Abstract
Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.
Transplantation; Pediatric Transplantation; Immunosuppression
INTRODUCTION
In the last two decades, significant developments in immunosuppressive therapies have provided transplant teams with more options for the care of transplant patients, with the promise of less toxicity and comparable or better efficacy. There are several potential target sites for immunosuppressive agents in transplantation, with examples demonstrating both established and new agents in Figures 1 and 2. The number of available immunosuppressive agents offers additional therapeutic strategies to provide better patient and allograft survival. The use of these newer agents in children has been limited in clinical studies, leading to off-label usage in pediatric centers based on small case studies. In addition, the long-term risks of newer immunosuppressive agents are not well documented and pose several challenges for clinicians.
Site of Action for Common Immunosuppression Agents in Cell Cycle. The mitotic phase (M) includes prophase, metaphase, anaphase, and telophase. G1 is the first growth phase and includes growth and normal metabolic roles. The synthesis phase (S) is responsible for DNA replication. The second growth phase (G2) includes growth and preparation for mitosis. Sirolimus and everolimus inhibit the cell cycle at the G1 phase, while FK778 inhibits the cell cycle early in the S phase. MMF, azathioprine, and cyclophosphamide directly inhibit nucleotide synthesis in the S phase.
Site of Action of Newer Agents Used in Treatment of Antibody Mediated Rejection (3939. Kirk AD, Turgeon NA, Iwakoshi NN. B cells and transplantation tolerance. Nat Rev Nephrol. 2010;6(10):584-93, http://dx.doi.org/10.1038/nrneph.2010.111.
http://dx.doi.org/10.1038/nrneph.2010.11... ). Abatacept, belatacept, and alemtuzimab inhibit binding at the sites of T and B cells. IVIG, plasmapheresis, and rituximab affect the plasma cells.
ALEMTUZUMAB
Alemtuzumab, a monoclonal antibody targeting the CD52 antigen present on T and B lymphocytes,
natural killer (NK) cells, and monocytes, was first used as an induction agent in kidney transplants
by Calne et al. in 1998 (11. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, et al. Prope tolerance,
perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients.
Lancet. 1998;351(9117):1701-2, http://dx.doi.org/10.1016/S0140-6736(05)77739-4.
http://dx.doi.org/10.1016/S0140-6736(05)...
,22. Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, et al. Campath
IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients.
Transplantation. 1999;68(10):1613-6,
http://dx.doi.org/10.1097/00007890-199911270-00032.
http://dx.doi.org/10.1097/00007890-19991...
). Although not approved by the United States Food and Drug Administration (FDA) for use in
transplantation surgeries, it has gained popularity as an induction agent (11. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, et al. Prope tolerance,
perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients.
Lancet. 1998;351(9117):1701-2, http://dx.doi.org/10.1016/S0140-6736(05)77739-4.
http://dx.doi.org/10.1016/S0140-6736(05)...
,33. Shapiro R, Basu A, Tan HP, Morgan C, Sharma V, Blisard D, et al. Kidney after
nonrenal transplantation-the impact of alemtuzumab induction. Transplantation. 2009;88(6):799-802,
http://dx.doi.org/10.1097/TP.0b013e3181b4aaf5.
http://dx.doi.org/10.1097/TP.0b013e3181b...
,44. De Serres SA, Mfarrej BG, Magee CN, Benitez F, Ashoor I, Sayegh MH, et al. Immune
profile of pediatric renal transplant recipients following alemtuzumab induction. J Am Soc
Nephrol. 2012;23(1):174-82, http://dx.doi.org/10.1681/ASN.2011040360.
http://dx.doi.org/10.1681/ASN.2011040360...
). An intravenous dose of 0.4-0.5 mg/kg, with a maximum dose of 30 mg, resulted in
prolonged lymphocyte depletion (55. Moudgil A, Puliyanda D. Induction therapy in pediatric renal transplant
recipients: an overview. Paediatr Drugs. 2007;9(5):323-41.,66. Tan HP, Donaldson J, Ellis D, Moritz ML, Basu A, Morgan C, et al. Pediatric
living donor kidney transplantation under alemtuzumab pretreatment and tacrolimus monotherapy:
4-year experience. Transplantation. 2008;86(12):1725-31,
http://dx.doi.org/10.1097/TP.0b013e3181903da7.
http://dx.doi.org/10.1097/TP.0b013e31819...
). The effects of alemtuzumab include a profound depletion of total T cells and
differential recovery of CD8+ T cells, with late and only partial recovery of the
CD4+ subsets and relative sparing of CD4+ memory cells (77. Ciancio G, Burke GW 3rd. Alemtuzumab (Campath-1H) in kidney transplantation.
Am J Transplant. 2008;8(1):15-20.
8. Trzonkowski P, Zilvetti M, Chapman S, Wieckiewicz J, Sutherland A, Friend P, et
al. Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant
recipients treated with reduced immunosuppression. Am J Transplant.
2008;8(2):338-47.-99. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, et al.
Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following
antibody-mediated T-cell depletion. Am J Transplant. 2005;5(3):465-74.).
Serres and colleagues prospectively characterized the T cell subsets following lymphocyte
depletion with alemtuzumab induction and the subsequent recovery patterns in children. Three months
following alemtuzumab induction, both memory and naïve cells were depleted to a similar extent.
Within the CD4+ memory subset, there was a slightly greater depletion of the central
memory subset (TCM) compared with the effector memory subset (TEM), the latter
of which is thought to be involved in acute cellular rejection
(p = 0.002). At 24 months post-transplant, the recovery rate of total
CD4+ T cells was slower than that of total CD8+ cells
(p = 0.01), but there was no difference in the magnitude of recovery
of naïve versus memory cells (p = 0.740). Of note, the recovery
of TEM cells was nearly twice that of TCM cells, which is suggestive of an
increased risk of late acute rejection (44. De Serres SA, Mfarrej BG, Magee CN, Benitez F, Ashoor I, Sayegh MH, et al. Immune
profile of pediatric renal transplant recipients following alemtuzumab induction. J Am Soc
Nephrol. 2012;23(1):174-82, http://dx.doi.org/10.1681/ASN.2011040360.
http://dx.doi.org/10.1681/ASN.2011040360...
). Interestingly,
similar to the findings of Pearl et al., who studied an adult population, Serres found that children
have an increased regulatory T-cell to TEM ratio in vivo, which may be
tolerogenic (44. De Serres SA, Mfarrej BG, Magee CN, Benitez F, Ashoor I, Sayegh MH, et al. Immune
profile of pediatric renal transplant recipients following alemtuzumab induction. J Am Soc
Nephrol. 2012;23(1):174-82, http://dx.doi.org/10.1681/ASN.2011040360.
http://dx.doi.org/10.1681/ASN.2011040360...
,99. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, et al.
Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following
antibody-mediated T-cell depletion. Am J Transplant. 2005;5(3):465-74.). The
percentage of children with circulating antibodies over the 2 years of the study was 23%, 50% of
whom developed antibodies between 12 and 24 months (44. De Serres SA, Mfarrej BG, Magee CN, Benitez F, Ashoor I, Sayegh MH, et al. Immune
profile of pediatric renal transplant recipients following alemtuzumab induction. J Am Soc
Nephrol. 2012;23(1):174-82, http://dx.doi.org/10.1681/ASN.2011040360.
http://dx.doi.org/10.1681/ASN.2011040360...
