Download Liver transplantation_03 (Treatment of acute cellular rejection)

Liver transplantation (Treatment of acute cellular rejection)
INTRODUCTION
1.
Acute cellular rejection following liver transplantation has decreased in incidence with use of
potent immunosuppressive agents, but it still affects 15 to 25% of liver transplantation
recipients. Most episodes occur within 1 month post-transplantation, although acute cellular
rejection may present later. A retrospective analysis of 970 liver transplantations found 11%
incidence of late acute cellular rejection (> 90 days post-transplantation) that was associated
with recent changes in and lower levels of immunosuppression. In addition to type and level
of immunosuppression, certain transplantation related characteristics may influence risk of
rejection. As example, patients who receive organ from living related donor may have lower
rate of acute cellular rejection compared with deceased donor liver transplantation recipient.
2.
The consequences of acute cellular rejection are variable. While it can predispose to
steroid-resistant rejection and graft loss, most episodes do not have long-term adverse
effects except in HCV-positive patients. Furthermore, acute cellular rejection identified by
protocol liver biopsy in absence of biochemical dysfunction often resolves without increasing
immunosuppression. There is even suggestion that such subclinical immune activation might
be beneficial in inducing degree of tolerance. The timing of rejection might affect outcomes.
In large retrospective study, compared with patients without episode of rejection, early acute
rejection was associated with better graft survival and late acute rejection was associated
with reduced graft survival. Patients who developed late acute cellular rejection had 28%
rate of chronic rejection and 6% risk of graft failure.
3.
This topic will review treatment of acute cellular rejection following liver transplantation. The
diagnosis of acute cellular rejection following liver transplantation is discussed separately.
DIAGNOSIS
1. The diagnosis of acute cellular rejection is usually suspected by elevations in serum ALT and
ALP, which typically precede clinical symptoms of jaundice and fever. However, biochemical
parameters are not sensitive or specific for detecting acute cellular rejection and do not
correlate with its severity. Thus, diagnosis should be confirmed by liver biopsy before
initiating treatment for rejection. Histologic features include endothelitis, non-suppurative
cholangitis, and mixed mononuclear cell portal inflammation.
TREATMENT
1.
High dose corticosteroids are usually first line therapy for acute cellular rejection.
Methylprednisolone doses vary among centers, ranging from 500 mg to 1000 mg boluses
given daily for 1 to 3 days. A gradual corticosteroid taper is provided at some centers
following bolus methylprednisolone. In RCT, 1000 mg of methylprednisolone followed by six
day taper from 200 mg/day to 20 mg/day was more effective for treatment of acute cellular
rejection and associated with less infectious complications than giving 1000 mg of
methylprednisolone on 3 consecutive days.
2.
3.
4.
Approximately 70 to 80% of episodes of acute cellular rejection resolve after course of high
dose corticosteroids, and second course is effective in many of remaining cases. Biochemical
and histologic improvement is generally observed within 3 to 5 days when corticosteroid is
successful. Some centers perform follow-up liver biopsy at completion of bolus
methylprednisolone to document histologic recovery.
The cumulative immunosuppressive effect of high dose corticosteroids increases
susceptibility to infections, including oral candidiasis, CMV, Aspergillus, PJP, and bacterial
pathogens. Other potential side effects include hyperglycemia, GIB, and mood changes. We
use prophylactic PPI and TMP-SMX and follow blood glucose during high dose corticosteroid.
Hepatitis C
A. Management of acute cellular rejection in patients with HCV infection requires special
B.
consideration. Treatment with corticosteroids or with T cell depletion is associated with
acceleration of HCV progression and increased mortality. Furthermore, biochemical and
histologic features of acute cellular and HCV are similar, making it difficult to distinguish
these disorders. As result, many centers defer treatment of mild acute cellular rejection
when it is not clearly primary cause of histologic injury, given tolerance of hepatic
allografts to mild rejection and negative consequences of treating rejection in patients
with HCV.
Repeated biopsies can be useful in assessing whether changes of mild acute cellular
rejection progress and become dominant histologic feature, prompting initiation of
bolus corticosteroid. An alternative approach to equivocal cases of acute cellular
rejection in patients with HCV is to increase CNI dose or to start additional agent, such
as MMF. Further studies are needed to identify methods to better distinguish acute
cellular rejection from HCV recurrence and to determine impact of various management
options on outcomes. Hepatic gene expression profiling represents one means to
differentiate between acute cellular rejection and HCV recurrence, although such
technology is not yet sufficiently developed for clinical application.
STEROID-RESISTANT REJECTION
1. 10% or less of patients with acute cellular rejection develop steroid-resistant rejection.
Agents including OKT3, thymoglobulin, anti-interleukin receptor antibodies, mycophenolate
mofetil, sirolimus, and tacrolimus have been used as rescue agents to treat such patients.
2.
Muromonab
A. Muromonab (OKT3) is murine monoclonal antibody to CD3 antigen-receptor complex
present on mature T lymphocytes. Binding of OKT3 to CD3 complex leads to clearance of
circulating T lymphocytes by reticuloendothelial system and interferes both with antigen
recognition by T cell receptor and with T cell activation. Persistent resolution of
steroid-resistant rejection is achieved in up to 60% of patients treated with OKT3.
Patients should be monitored carefully while receiving OKT3, especially after the first 2
to 3 doses. The toxicity of OKT3 is discussed elsewhere)
3.
4.
