbated by calcineurininhibitor therapy. Patients were maintained on belatacept until renal function improved to CKD stage 1 to 2. The one patient who received a simultaneous liver-kidney was a predialysis African-American male with minimal muscle mass who had long-standing CKD from hypertension and diabetes mellitus. He was started on belatacept posttransplant for delayed graft function and acute kidney injury following transplantation. It has been shown by Thuluvath et al. that liver transplant recipients with CKD stage 4 or worse (who survived at least 6 months post-liver transplant) had markedly decreased 1-, 2-, and 3-year survival. Other single-center studies have demonstrated strikingly increased mortality in liver transplant recipients requiring postoperative dialysis (40% survival at 3 years vs. 80%) (15). Similar trends noted in other centers have ascribed the decreased survival to increased infectious complications seen in this patient population (16). As an increasing proportion of liver transplant recipients have perioperative renal dysfunction resulting from preferential allocation via the MELD system, liver transplant teams continue to be challenged by renal dysfunction in these recipients. This can be expected to be exacerbated by the increasingly large proportion of patients with hepatitis C in the United States population. In this report of the authors’ initial experience with belatacept in liver transplant recipients with hepatitis C, it appears that belatacept is safe and well tolerated in this population. Recipients rapidly recovered renal function, and a significant incidence of rejection in this small group was not encountered. All patients were transitioned off belatacept during the study period. It is believed that these preliminary findings justify further studies in a larger, randomized clinical trial.
MATERIALS AND METHODS From December 19, 2011 to January 25, 2013, seven liver transplant recipients with hepatitis C were treated with belatacept immunosuppression
in the perioperative period. A retrospective review of these cases was performed after obtaining Institutional Review Board approval. The use of belatacept in liver transplant recipients was approved by the institutional Pharmacy and Therapeutics committee. Detailed informed consent was obtained in which the FDA warning regarding the use of belatacept in liver transplantation was specifically discussed. Patients who were seronegative for Epstein-Barr virus were excluded. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. All patients received methylprednisolone at the time of implantation and were maintained on mycophenolate mofetil (MMF, CellCept; Roche) or mycophenolic acid (Myfortic; Novartis). Steroids were tapered off by postoperative day 3. The general immunosuppressive protocol for liver transplant recipients with renal dysfunction at the time of transplant (Table 3a) includes basiliximab (20 mg, Simulect; Novartis) on POD 0 and 3. Belatacept (Nulojix; Bristol-Myers-Squibb) therapy was initiated between postoperative days (POD) 2 and 90. Belatacept (10 mg/kg) was administered intravenously over 30 minutes on days 0, 4, 14, and 28 and then monthly for two additional months (Table 3b). The dose was then decreased to 5 mg/kg and given monthly thereafter. This regimen corresponds to the regimen used in kidney transplantation (low intensity, or LI). Tacrolimus (Prograf; Fujisawa) or cyclosporine (Neoral; Novartis) were resumed or initiated within 3 months. Unexplained elevations in liver function tests were initially evaluated with duplex ultrasonography of the liver allograft to assess vascular patency. If hepatic vascular flow was normal, percutaneous liver biopsy was performed and evaluated using hematoxylin and eosin staining. Cytomegalovirus prophylaxis was with valganciclovir (Valcyte; Roche) for 6 months. Patients were maintained on trimethoprim and sulfamethoxazole (Bactrim DS, Roche) for 1 year and fluconazole (Diflucan, Pfizer) for 1 month. Renal function was assessed by calculated glomerular filtration rate (GFR) using the Cockcroft-Gault formula, and the calculated GFR correlated to Kidney Disease Outcomes Quality Initiative Chronic Kidney Disease stages. Data is presented as meanTstandard deviation.
ACKNOWLEDGMENT The authors wish to thank Christine Webster for her assistance in the preparation of this manuscript.
REFERENCES 1. 2. 3.
4.