).
Few studies exist on the use of alemtuzumab in children. Retrospective, small case studies have
revealed equal efficacy between alemtuzimab induction and other induction agents, such as daclizumab
and Thymoglobulin®, based on one-year actuarial patient and graft survival and renal function
(55. Moudgil A, Puliyanda D. Induction therapy in pediatric renal transplant
recipients: an overview. Paediatr Drugs. 2007;9(5):323-41.,1010. Ciancio G, Burke GW, Gaynor JJ, Carreno MR, Cirocco RE, Mathew JM, et al. A
randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus,
mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation.
2005;80(4):457-65, http://dx.doi.org/10.1097/01.tp.0000165847.05787.08.
http://dx.doi.org/10.1097/01.tp.00001658...
). Tan et al.
retrospectively reviewed 42 consecutive living donor kidney transplantations performed over 4 years,
in which the recipients received alemtuzumab prior to graft revascularization followed by tacrolimus
monotherapy with spaced weaning. Of the 42 living donor transplants, 13 underwent transplant
biopsies for a rising serum creatinine from baseline, and only 2 patients (4.8%) were diagnosed with
acute cellular rejection (ACR). Every three months, the recipients were screened for anti-HLA
antibodies and donor-specific antibodies were identified and characterized by Luminex assays. None
of the patients in this study developed antibody-mediated rejection (AMR) (66. Tan HP, Donaldson J, Ellis D, Moritz ML, Basu A, Morgan C, et al. Pediatric
living donor kidney transplantation under alemtuzumab pretreatment and tacrolimus monotherapy:
4-year experience. Transplantation. 2008;86(12):1725-31,
http://dx.doi.org/10.1097/TP.0b013e3181903da7.
http://dx.doi.org/10.1097/TP.0b013e31819...
).
There are certain settings in kidney transplantation where alemtuzumab may not necessarily be the
ideal induction agent. In a small case series of complicated pediatric kidney transplant cases
described by Bartosh and colleagues, alemtuzumab was associated with higher rates of rejection
(1111. Bartosh SM, Knechtle SJ, Sollinger HW. Campath-1H use in pediatric renal
transplantation. Am J Transplant. 2005;5(6):1569-73.). In addition, the use of alemtuzumab may be problematic
in kidney transplantations following a liver transplant in a hepatitis C virus-positive recipient or
a recently transplanted patient who received heavy immunosuppression for the nonrenal organ, as this
can be associated with higher rates of infection and a possible increased risk of post-transplant
lymphoproliferative disorder (PTLD) (33. Shapiro R, Basu A, Tan HP, Morgan C, Sharma V, Blisard D, et al. Kidney after
nonrenal transplantation-the impact of alemtuzumab induction. Transplantation. 2009;88(6):799-802,
http://dx.doi.org/10.1097/TP.0b013e3181b4aaf5.
http://dx.doi.org/10.1097/TP.0b013e3181b...
).
SIROLIMUS
The introduction of cyclosporine in the 1980s dramatically transformed the field of
transplantation. The success of calcineurin inhibitor (CNI)-based immunosuppression, however, is
limited by nephrotoxicity. This limitation has led to an interest in CNI-free immunosuppressive
regimens, but a solution remains elusive. Children with end-stage liver, intestinal, lung, and heart
diseases are able to undergo organ transplantation, but the long-term consequences following
non-renal solid organ transplantation include chronic kidney disease, end-stage renal disease, and
the need for future kidney transplantation (1212. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal
failure after transplantation of a nonrenal organ. N Engl J Med.
2003;349(10):931-40.). The
withdrawal of CNIs after a period of time after transplantation and conversion to CNI-free regimens
have been attempted with mixed results (1313. Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, et al. Multicenter
trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation.
2001;71(9):1282-7, http://dx.doi.org/10.1097/00007890-200105150-00017.
http://dx.doi.org/10.1097/00007890-20010...
14. Schena FP, Pascoe MD, Alberu J, del Carmen Rial M, Oberbauer R, Brennan DC, et
al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft
recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation.
2009;87(2):233-42, http://dx.doi.org/10.1097/TP.0b013e3181927a41.
http://dx.doi.org/10.1097/TP.0b013e31819...
-1515. Flechner SM, Glyda M, Cockfield S, Grinyó J, Legendre Ch, Russ G, et al.
The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate
mofetil in renal allograft recipients. Am J Transplant.
2011;11(8):1633-44.). In recent years, there have been promising new agents that
have become available for clinical use.
Sirolimus is a macrolide compound derived from Actinomyces hygroscopicus. It is
structurally similar to tacrolimus and was introduced for clinical use in organ transplantation in
1999 (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
). Sirolimus binds to the mammalian target of
rapamycin (mTOR) in T cells, suppressing T-cell proliferation by inhibiting the progression from the
G1 to S phase of the cell cycle. Sirolimus allows T cell activation but prevents the cells from
proliferating in response to IL-2, which inhibits growth factor-induced proliferation of lymphocytes
and cells of mesenchymal origin. Sirolimus has anti-proliferative effects on fibroblasts,
endothelial cells, and smooth muscle cells that make it a promising agent for the prevention of
chronic allograft nephropathy and the progression of kidney disease in non-renal solid organ
transplantation (1515. Flechner SM, Glyda M, Cockfield S, Grinyó J, Legendre Ch, Russ G, et al.
The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate
mofetil in renal allograft recipients. Am J Transplant.
2011;11(8):1633-44.,1717. Gao XM, Wong G, Wang B, Kiriazis H, Moore XL, Su YD, et al. Inhibition of mTOR
reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens.
2006;24(8):1663-70, http://dx.doi.org/10.1097/01.hjh.0000239304.01496.83.
http://dx.doi.org/10.1097/01.hjh.0000239...
18. Paoletti E, Cannella G. Reducing the risk of left ventricular hypertrophy in
kidney transplant recipients: the potential role of mammalian target of rapamycin. Transplant Proc.
2009;41(6 Suppl):S3-5, http://dx.doi.org/10.1016/j.transproceed.2009.06.091.
http://dx.doi.org/10.1016/j.transproceed...
19. Wang S, Wilkes MC, Leof EB, Hirschberg R. Noncanonical TGF-beta pathways, mTORC1
and Abl, in renal interstitial fibrogenesis. Am J Physiol Renal Physiol.
2010;298(1):F142-9, http://dx.doi.org/10.1152/ajprenal.00320.2009.
http://dx.doi.org/10.1152/ajprenal.00320...
20. Chinnock TJ, Shankel T, Deming D, Cutler D, Sahney S, Fitts J, et al.
Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric
heart transplant recipients. Pediatr Transplant. 2011;15(7):746-9,
http://dx.doi.org/10.1111/j.1399-3046.2011.01566.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
21. Gibelli NE, Tannuri U, Pinho-Apezzato ML, Tannuri AC, Maksoud-Filho JG, Andrade
WC, et al. Sirolimus in pediatric liver transplantation: a single-center experience. Transplant
Proc. 2009;41(3):901-3, http://dx.doi.org/10.1016/j.transproceed.2009.01.054.
http://dx.doi.org/10.1016/j.transproceed...
22. Herlenius G, Felldin M, Nordén G, Olausson M, Bäckman L, Gustafsson B,
et al. Conversion from calcineurin inhibitor to either mycophenolate mofetil or sirolimus improves
renal function in liver transplant recipients with chronic kidney disease: results of a prospective
randomized trial. Transplant Proc. 2010;42(10):4441-8,
http://dx.doi.org/10.1016/j.transproceed.2010.09.113.
http://dx.doi.org/10.1016/j.transproceed...
-2323. Gustafsson F, Ross HJ. Renal-sparing strategies in cardiac transplantation. Curr
Opin Organ Transplant. 2009;14(5):566-70,
http://dx.doi.org/10.1097/MOT.0b013e32832e6f7b.
http://dx.doi.org/10.1097/MOT.0b013e3283...
).
Sirolimus is a hydrophobic agent that has rapid bioavailability. Variable effects can occur
depending on food consumption, with oral suspension bioavailability decreasing with high-fat meals
but increasing if tablets are administered. It is metabolized by the cytochrome P450 3A isoenzyme in
the intestinal wall and liver. The half-life of sirolimus in adult renal transplant patients is
62±16 hours, but small trials have demonstrated more rapid clearance in younger children (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
,2424. Mukherjee S, Mukherjee U. A comprehensive review of immunosuppression used for
liver transplantation. J Transplant. 2009;2009:701464.).
The most common side effects of sirolimus are dose-related and include hyperlipidemia and a
variety of cytopenias. Interstitial lung disease and mouth ulcers have also been reported in adult
and pediatric patients treated with sirolimus. Although sirolimus is not generally thought to be
nephrotoxic, it can be associated with proteinuria, which can lead to nephrotic syndrome and
subsequent kidney injury (2525. Boratyńska M, Banasik M, Watorek E, Falkiewicz K, Patrzałek D,
Szyber P, et al. Conversion to sirolimus from cyclosporine may induce nephrotic proteinuria and
progressive deterioration of renal function in chronic allograft nephropathy patients. Transplant
Proc. 2006;38(1):101-4, http://dx.doi.org/10.1016/j.transproceed.2005.12.023.
http://dx.doi.org/10.1016/j.transproceed...
).
The use of sirolimus in children has not been well described, with most of the available clinical
information originating from single-center case studies. Many groups are attempting CNI minimization
and avoidance protocols with mTOR inhibitors, such as everolimus or sirolimus, to prevent
post-transplant CKD. Chinnock and colleagues minimized CNI exposure by adding sirolimus to the
immunosuppression protocol when pediatric heart transplant recipients developed renal insufficiency
(GFR<60 mL/min/1.73 m2) and found that renal function improved or stabilized
following CNI minimization (2020. Chinnock TJ, Shankel T, Deming D, Cutler D, Sahney S, Fitts J, et al.
Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric
heart transplant recipients. Pediatr Transplant. 2011;15(7):746-9,
http://dx.doi.org/10.1111/j.1399-3046.2011.01566.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
). Hynes and colleagues
examined the use of sirolimus-based calcineurin inhibitor-free immunosuppression in renal
transplantation. They found that sirolimus-based immunosuppression could be successfully used in
low-risk patients and first-time transplant recipients without histological evidence of acute
rejection on a three-month surveillance biopsy. After five years, they found that apthous ulcers and
BK virus viremia were the most prevalent adverse events (2626. Hymes LC, Warshaw BL. Five-year experience using sirolimus-based, calcineurin
inhibitor-free immunosuppression in pediatric renal transplantation. Pediatr Transplant.
2011;15(4):437-41, http://dx.doi.org/10.1111/j.1399-3046.2011.01477.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
).
The role of sirolimus in CNI minimization is also being explored in other solid organ
transplantations. Gibelli and colleagues found that conversion from CNI to sirolimus was safe, with
no increased rates of rejection following pediatric liver transplantation (2121. Gibelli NE, Tannuri U, Pinho-Apezzato ML, Tannuri AC, Maksoud-Filho JG, Andrade
WC, et al. Sirolimus in pediatric liver transplantation: a single-center experience. Transplant
Proc. 2009;41(3):901-3, http://dx.doi.org/10.1016/j.transproceed.2009.01.054.
http://dx.doi.org/10.1016/j.transproceed...
).
EVEROLIMUS
Everolimus is a macrocyclic lactone that was first isolated from Streptomyces
hygroscoicus. It is a derivative of sirolimus and shares its mechanism of action. The
advantages of everolimus are that it is more hydrophilic, demonstrating a shorter half-life of
approximately 30 hours, and has greater bioavailability compared with sirolimus. Everolimus is
metabolized by the cytochrome 450 3A isoenzymes and, similar to sirolimus, is also affected by
dietary changes (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
).
Based on experimental animal models and experience in cardiac transplantation, everolimus also
appears to have antiproliferative effects on vascular smooth muscle cells and fibroblasts (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
,2727. Mjörnstedt L, Sørensen SS, von Zur Mühlen B, Jespersen B, Hansen
JM, Bistrup C, et al. Improved renal function after early conversion from a calcineurin inhibitor to
everolimus: a randomized trial in kidney transplantation. Am J Transplant.
2012;12(10):2744-53.). The
antiproliferative action of everolimus in the arterial wall has been shown to inhibit atherogenic
and intimal wall remodeling in pre-clinical studies. It is also involved in a critical part of the
cell cycle that has significant antineoplastic potential as a promoter of apoptosis and inhibitor of
angiogenesis (2828. Pape L, Ganschow R, Ahlenstiel T. Everolimus in pediatric transplantation. Curr
Opin Organ Transplant. 2012;17(5):515-9,
http://dx.doi.org/10.1097/MOT.0b013e328356b080.
http://dx.doi.org/10.1097/MOT.0b013e3283...
).
Ettenger and colleagues used a CNI minimization protocol comprising everolimus, cyclosporine, and
corticosteroids following kidney transplantation. Of the 19 pediatric patients enrolled, 15 were
followed for 3 years. The patient survival rate was 100%, and the allograft survival rate was 93%.
Three patients had infectious complications, 4 patients developed rejection, 4 patients required
treatment with statins for hypercholesterolemia, and the average serum creatinine was 1.1 mg/dL
after 3 years (2929. Ettenger R, Hoyer PF, Grimm P, Webb N, Loirat C, Mahan JD, et al. Multicenter
trial of everolimus in pediatric renal transplant recipients: results at three year. Pediatr
Transplant. 2008;12(4):456-63, http://dx.doi.org/10.1111/j.1399-3046.2007.00832.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
). Another prospective study examined 20
children who received basiliximab, cyclosporine A, and prednisolone for immunosuppression. Two weeks
following kidney transplantation, everolimus was initiated and cyclosporine A was reduced by 50%.