Gaston RS. Chronic calcineurin inhibitor nephrotoxicity: reflections on an evolving paradigm. Clin J Am Soc Nephrol 2009; 4: 2029. de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 2000; 35: 333. Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant 2012;12: 630. Grinyo J, Alberu J, Contieri FL, 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.
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LaMattina et al.
* 2013 Lippincott Williams & Wilkins
5. 6. 7. 8.
9. 10.
Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002; 35: 1179. Lamattina JC, Foley DP, Mezrich JD, et al. Chronic kidney disease stage progression in liver transplant recipients. Clin J Am Soc Nephrol 2011; 6: 1851. Fisher NC, Nightingale PG, Gunson BK, et al. Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation 1998; 66: 59. Gonwa TA, Mai ML, Melton LB, et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation 2001; 72: 1934. Sharma P, Welch K, Eikstadt R, et al. Renal outcomes after liver transplantation in the model for end-stage liver disease era. Liver Transpl 2009; 15: 1142. Klintmalm GB, Davis GL, Teperman L, et al. A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C. Liver Transpl 2011; 17: 1394.
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Llado L, Fabregat J, Castellote J, et al. Impact of immunosuppression without steroids on rejection and hepatitis C virus evolution after liver transplantation: results of a prospective randomized study. Liver Transpl 2008; 14: 1752. Garcia-Valdecasas JC, Feng S, Lake JR, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II study. Liver Transpl 2011; 17: S79. 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. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535. Zand MS, Orloff MS, Abt P, et al. High mortality in orthotopic liver transplant recipients who require hemodialysis. Clin Transplant 2011; 25: 213. Singh N, Gayowski T, Wagener MM. Posttransplantation dialysisassociated infections: morbidity and impact on outcome in liver transplant recipients. Liver Transpl 2001; 7: 100.
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Safety of Belatacept Bridging Immunosuppression in Hepatitis CYPositive Liver Transplant Recipients With Renal Dysfunction John C. LaMattina,1,3 Mihaela P. Jason,1 Steven I. Hanish,1 Shane E. Ottmann,1 David K. Klassen,2 Darryn Potosky,2 William R. Hutson,2 and Rolf N. Barth1 Background. Perioperative renal dysfunction in liver transplant recipients complicates maintenance immunosuppressive therapy, particularly in patients with hepatitis C. Calcineurin inhibitors exacerbate renal dysfunction and mammalian target-of-rapamycin inhibitors are generally avoided because of perceived perioperative risks. The authors’ experience with seven liver transplant patients who received belatacept and mycophenolic acid maintenance immunosuppression is reported. Methods. A retrospective review of adult liver transplant recipients with hepatitis C receiving belatacept was conducted under Institutional Review Board approval. All patients were Epstein-Barr virus IgG seropositive. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. Results. Between December 19, 2011 and January 25, 2013, seven liver transplant recipients with hepatitis C received belatacept immunosuppression in the perioperative period. The primary indication for belatacept was perioperative renal dysfunction. Belatacept was initiated between 2 and 90 days posttransplant and the duration of belatacept therapy ranged from 19 to 89 days. Patients were transitioned onto calcineurin inhibitor therapy when they reached chronic kidney disease stage 2 or better. Six-month patient and graft survival was 86%. There was one episode of graft rejection on belatacept therapy in a patient who had also had early rejection before initiation of belatacept. Conclusions. The results in this initial group of patients suggest that belatacept with mycophenolic acid may be a safe maintenance immunosuppression regimen in hepatitis CYpositive liver transplant recipients with renal dysfunction, and that this regimen can serve as an effective bridge to calcineurin inhibitor therapy. Keywords: Costimulatory blockade, Chronic kidney disease. (Transplantation 2014;97: 133Y137)
elatacept is a first-in-class immunosuppressant that interferes with T-cell activation via blockade of the CD80/ 86 molecules on antigen-presenting cells. It was approved for use in renal transplantation in June 2011. Because of unfavorable results obtained in phase II trials, its use has not been expanded to liver transplantation. While the long-term