Pape and colleagues found that the mean GFR at 1 and 3 years was 71 and 61 mL/min/1.73
m2, respectively. There were no cases of post-transplant lymphoproliferative disorder,
acute rejection, or polyoma nephropathy, and 85% of the patients remained on the original
immunosuppressive regimen (3030. Pape L, Lehner F, Blume C, Ahlenstiel T. Pediatric kidney transplantation
followed by de novo therapy with everolimus, low-dose cyclosporine A, and steroid elimination:
3-year data. Transplantation. 2011;92(6):658-62,
http://dx.doi.org/10.1097/TP.0b013e3182295bed.
http://dx.doi.org/10.1097/TP.0b013e31822...
).
Although only limited pediatric studies have been performed to evaluate the efficacy of
everolimus in liver and heart transplantation, the early adult data are promising. A study in
pediatric heart transplant recipients showed that conversion to CNI-free immunosuppression with
everolimus and mycophenolate when the GFR fell below 75 mL/min/1.73 m2 resulted in
improved renal function within 6 months of CNI withdrawal in pediatric heart transplant recipients
(3131. Behnke-Hall K, Bauer J, Thul J, Akintuerk H, Reitz K, Bauer A, et al. Renal
function in children with heart transplantation after switching to CNI-free immunosuppression with
everolimus. Pediatr Transplant. 2011;15(8):784-9,
http://dx.doi.org/10.1111/j.1399-3046.2011.01550.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
). The possible benefit of the anti-fibrotic effects of
everolimus, as well as its lack of nephrotoxicity, make it a promising immunosuppressive agent in
pediatric transplantation (2828. Pape L, Ganschow R, Ahlenstiel T. Everolimus in pediatric transplantation. Curr
Opin Organ Transplant. 2012;17(5):515-9,
http://dx.doi.org/10.1097/MOT.0b013e328356b080.
http://dx.doi.org/10.1097/MOT.0b013e3283...
).
BELATACEPT
Belatacept is a biological agent that is a selective co-stimulation blocker of T cells. It is a
fully human fusion protein of the CTLA4 extracellular domain with fragments of the Tc domain of
human IgG1, and it has a binding affinity to CD86/CD80 on the antigen-presenting cell, thus
resulting in the blockade of T-cell activation (3232. Arora S, Tangirala B, Osadchuk L, Sureshkumar KK. Belatacept: a new biological
agent for maintenance immunosuppression in kidney transplantation. Expert Opin Biol Ther.
2012;12(7):965-79, http://dx.doi.org/10.1517/14712598.2012.683522.
http://dx.doi.org/10.1517/14712598.2012....
,3333. Goldzweig O, Hashkes PJ. Abatacept in the treatment of polyarticular JIA:
development, clinical utility, and place in therapy. Drug Des Devel Ther.
2011;5:61-70.). The activation of T cells involves the presentation of a
peptide by an antigen-presenting cell to the T cell receptor, followed by costimulatory associations
between the ligands on the antigen-presenting cell and T cell receptors (3333. Goldzweig O, Hashkes PJ. Abatacept in the treatment of polyarticular JIA:
development, clinical utility, and place in therapy. Drug Des Devel Ther.
2011;5:61-70.). In addition, belatacept indirectly inhibits antigen-specific antibody (IgG,
IgM, and IgA) production by B lymphocytes, resulting in lower mean immunoglobulin concentrations
compared with that resulting from cyclosporine-based therapy (3232. Arora S, Tangirala B, Osadchuk L, Sureshkumar KK. Belatacept: a new biological
agent for maintenance immunosuppression in kidney transplantation. Expert Opin Biol Ther.
2012;12(7):965-79, http://dx.doi.org/10.1517/14712598.2012.683522.
http://dx.doi.org/10.1517/14712598.2012....
). Belatacept requires intravenous infusion, and the total infusion dose is based on the
body weight of the patient. A dose of 10 mg/kg is administered on the day of transplantation, day 5,
and at 2, 4, 8, and 12 weeks, followed by 5 mg/kg at the end of week 16 and every 4 weeks thereafter
for maintenance (3232. Arora S, Tangirala B, Osadchuk L, Sureshkumar KK. Belatacept: a new biological
agent for maintenance immunosuppression in kidney transplantation. Expert Opin Biol Ther.
2012;12(7):965-79, http://dx.doi.org/10.1517/14712598.2012.683522.
http://dx.doi.org/10.1517/14712598.2012....
,3434. Bristol-Myers Squibb. Nulojix: Highlights of Prescribing Information. Retrieved
from http://packageinserts.bms.com/pi/pi_nulojix.pdf (2013).).
The BENEFIT trial has resulted in the publication of data on adult kidney transplant recipients, including three year outcome data. BENEFIT was a randomized, three-year, phase III study in adults receiving either a standard deceased or living donor kidney transplant. The patients were randomized to a more intense regimen (MI), a less intense regimen (LI), or cyclosporine. Of the 666 patients who completed at least 3 years of therapy, 92% of the MI, 92% of the LI, and 89% of the cyclosporine patients survived with a functioning allograft. At 3 years, the average calculated GFR was 21 mL/min/1.73 m2 higher in the belatacept group compared with the cyclosporine group. This difference in GFR between the belatacept and cyclosporine groups was enough to classify the mean GFR as stage II (65 mL/min/1.73 m2) verses stage III (44 mL/min/1.73 m2) chronic kidney disease. Overall, stage II or better chronic kidney disease represented 69% of the MI, 71% of the LI, and only 29% of the cyclosporine-based treatment groups at 3 years. In addition to improved renal function, donor-specific antibodies occurred in 6% of MI, 5% of LI, and 11% of the cyclosporine treatment arms. The cumulative rates of acute rejection were 24% in the MI, 17% in the LI, and 10% in the cyclosporine group at year 3. Despite an early increased occurrence of acute rejection and post-transplant proliferative disorder, especially in EBV seronegative patients, belatacept-treated patients maintained a comparable rate of patient and graft survival with cyclosporine but had better renal function (3535. Vincenti F, Larsen CP, Alberu J, Bresnahan B, Garcia VD, Kothari 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(1):210-7.).
To date, clinical trials using belatacept have been conducted exclusively in adult patients, and
no clinical trials in children have been listed through the National Institute of Health (3636. U.S. National Institutes of Health. ClinicalTrials.gov. Available from:
www.clinicaltrials.gov.
www.clinicaltrials.gov...
). Abatacept is a first-generation biological agent with a
similar mechanism of action to belatacept, but it is used in patients with autoimmune disorders and
not transplant patients. The pharmacokinetics of either abatacept or belatacept have not been
studied specifically in children or adolescents. The efficacy of abatacept in the treatment of
juvenile rheumatoid arthritis was studied by the Pediatric Rheumatology International Trials
Organization and the Pediatric Rheumatology Collaborative Study Group in a population with ages
ranging from 6-17 years. The trial was a randomized, double-blind, placebo-controlled withdrawal
study that was performed at 45 centers in Europe and the United States between 2004 and 2006 and
enrolled 190 patients. Several adverse events were documented, including a total of 95 infections in
the open-label, lead-in, and controlled withdrawal phases and 1 serious infection secondary to
varicella zoster. In the open-label, long-term extension phase spanning an average of 35 months,
there were 6 serious infections, including dengue fever, erysipelas, gastroenteritis, herpes zoster,
bacterial meningitis, and pyelonephritis. EBV or CMV disease was not mentioned (3737. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, et al.
Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind,
placebo-controlled withdrawal trial. Lancet. 2008;372(9636):383-91,
http://dx.doi.org/10.1016/S0140-6736(08)60998-8.
http://dx.doi.org/10.1016/S0140-6736(08)...
). In 2009, the United States Food and Drug Administration (FDA)
examined the 5-year post-marketing data of 90 patients treated with abatacept. Six serious adverse
events were reported, four of which occurred in the United States. One case of multiple sclerosis
(MS) and lymphoma occurred one month after starting abatacept, and the other serious events included
skin infection, dyspnea, purpura, and transaminitis. The child who developed MS also developed
temporal lobe epilepsy 19 months after starting abatacept for the treatment of JIA. He was also on
methotrexate and ondansetron, which have been associated with the development of epilepsy. The child
who developed lymphoma initially developed lymphomatoid papulosis 1 month after starting abatacept
for vasculitis and had been on immunosuppressive therapy for 10 years (3838. Elizabeth L. Durmowicz. Pediatric Focused Safety Review: Abatacept
(Orencia®). Pediatric Advisory Committee Meeting. 2009. Available from:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/ucm193143.pdf.
http://www.fda.gov/downloads/AdvisoryCom...
).
Although belatacept has not been used in pediatric transplantation, it may have a role in the future. The method of administration may positively affect rates of medication administration non-compliance, which is a particular problem in adolescent and young adult transplant management. The higher rates of PTLD were concentrated in patients who were seronegative for Epstein-Bar virus (EBV) and those who were in the MI arm (3535. Vincenti F, Larsen CP, Alberu J, Bresnahan B, Garcia VD, Kothari 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(1):210-7.). This may be problematic for the extension of belatacept in pediatric patients, as many of these patients are seronegative for EBV at the time of transplantation.
BORTEZOMIB
Historically, T-cell-mediated mechanisms have been considered to be the main cause of allograft
rejection. However, the role of humoral responses, particularly those mediated by alloantibodies,
has increasingly being implicated in allograft rejection (3939. Kirk AD, Turgeon NA, Iwakoshi NN. B cells and transplantation tolerance. Nat Rev
Nephrol. 2010;6(10):584-93, http://dx.doi.org/10.1038/nrneph.2010.111.
http://dx.doi.org/10.1038/nrneph.2010.11...
). As antibody-mediated rejection (AMR) has gained recognition, so has the realization
that traditional therapies for AMR, including IVIG, plasmapheresis, rituximab, and antilymphocyte
preparations, are inconsistent in efficacy (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor
therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.).
Bortezomib is a proteasome inhibitor. The 26S proteasome is the site of degradation of nearly all intracellular proteins. Damaged and misfolded proteins, as well as proteins targeted for degradation, are all degraded in the proteasome. Proteasome inhibition induces endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and terminal UPR. The UPR involves the inhibition of translation and, therefore, immunoglobulin production, and it also increases the cellular capacity to repair misfolded or unfolded proteins. Proteasome inhibition also induces programmed cell death by cell cycle arrest in cells undergoing mitosis at specific checkpoints (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.). In vivo studies have demonstrated that proteasome inhibitors can result in the deletion of non-transformed plasma cells, which manufacture alloantibodies (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.).
Bortezomib is approved by the FDA for the treatment of multiple myeloma (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor
therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.). A variety of protocols exist for treatment of AMR with boretzomib, and
examples are listed in Table 1. In transplant patients,
it was initially studied for the treatment of refractory AMR. Bortezomib has been demonstrated to
reduce donor-specific antibodies in both heart and kidney transplant patients (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor
therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.
41. Cenci S, Sitia R. Managing and exploiting stress in the antibody factory. FEBS
Lett. 2007;581(19):3652-7, http://dx.doi.org/10.1016/j.febslet.2007.04.031.
http://dx.doi.org/10.1016/j.febslet.2007...
-4242. van Anken E, Romijn EP, Maggioni C, Mezghrani A, Sitia R, Braakman I, et al.
Sequential waves of functionally related proteins are expressed when B cells prepare for antibody
secretion. Immunity. 2003;18(2):243-53,
http://dx.doi.org/10.1016/S1074-7613(03)00024-4.
http://dx.doi.org/10.1016/S1074-7613(03)...
). Everly and colleagues used
bortezomib to treat patients with refractory renal allograft rejection and found that bortezomib
therapy was associated with improved renal function and renal allograft histology, as well as
reductions in DSA levels. To remove circulating antibodies, plasmapheresis is necessary in addition
to bortezomib administration (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor
therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.,4343. Everly MJ, Everly JJ, Susskind B, Brailey P, Arend LJ, Alloway RR, et al.
Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection.
Transplantation. 2008;86(12):1754-61,
http://dx.doi.org/10.1097/TP.0b013e318190af83.
http://dx.doi.org/10.1097/TP.0b013e31819...
). Utilizing rituximab at the start of treatment was found to reduce plasma cell
antibody production prior to depletion with bortezomib (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor
therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.).
Morrow and colleagues treated four pediatric heart transplant patients with refractory AMR, who had
failed plasmapheresis, intravenous immunoglobulin, and rituximab, with intravenous bortezomib,
rituximab, and plasmapheresis. The patients had improved systolic function, and conversion to
C4d-negative biopsies was observed in 75% of patients. Additionally, 25% of patients became
IgG-negative and had a prompt and precipitous reduction in DSAs (4444. Morrow WR, Frazier EA, Mahle WT, Harville TO, Pye SE, Knecht KR, et al. Rapid
reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of
antibody-mediated rejection with bortezomib in pediatric heart transplant patients. Transplantation.
2012;93(3):319-24, http://dx.doi.org/10.1097/TP.0b013e31823f7eea.
http://dx.doi.org/10.1097/TP.0b013e31823...
). Although studies have demonstrated the effectiveness of bortezomib, there are several
case reports and small case studies that revealed bortezomib to be ineffective in prolonging graft
survival, despite decreasing the DSA load, in prolonged or refractory AMR (4545. Schwaiger E, Regele H, Wahrmann M, Werzowa J, Haidbauer B, Schmidt A, et al.
Bortezomib for the treatment of chronic antibody-mediated kidney allograft rejection: a case report.
Clin Transpl. 2010:391-6.,4646. Wong W, Lee RA, Saidman SL, Smith RN, Zorn E. Bortezomib in kidney transplant
recipients with antibody mediated rejection: three case reports. Clin Transpl.
2009:401-5.).
The University of Cincinnati developed a collaborative study group of transplant centers, the START collaboration, and has studied the use of bortezomib in over 91 solid organ transplants with 107 episodes of AMR. The experience included both adult and pediatric kidney, pancreas, and intestinal, as well as pediatric and adult heart, transplant recipients. Bortezomib provided effective treatment in all types of solid organ transplants studied (4040. Woodle ES, Walsh RC, Alloway RR, Girnita A, Brailey P. Proteasome inhibitor therapy for antibody-mediated rejection. Pediatr Transplant. 2011;15(6):548-56.).
ECULIZUMAB
Atypical hemolytic uremic syndrome (aHUS) is a disease of the microvasculature characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury, with more than 50% of patients progressing to end-stage renal disease (ESRD) (4747. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.,4848. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2011;6(6):1488-94.). The diagnosis of aHUS is made based on a lack of associated disease, criteria for Shigatoxin-HUS, and criteria for thrombotic thrombocytopenic purpura (TTP), with serum ADAMTS 13 activity >10%. Onset can vary from infancy to adulthood. Additionally, 2-10% die, 1/3 progress to ESRD after the first episode, and 50% of the patients have relapses. There is a high risk of post-transplant recurrence, except in the setting of membrane cofactor protein disease, in which case most patients have preserved renal function. The most frequent mutations are located in complement factor H (CFH), and the disease recurs in nearly 80% of patients transplanted with CFH mutations (4747. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.,4949. Krid S, Roumenina LT, Beury D, Charbit M, Boyer O, Frémeaux-Bacchi V, et al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant. 2012;12(7):1938-44.).
The known pathogenesis of aHUS is primarily related to the dysregulation of the complement
cascade. In approximately 50% of affected patients, mutations in genes encoding complement proteins
result in impaired regulation of the complement alternative pathway, leading to inappropriate
complement activation in platelets and endothelial cells, primarily within the kidney (5050. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab
prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol.
2011;26(8):1325-9, http://dx.doi.org/10.1007/s00467-011-1879-9.
http://dx.doi.org/10.1007/s00467-011-187...
). Until recently, renal transplantation alone has not been an
effective treatment option for aHUS patients because of high morbidity and mortality rates primarily
associated with disease recurrence and premature liver failure secondary to uncontrolled complement
activation (4848. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al. Pre-emptive
eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome.
Clin J Am Soc Nephrol. 2011;6(6):1488-94.,5050. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab
prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol.
2011;26(8):1325-9, http://dx.doi.org/10.1007/s00467-011-1879-9.
http://dx.doi.org/10.1007/s00467-011-187...
).
Several combined liver-kidney transplants have been performed with the goal to have the transplanted
liver supply normal complement regulatory proteins in patients with aHUS. However, this approach
does not address the problem in patients with CFH autoantibodies (4848. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al. Pre-emptive
eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome.
Clin J Am Soc Nephrol. 2011;6(6):1488-94.,5151. Cheong HI. Trombotic microangiopathy: can liver-kidney transplantation cure
aHUS? Nat Rev Nephrol. 2009;5(10):556-7, http://dx.doi.org/10.1038/nrneph.2009.148.
http://dx.doi.org/10.1038/nrneph.2009.14...
52. Koskinen AR, Tukiainen E, Arola J, Nordin A, Höckerstedt HK, Nilsson B, et
al. Complement activation during liver transplantation-special emphasis on patients with atypical
hemolytic uremic syndrome. Am J Transplant. 2011;11(9):1885-95.
53. Haller W, Milford DV, Goodship TH, Sharif K, Mirza DF, McKiernan PJ. Successful
isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in
complement factor H. Am J Transplant. 2010;10(9):2142-7,
http://dx.doi.org/10.1111/j.1600-6143.2010.03228.x.
http://dx.doi.org/10.1111/j.1600-6143.20...
-5454. Kavanagh D, Richards A, Goodship T, Jalanko H. Transplantation in atypical
hemolytic uremic syndrome. Semin Thromb Hemost. 2010;36(6):653-9,
http://dx.doi.org/10.1055/s-0030-1262887.
http://dx.doi.org/10.1055/s-0030-1262887...
).
Kidney transplantation markedly activates the alternative pathway of the complement system,
resulting in a poor outcome in aHUS patients with mutations in FH (5050. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab
prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol.
2011;26(8):1325-9, http://dx.doi.org/10.1007/s00467-011-1879-9.
http://dx.doi.org/10.1007/s00467-011-187...
). The identification of anticomplement therapy has led to a safer approach than kidney
transplantation alone. Eculizumab is a complete, humanized C5 monoclonal antibody that inhibits
complement factor 5a, blocking terminal complement activation and the formation of membrane attack
complexes (4848. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al. Pre-emptive
eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome.
Clin J Am Soc Nephrol. 2011;6(6):1488-94.
49. Krid S, Roumenina LT, Beury D, Charbit M, Boyer O, Frémeaux-Bacchi V, et
al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with
CFH/CFHR1 hybrid protein. Am J Transplant. 2012;12(7):1938-44.-5050. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab
prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol.
2011;26(8):1325-9, http://dx.doi.org/10.1007/s00467-011-1879-9.
http://dx.doi.org/10.1007/s00467-011-187...
). The
prophylactic use of eculizumab and plasmapheresis in kidney transplant recipients with aHUS has
demonstrated favorable outcomes in several case reports involving genetic defects, including CFH,
C3, complement factor H-related proteins (CFHR1 and CFH hybrids) (4848. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al. Pre-emptive
eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome.
Clin J Am Soc Nephrol. 2011;6(6):1488-94.,5050. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab
prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol.
2011;26(8):1325-9, http://dx.doi.org/10.1007/s00467-011-1879-9.
http://dx.doi.org/10.1007/s00467-011-187...
,5555. Nürnberger J, Philipp T, Witzke O, Opazo Saez A, Vester U, Baba HA, et al.
Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med.
2009;360(5):542-4.
56. Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al.
Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation.
Am J Transplant. 2012;12(12):3337-54.-5757. Al-Akash SI, Almond PS, Savell VH Jr, Gharaybeh SI, Hogue C. Eculizumab induces
long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr
Nephrol. 2011;26(4):613-9, http://dx.doi.org/10.1007/s00467-010-1708-6.
http://dx.doi.org/10.1007/s00467-010-170...
).
There is also growing interest in using eculizumab to prevent complement-mediated injury in
kidney transplantation, ranging from use in the positive cross-match donor to prevention of
antibody-mediated rejection in sensitized recipients to the prevention of delayed graft function in
deceased donors. Currently, several adult studies are actively recruiting participants (3636. U.S. National Institutes of Health. ClinicalTrials.gov. Available from:
www.clinicaltrials.gov.
www.clinicaltrials.gov...
). Eculizumab was used as a rescue treatment for severe AMR or
prevention of AMR. Early results from the Mayo Clinic showed that eculizumab prevents the
development of acute AMR in cross-match-positive patients. Eculizumab was added to the
desensitization protocol with mixed results. One of 16 patients developed AMR, and 6 patients
developed chronic AMR by 3.8 months post-transplantation (5858. Locke JE, Magro CM, Singer AL, Segev DL, Haas M, Hillel AT, et al. The use of
antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection.
Am J Transplant. 2009;9(1):231-5.