B
The authors declare no funding or conflicts of interest. 1 Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD. 2 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. 3 Address correspondence to: John C. LaMattina, M.D., Division of Transplantation, University of Maryland School of Medicine 29 South Greene Street, Suite 200 Baltimore, MD 21201. E-mail: [email protected] J.C.L. participated in making the concept and design, analyzing and interpreting the data and statistics, and drafting the article. M.P.J. participated in making the concept and design, collecting the data, and performing a critical revision of the article. S.I.H. participated in performing a critical revision of the article. S.E.O. participated in performing a critical revision of article. D.K.K. participated in making the concept and design, and analyzing and
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nephrotoxicity of present alternative immunosuppressive agents is widely reported (1, 2), the 3-year follow-up of renal transplant patients on de novo belatacept therapy in combination with mycophenolate mofetil and initial steroids has shown favorable renal function over time (3). Additionally, improvement in renal function has been noted when patients were switched from a calcineurin inhibitorYbased regimen to belatacept (4). As surgical technique and intensive care capabilities continue to improve perioperative outcomes, increasing focus
interpreting the data and statistics. D.P. participated in performing a critical revision of the article. W.R.H. participated in making the concept and design, and performing a critical revision of the article. R.N.B. participated in making the concept and design, analyzing and interpreting the data and statistics, and performing a critical revision of the article. Received 20 August 2013. Revision requested 9 September 2013. Accepted 17 October 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9702-133 DOI: 10.1097/01.TP.0000438635.44461.2e
www.transplantjournal.com
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is being directed towards long-term outcomes. Numerous groups have reported pretransplant native renal function and its impact on long-term patient survival (5). Furthermore, it is clear that perioperative renal dysfunction is predictive of future chronic kidney disease (6Y8). Following the introduction of the MELD allocation system, an increasing number of liver transplant patients have a component of acute or chronic kidney disease at the time of liver transplantation (9). The nephrotoxicity profile of available agents complicates the selection of immunosuppressants in liver transplant recipients. Mammalian target-of-rapamycin inhibitors are generally avoided in the perioperative period secondary to complications with wound healing, thrombocytopenia, and the theoretical risk of hepatic artery thrombosis. This is compounded in patients with hepatitis C, in whom many centers attempt to minimize steroid use because of the risk of recurrent hepatitis C in the allograft despite disparate results in randomized trials (10, 11). As the number of patients undergoing liver transplantation for hepatitis C at the center now exceeds 50%, and there have been increasing degrees of renal dysfunction in the patients, this study sought to develop an immunosuppressive strategy that would minimize nephrotoxicity without a dependence on steroid use. There are presently no published studies regarding the use of belatacept in liver transplantation.
RESULTS Recipient Demographics Recipient demographics are presented in Table 1. Indications for Belatacept Belatacept was initiated in all patients because of perioperative renal dysfunction manifested by perioperative dialysis dependence (n=3) or posttransplant oliguria with
TABLE 1.
Demographics
Age, yr Male gender (n, %) Race (n, %) African-American Caucasian BMI, kg/m2 Physiologic MELD Pretransplant diabetes (n, %) Pretransplant HTN (n, %) EBV seropositive (n, %) Indication for transplant (n, %) Hepatitis C Alcoholic liver disease and hepatitis C Simultaneous liver-kidney (n, %) Donor type Donation after brain death donor (n, %) Living donor (n, %) Donor age, yr
55.3T6.4 5 (71%) 1 (14%) 6 (86%) 28.2T4.3 22T11 2 (29%) 3 (43%) 7 (100%) 5 (71%) 2 (29%) 1 (14%) 6 (86%) 1 (14%) 50.0T20.7
BMI, body mass index; EBV, Epstein-Barr virus; HTN, hypertension; MELD, model for end-stage liver disease.