59. Gloor J, Stegall MD. Sensitized renal transplant recipients: current protocols
and future directions. Nat Rev Nephrol. 2010;6(5):297-306,
http://dx.doi.org/10.1038/nrneph.2010.34.
http://dx.doi.org/10.1038/nrneph.2010.34...
-6060. Lonze BE, Dagher NN, Simpkins CE, Locke JE, Singer AL, Segev DL, et al.
Eculizumab, bortezomib and kidney paired donation facilitate transplantation of a highly sensitized
patient without vascular access. Am J Transplant. 2010;10(9):2154-60.).
FK778
FK778 (manitimus) is a synthetic malononitrilamide derivative of the active leflunomide
metabolite, teriflunomide, which has been demonstrated to have both immunosuppressive and
anti-proliferative activities. It inhibits both T-cell and B-cell functions by blocking de
novo pyrimidine synthesis, inhibiting tyrosine kinase activity, and suppressing IgG and IgM
antibody production, as shown both in vitro and in vivo (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
,6161. Wlodarczyk Z, Vanrenterghem Y, Krämer BK, Squifflet JP, Ostrowski M. A
multicenter, randomized, double-blind study comparing different FK778 doses (manitimus) with
tacrolimus and steroids vs. MMF with tacrolimus and steroids in renal transplantation. BMC Nephrol.
2012;13:68, http://dx.doi.org/10.1186/1471-2369-13-68.
http://dx.doi.org/10.1186/1471-2369-13-6...
). In addition, FK778
prevents vascular remodeling after intimal injury and blocks the replication of the herpes virus
family in vitro (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
). Animal studies
examining the role of FK778 in liver regeneration and acute rejection have been carried out in rats
that underwent segmental liver transplantation. FK778 was found to be antihepatotrophic and
antiproliferative in rat liver regeneration (6262. Biglarnia AR, Lorant T, Lee HS, Tufveson G, Tötsch M, Malagó M. Liver
regeneration is impaired by FK778 in partially hepatectomized rats, while supplemental uridine
restores both liver growth and hepatocyte proliferation. Hepatol Res. 2009;39(1):86-92,
http://dx.doi.org/10.1111/j.1872-034X.2008.00402.x.
http://dx.doi.org/10.1111/j.1872-034X.20...
). FK778 was
also found to prevent acute allograft rejection and reverse ongoing rejection in rats undergoing
liver, heart, or kidney transplantation. Combination therapy with tacrolimus was also found to be
more beneficial than FK778 monotherapy (6363. Yamamoto S, Okuda T, Yamasaki K, Tanaka H, Takemura S, Minamiyama Y, et al.
FK778 controls acute rejection after rat liver allotransplantation showing positive interaction with
FK506. Transplant Proc. 2005;37(1):126-9,
http://dx.doi.org/10.1016/j.transproceed.2005.02.016.
http://dx.doi.org/10.1016/j.transproceed...
,6464. Bilolo KK, Ouyang J, Wang X, Zhu S, Jiang W, Qi S, et al. Synergistic effects of
malononitrilamides (FK778, FK779) with tacrolimus (FK506) in prevention of acute heart and kidney
allograft rejection and reversal of ongoing heart allograft rejection in the rat. Transplantation.
2003;75(11):1881-7, http://dx.doi.org/10.1097/01.TP.0000064710.78335.D3.
http://dx.doi.org/10.1097/01.TP.00000647...
).
A phase II, multi-center, randomized, double-blind study compared FK778 with tacroilmus and
steroids verses MMF with tacrolimus and steroids in renal transplantation patients and found that at
low levels, FK778 and MMF had similar efficacy (6161. Wlodarczyk Z, Vanrenterghem Y, Krämer BK, Squifflet JP, Ostrowski M. A
multicenter, randomized, double-blind study comparing different FK778 doses (manitimus) with
tacrolimus and steroids vs. MMF with tacrolimus and steroids in renal transplantation. BMC Nephrol.
2012;13:68, http://dx.doi.org/10.1186/1471-2369-13-68.
http://dx.doi.org/10.1186/1471-2369-13-6...
).
Unfortunately, as there were not sufficiently good results to justify phase III studies of FK778,
this agent is not being further developed.
JAK3 INHIBITORS
The Janus kinase family is a group of four cytoplasmic, non-receptor tyrosine kinases. JAK3 is
highly expressed in lymphoid cells and is activated only by cytokines that bind to gamma
chain-containing receptors. It is a potential immunosuppressive target because JAK3 activation leads
to the dimerization of the STAT 5 transcription factor, which is specific for IL-2 cytokines. JAK3
controls various cytokine-regulated signal transduction pathways, including lymphocyte
proliferation, differentiation, and apoptosis (6565. Tofacitinib. Drugs R D. 2010;10(4):271-84.). Concerns
regarding JAK3 inhibition exist because the loss of NK cells may lead to impaired innate immunity
and memory. Additionally, as it is very similar to JAK2, which mediates signaling of hematopoiesis,
its inhibition could potentially lead to anemia, leukopenia, and thrombocytopenia (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
).
CP-690550, tofacitinib, is an oral JAK3 inhibitor with the potential to prevent transplant rejection and treat autoimmune diseases. Phase I and II clinical trials have demonstrated that tofacitinib is efficacious and safe in preventing organ transplant rejection (6666. West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs. 2009;10(5):491-504.). In a phase 2b trial, tofacitinib was equivalent to cyclosporine in preventing acute rejection and was associated with improved renal function and less chronic allograft disease. At the dose studied, tofacitinib caused side effects, and adverse events occurred in over 10% of the treatment group. Adverse events included serious infection and CMV disease, post-transplant proliferative disorder, anemia, and neutropenia. One anticipated challenge will be the monitoring of drug levels, and a decision has not yet been made to start phase III trials.
FTY 720
FTY720, fingolimod, is derived from a fungal sphingosine-like metabolite. It is a sphingosine
1-phosphate receptor modulator that is able to entrap lymphocytes in secondary lymphoid organs, thus
reducing their availability for cell-mediated immune responses in allografts (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
,6767. David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of fingolimod.
Clin Pharmacokinet. 2012;51(1):15-28,
http://dx.doi.org/10.2165/11596550-000000000-00000.
http://dx.doi.org/10.2165/11596550-00000...
). Fingolimod use has been associated
with bradycardia, macular edema, and increased airway resistance. Additionally, when combined with
tacrolimus, it did not demonstrate a significant therapeutic advantage over MMF in preventing acute
rejection in kidney transplant recipients (1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
,6868. Hoitsma AJ, Woodle ES, Abramowicz D, Proot P, Vanrenterghem Y; FTY720 Phase II
Transplant Study Group. FTY720 combined with tacrolimus in de novo renal transplantation: 1-year,
multicenter, open-label randomized study. Nephrol Dial Transplant. 2011;26(11):3802-5,
http://dx.doi.org/10.1093/ndt/gfr503.
http://dx.doi.org/10.1093/ndt/gfr503...
). Although it has not moved forward in the treatment of
transplant recipients, it may have a role in treating patients with autoimmune diseases.