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decreasing creatinine clearance (n=4). Hepatitis C provided a relative contraindication to steroid therapy in these patients. Belatacept was typically started within the first 2 weeks postoperatively (POD 8T5), with the exception of one outlier that was started on POD 90 after failing multiple attempts at low-dose tacrolimus and cyclosporine regimens. Renal Function at Initiation of Belatacept Three patients were on renal replacement therapy at the time of belatacept initiation. The average dialysis time was 9.0T6.7 days. The calculated creatinine clearance was 27T5 mL/min/1.73 m2 in the remaining four patients. The timing of initiation and cessation of belatacept therapy is outlined in Table 2. Recovery of Renal Function All patients recovered renal function. All patients were transitioned to calcineurin inhibitorYbased maintenance immunosuppressive therapy once they approached chronic kidney disease (CKD) stages 1 to 2. Of patients who were on dialysis at the time of belatacept initiation (n=3), the average time on dialysis after belatacept initiation was 5.3T2.9 days. The mean calculated GFR upon transition to calcineurin inhibitors was 86T23 mL/min/1.73 m2, an improvement of 59T28 mL/min/1.73 m2 as compared to before the initiation of belatacept. Patients were maintained on belatacept for 63T21 days. Liver Allograft Rejection One biopsy-proven episode of rejection occurred in a patient on belatacept therapy. This patient had also experienced Banff 5 to 6 rejection before the initiation of belatacept therapy while on low-dose tacrolimus and mycophenolic acid. The rejection episode on belatacept was graded as Banff 4. Patient and Graft Survival All patients and allografts survived for the duration of belatacept therapy. Six-month patient and graft survival was 86%. One patient died of metastatic cholangiocarcinoma. Preoperative imaging had demonstrated a 3-cm lesion thought to be hepatocellular carcinoma. However, on final explant pathology, the mass was consistent with an intrahepatic cholangiocarcinoma greater than 3 cm.
DISCUSSION Although belatacept is presently approved for use in renal transplantation, there is a warning advising against its use in liver transplantation: ‘‘Use of NULOJIX in liver transplant patients is not recommended. In a clinical trial of liver transplant patients, use of NULOJIX regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms.’’ Clinicians have been appropriately cautious in expanding the use of belatacept to liver transplant recipients in the context of such a warning. The data upon which the recommendation was made was published in abstract form (12). It is notable that in this study, 250 liver transplant patients were randomized to receive either tacrolimus with mycophenolate mofetil, tacrolimus alone, more intense
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
TABLE 2.
Belatacept and renal function
Patient Gender 1 2 3 4 5 6 7
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Ethnicity
Male Caucasian Male Caucasian Female Caucasian Male Caucasian Male Caucasian Male African-American Female Caucasian
Days on dialysis CrCl at True Pre-tx Belatacept CrCl at after Days on transition, MELD Pre-tx days on initiated initiation, Age score dialysis dialysis (POD) mL/min/1.73 m2 initiation belatacept mL/min/1.73 m2 45 60 54 61 47 62 58
31 36 30 9 5 26 15
Yes Yes Yes No No No No
7 2 18 None None None None
8 2 3 10 16 11 90
32 On dialysis On dialysis On dialysis 29 28 18
None 9 2 5 None None None
80 57 57 89 71 19 69
76 58 85 114 93 57 120
Marked improvement in creatinine clearance was noted in each patient undergoing belatacept immunosuppression. Pre-tx, pre-transplant; MELD, model for end-stage liver disease; POD, postoperative day; CrCl, creatinine clearance.