ALEFACEPT
Alefacept, LFA-3-Ig, is a dimeric fusion protein consisting of the CD2-binding portion of the
human lymphocyte function-associated antigen-3 (LFA-3) linked to the Fc portion of human IgG1. It is
thought to neutralize the effect of CD2-expressing T-cells by complement-mediated lysis, interrupt
the CD2 interaction with LFA-3, limit helper T-cell adhesion to antigen-presenting cells, and
disrupt effector T-cell receptor engagement with antigens and major histocompatibility complex
molecules (6969. Weaver TA, Charafeddine AH, Agarwal A, Turner AP, Russell M, Leopardi FV, et al.
Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med.
2009;15(7):746-9, http://dx.doi.org/10.1038/nm.1993.
http://dx.doi.org/10.1038/nm.1993...
). A pilot study assessing the safety and
efficacy of alefacept in de novo kidney transplant recipients was terminated
because of increased risks that were greater than expected based on the standard of care. However,
alefacept is currently undergoing clinical trials for the prevention of graft versus host disease
(1616. Coelho T, Tredger M, Dhawan A. Current status of immunosuppressive agents for
solid organ transplantation in children. Pediatr Transplant. 2012;16(2):106-22,
http://dx.doi.org/10.1111/j.1399-3046.2012.01644.x.
http://dx.doi.org/10.1111/j.1399-3046.20...
,3636. U.S. National Institutes of Health. ClinicalTrials.gov. Available from:
www.clinicaltrials.gov.
www.clinicaltrials.gov...
).
ASKP1240
ASKP1240 is a novel, human anti-CD40 monoclonal antibody that is currently in pre-clinical trials as a new immunosuppressive agent that may promote tolerance induction in organ transplantation. ASKP1240 has been demonstrated to prolong renal allograft survival in non-human primates (NHPs), although the allografts eventually underwent chronic allograft nephropathy. Oura and colleagues completed a two-week ASKP1240 induction treatment in NHPs and found that although it prolonged liver allograft survival, the function of the graft deteriorated due to chronic rejection. Following a six-month ASKP1240 maintenance monotherapy protocol, cellular and humoral alloimmune responses were suppressed, rejection was prevented, and no serious side effects were observed in hepatic allograft recipients (7070. Oura T, Yamashita K, Suzuki T, Fukumori D, Watanabe M, Hirokata G, et al. Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates. Am J Transplant. 2012;12(7):1740-54.).
A clinical trial assessing the bioavailability of ASKP1240 in healthy subjects after intravenous
and subcutaneous administration was recently completed in September 2012 and demonstrated that
ASKP1240 was well tolerated in the range of 50 to 500 mg, with no evidence of cytokine release
syndrome or thromboembolic events. There was no difference in the incidence of infection based on
dose, but B cell CD40 receptor occupancy trended to be prolonged as the dose increased (7171. Yang H, Vincenti F, Klintmalm G, Steinber S, Wang L, Shang W, et al. J.
MON.CO20.02 A Phase 1b, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Single Dose,
Pharmacokinetic, Pharmacodynamic, Safey and Tolerability Study of ASKP1240 in de novo Kidney
Transplantation. 24th International Congress of the Transplantation Society; 2012.). Phase II trials are currently in development (3636. U.S. National Institutes of Health. ClinicalTrials.gov. Available from:
www.clinicaltrials.gov.
www.clinicaltrials.gov...
).
CMX001
CMX001 is a novel, broad-spectrum lipid antiviral conjugate that produces high levels of the
active antiviral agent cidofovir diphosphate and is active against multiple double-stranded DNA
viruses, such as JC and BK viruses (7272. Painter W, Robertson A, Trost LC, Godkin S, Lampert B, Painter G. First
pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a
broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob Agents Chemother.
2012;56(5):2726-34, http://dx.doi.org/10.1128/AAC.05983-11.
http://dx.doi.org/10.1128/AAC.05983-11...
). It is a lipid
conjugate of the acyclic nucleotide phosphonate cidofovir. The utility of cidofovir is limited by
the high incidence of acute kidney toxicity and intravenous administration. Compared to cidofovir,
CMX001 has greater potency in vitro against all double stranded DNA viruses that
cause human disease, a higher genetic barrier to resistance, no evidence of nephrotoxicity in humans
or animals, and is available as an oral agent (7373. Lanier R, Trost L, Tippin T, Lampert B, Robertson A, Foster S, et al.
Development of CMX001 for the Treatment of Poxvirus Infections. Viruses. 2010;2(12):2740-2762,
http://dx.doi.org/10.3390/v2122740.
http://dx.doi.org/10.3390/v2122740...
).
Painter and colleagues conducted a randomized, double-blind, placebo-controlled, parallel-group,
dose-escalation study in healthy volunteers to examine the pharmacokinetics and safety of CMX001.
They found that CMX001 is orally bioavailable and well tolerated in healthy volunteers at doses of
up to 2 mg/kg, which corresponds to approximately 140 mg in a typical adult (7272. Painter W, Robertson A, Trost LC, Godkin S, Lampert B, Painter G. First
pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a
broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob Agents Chemother.
2012;56(5):2726-34, http://dx.doi.org/10.1128/AAC.05983-11.
http://dx.doi.org/10.1128/AAC.05983-11...
). BKV is associated with nephropathy, as well as hemorrhagic cystistis (7474. Rinaldo CH, Gosert R, Bernhoff E, Finstad S, Hirsch HH. 1-O-hexadecyloxypropyl
cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular
epithelial cells. Antimicrob Agents Chemother. 2010;54(11):4714-22,
http://dx.doi.org/10.1128/AAC.00974-10.
http://dx.doi.org/10.1128/AAC.00974-10...
). Treating polyomavirus BK (BKV) is of notable importance in
kidney transplant recipients, as current agents, with the exception of immunosuppressive reduction,
which places transplant recipients at increased risk for rejection, have not been consistently
effective in reducing BK viral loads. Comparisons of CMX001 and cidofovir have demonstrated that
CMX001 had more rapid and enduring effects on BKV DNA than cidofovir at lower levels and had fewer
side effects on relevant host cells in vitro (7474. Rinaldo CH, Gosert R, Bernhoff E, Finstad S, Hirsch HH. 1-O-hexadecyloxypropyl
cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular
epithelial cells. Antimicrob Agents Chemother. 2010;54(11):4714-22,
http://dx.doi.org/10.1128/AAC.00974-10.
http://dx.doi.org/10.1128/AAC.00974-10...
). No human studies in transplant recipients with BK nephropathy or viremia have been
published to date, although an anti-viral agent against BKV without associated nephrotoxicity is
promising and could positively impact the management of BKV.
CONCLUSION
Despite the advances in immunosuppressive therapy, the optimal immunosuppressive regimen remains elusive. Over the years, research in immunosuppressive therapy has intensified, and several promising agents targeting different sites of the immune system are under development. Important goals in finding new agents include reducing nephrotoxicity; preserving both short- and long-term graft function; and reducing the risk of opportunistic infections, PTLD, malignancy, and other side effects. These goals are particularly critical in pediatric transplant recipients due to their life expectancy and the need to prevent additional chronic medical conditions.
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Jan 2014