(MI) belatacept with mycophenolate mofetil, or less intense (LI) belatacept with mycophenolate mofetil. All patients received steroids for 3 months. In this study, the two belatacept dosing regimens (MI and LI) were similar to the dosing protocols used in the two large randomized trials of belatacept in renal transplantation (13, 14). However, patients in the liver study received one additional dose of belatacept on postoperative day 3. The Food and Drug Administration (FDA)-approved protocol for renal transplantation corresponded to the LI regimen in the renal trials, and it is this protocol that is utilized in our present study (Table 3b). In the phase II study of belatacept in liver transplantation, the primary endpoints of death, graft loss, and acute rejection were more common. In analysis and in consultation with the study authors (Klintmalm, personal communication), it appeared that the majority of deaths in the belatacept cohort were secondary to postoperative complications not directly attributable to belatacept therapy. While acute rejection was more common with belatacept therapy as compared to tacrolimus and mycophenolate mofetil, renal function was improved, and fewer episodes of neurotoxicity and hypertension were noted. As our center has a disproportionate number of recipients whose primary indication for transplantation is
hepatitis C, we have been increasingly faced with the challenges associated with immunosuppressive management in hepatitis CYpositive recipients with renal dysfunction. This population is poorly served by the presently available immunosuppressive regimens. After careful assessment of the phase II liver transplant report, available data regarding the use of belatacept in renal transplantation, and lengthy discussion regarding the risk-to-benefit ratio of its use in closely followed liver transplant recipients, we incorporated belatacept into the institutional immunosuppressive protocol in patients who did not tolerate our standard maintenance therapy of tacrolimus and mycophenolic acid. This was not used as de novo therapy, and patients were transitioned to a calcineurin inhibitorYbased regimen as renal function improved. To avoid the potential for posttransplant lymphoproliferative disorder, only recipients who were seropositive for Epstein-Barr virus were eligible for belatacept. Although a myriad of studies have demonstrated an association between the use of calcineurin inhibitors and the subsequent development of CKD, large single-center studies were unable to demonstrate that an improvement in renal function occurred with decreased dosing of calcineurin inhibitors (7) or that calcineurin inhibitor exposure independently predicted subsequent kidney disease (9). Nonetheless,
TABLE 3A. Standard regimen for hepatitis CYpositive patients with perioperative renal dysfunction undergoing liver transplantation POD 0
POD 1
POD 2
POD 3
With improving renal function
Induction Steroids
Basiliximab 20 mg Basiliximab 20 mg Methylprednisilone Methylprednisilone Methylprednisilone 250 mg 125 mg 65 mg Antimetabolite Mycophenolate Mycophenolate Mycophenolate mofetil Mycophenolate mofetil Mycophenolate mofetil mofetil mofetil 500 mg bid 500 mg bid 500 mg bid or 500 mg bid 500 mg bid mycophenolic acid 360 mg bid Calcineurin inhibitor Tacrolimus (goal 6Y8 ng/mL) Tacrolimus is introduced on postoperative day (POD) 1 in patients with normal renal function, but is generally held in patients with perioperative renal dysfunction. Basiliximab induction is not used in patients with normal renal function.
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TABLE 3B.
Transplantation
& Volume 97, Number 2, January 27, 2014
Belatacept protocol
Belatacept dose Mycophenolic acid dose (daily)
Day 0
Day 4
Day 14
Day 28
Month 2
Month 3
Monthly
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
10 mg/kg 360 mg bid
5 mg/kg 360 mg bid
Belatacept was used in patients with hepatitis C who experienced prolonged perioperative renal dysfunction or could not tolerate calcineurin inhibitor therapy. Such patients received induction, a 3-day rapid steroid taper as above, and were maintained on mycophenolic acid. Belatacept was initiated when it became evident that the patients would not be maintained on a calcineurin inhibitor.
the potential correlation between calcineurin inhibitor use and worsening renal function encouraged the authors to utilize belatacept in patients who were not good candidates for prolonged therapy with steroids and mycophenolic acid. It was hypothesized that this would lead to rapid cessation of renal replacement therapy and dialysis catheter removal, facilitating discharge and return to baseline function. While the time spent on dialysis posttransplant was indeed short, as one would expect with a component of hepatorenal syndrome resolving following liver transplantation, these patients continued to demonstrate renal dysfunction. The authors expected this dysfunction, manifested by a CKD stage 3 or greater, to be exacerbated by calcineurininhibitor therapy. Patients were maintained on belatacept until renal function improved to CKD stage 1 to 2. The one patient who received a simultaneous liver-kidney was a predialysis African-American male with minimal muscle mass who had long-standing CKD from hypertension and diabetes mellitus. He was started on belatacept posttransplant for delayed graft function and acute kidney injury following transplantation. It has been shown by Thuluvath et al. that liver transplant recipients with CKD stage 4 or worse (who survived at least 6 months post-liver transplant) had markedly decreased 1-, 2-, and 3-year survival. Other single-center studies have demonstrated strikingly increased mortality in liver transplant recipients requiring postoperative dialysis (40% survival at 3 years vs. 80%) (15). Similar trends noted in other centers have ascribed the decreased survival to increased infectious complications seen in this patient population (16). As an increasing proportion of liver transplant recipients have perioperative renal dysfunction resulting from preferential allocation via the MELD system, liver transplant teams continue to be challenged by renal dysfunction in these recipients. This can be expected to be exacerbated by the increasingly large proportion of patients with hepatitis C in the United States population. In this report of the authors’ initial experience with belatacept in liver transplant recipients with hepatitis C, it appears that belatacept is safe and well tolerated in this population. Recipients rapidly recovered renal function, and a significant incidence of rejection in this small group was not encountered. All patients were transitioned off belatacept during the study period. It is believed that these preliminary findings justify further studies in a larger, randomized clinical trial.
MATERIALS AND METHODS From December 19, 2011 to January 25, 2013, seven liver transplant recipients with hepatitis C were treated with belatacept immunosuppression
in the perioperative period. A retrospective review of these cases was performed after obtaining Institutional Review Board approval. The use of belatacept in liver transplant recipients was approved by the institutional Pharmacy and Therapeutics committee. Detailed informed consent was obtained in which the FDA warning regarding the use of belatacept in liver transplantation was specifically discussed. Patients who were seronegative for Epstein-Barr virus were excluded. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. All patients received methylprednisolone at the time of implantation and were maintained on mycophenolate mofetil (MMF, CellCept; Roche) or mycophenolic acid (Myfortic; Novartis). Steroids were tapered off by postoperative day 3. The general immunosuppressive protocol for liver transplant recipients with renal dysfunction at the time of transplant (Table 3a) includes basiliximab (20 mg, Simulect; Novartis) on POD 0 and 3. Belatacept (Nulojix; Bristol-Myers-Squibb) therapy was initiated between postoperative days (POD) 2 and 90. Belatacept (10 mg/kg) was administered intravenously over 30 minutes on days 0, 4, 14, and 28 and then monthly for two additional months (Table 3b). The dose was then decreased to 5 mg/kg and given monthly thereafter. This regimen corresponds to the regimen used in kidney transplantation (low intensity, or LI). Tacrolimus (Prograf; Fujisawa) or cyclosporine (Neoral; Novartis) were resumed or initiated within 3 months. Unexplained elevations in liver function tests were initially evaluated with duplex ultrasonography of the liver allograft to assess vascular patency. If hepatic vascular flow was normal, percutaneous liver biopsy was performed and evaluated using hematoxylin and eosin staining. Cytomegalovirus prophylaxis was with valganciclovir (Valcyte; Roche) for 6 months. Patients were maintained on trimethoprim and sulfamethoxazole (Bactrim DS, Roche) for 1 year and fluconazole (Diflucan, Pfizer) for 1 month. Renal function was assessed by calculated glomerular filtration rate (GFR) using the Cockcroft-Gault formula, and the calculated GFR correlated to Kidney Disease Outcomes Quality Initiative Chronic Kidney Disease stages. Data is presented as meanTstandard deviation.
ACKNOWLEDGMENT The authors wish to thank Christine Webster for her assistance in the preparation of this manuscript.
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