Thymoglobulin
A. Thymoglobulin is polyclonal lymphocyte preparation that was shown to reverse
steroid-resistant rejection in kidney transplantation recipients. Although there are
limited data in patients who have undergone liver transplantation, many centers use
thymoglobulin to treat steroid-resistant liver allograft rejection to avoid side effects of
OKT3. Thymoglobulin is administered at 1.5 mg/kg/day (based upon IBW) for 5 days.
The dose is titrated to achieve absolute lymphocyte count ≤ 200 mm3. WBC and platelet
counts are followed for evidence of toxicity.
Anti-IL-2 receptor antibodies
A. Basiliximab and daclizumab are monoclonal antibodies that bind to IL-2) receptor on T
cells. They block IL-2 mediated T cell proliferation, and thus inhibit T cell response to
B.
5.
alloantigens that produces allograft damage in acute cellular rejection. Anti-IL-2 receptor
antibodies were effective as induction agent in liver transplantation. When used for
induction therapy, basiliximab is dosed at 20 mg on days 0 and 4, and daclizumab is
dosed at 1 mg/kg on day 0 and 0.5 mg/kg on day 4 after transplantation.
Treatment of steroid-resistant rejection with anti-IL-2 receptor antibodies has been
reported in small number of patients. One series included 25 patients with
steroid-resistant acute or chronic cellular rejection, most of whom were also started on
MMF. Basiliximab or daclizumab was associated with resolution of steroid-resistant
rejection in 12 of 16 patients with acute cellular rejection (75%). Of remaining 4 patients,
2 developed chronic rejection, 1 required repeat transplantation, and 1 died with graft
failure. By contrast, graft dysfunction persisted in 9 patients who were being treated for
chronic rejection. Five of 25 patients (20%) treated in this series had significant
infectious complications, including bacterial infections, pulmonary aspergillosis, and
CMV reactivation, resulting in two deaths.
Mycophenolate mofetil
A. MMF inhibits synthesis of purines necessary for lymphocyte activation. It was developed
to replace azathioprine and has been used in liver and kidney transplantation as primary
immunosuppressive agent, and for treatment of refractory rejection.
B. A number of studies have evaluated MMF for treatment of refractory rejection in liver
transplantation recipients. In illustrative series, MMF (2 to 3 g/day) was added to
C.
tacrolimus or cyclosporine in 47 patients with steroid-resistant acute cellular rejection,
12 of whom did not respond to OKT3. Liver enzymes normalized in 81% of patients.
Another study evaluated efficacy of high doses of MMF (3 g TID for the first month) for
treatment of steroid-resistant rejection in LDLT recipients. 44 of 54 patients (81%)
responded to MMF and only 10 required OKT3 for refractory rejection.
The recommended dose of MMF is 1 g BID. GI disturbance is common side effect.
Initiating therapy at 500 mg twice daily and then titrating the dose upward may increase
tolerability. MMF does not cause significant nephrotoxicity or hepatotoxicity, and is
associated with less bone marrow suppression than azathioprine.
6.
Sirolimus
A. Sirolimus is structurally similar to tacrolimus and binds to FK binding protein 12. Unlike
B.
7.
tacrolimus, sirolimus blocks immune responses by inhibiting mechanistic target of
rapamycin (mTOR) signaling pathway, which regulates cell growth and proliferation.
Sirolimus also inhibits IL-2 and IL-4 dependent proliferation of T and B cells.
In open label and retrospective analyses, patients receiving sirolimus as primary
immunosuppressive agent had relatively low rates of acute cellular rejection and
steroid-resistant rejection. Sirolimus was associated with hepatic artery thrombosis in
two large multicenter studies, leading to "black box" warning regarding its use as
induction agent in liver transplantation. Reported side effects include impaired wound
healing, cytopenia, dermatitis, interstitial pneumonitis, edema, pleural and pericardial
effusions, joint pain, and oral aphthous ulcers. Hyperlipidemia and nephrotoxicity occur
more commonly when cyclosporine is combined with sirolimus. On positive side,
sirolimus is not associated with nephrotoxicity or neurotoxicity when given alone.
Sirolimus given in combination with tacrolimus may cause less nephrotoxicity than
combination of sirolimus and cyclosporine. Sirolimus has benefit in patients with HCC.
C. There are limited data regarding treatment of steroid-resistant rejection with sirolimus.
In one preliminary report, steroid-resistant rejection resolved in 8 of 14 patients (57%)
who received sirolimus.
Tacrolimus
A. Tacrolimus is used as immunosuppressive agent in most liver transplantation recipients.
However, in those receiving cyclosporine, conversion from cyclosporine to tacrolimus
can be effective in treating steroid-resistant acute cellular rejection and early chronic
rejection. In one report, 9 of 16 (56%) patients converted to tacrolimus for
OKT3-refractory rejection showed normalization of liver enzymes at an average of 60
days, and a one-year graft survival rate of 85%. In another series, biochemical and
histologic normalization occurred in 10 of 18 patients (56%) with steroid-resistant or
OKT3-refractory rejection.
RETRANSPLANTATION
1. Approximately 4% or less of liver transplantation recipients develop severe ductopenic
chronic rejection. The risk of chronic ductopenic rejection appears to be increased in patients
2.
who have had repeated episodes of acute cellular rejection.
Patients who progress to chronic rejection should be considered for re-transplantation. In
such cases, reduction of immunosuppression should be considered in the preoperative period
in effort to reduce infectious complications associated with re-transplantation.
SUMMARY AND RECOMMENDATIONS
1. Acute cellular rejection has decreased in incidence with the use of potent
2.
3.
4.
5.
immunosuppressive agents, but it still affects 15 to 25% of liver transplantation recipients.
The diagnosis of acute cellular rejection is usually suspected by elevations in serum ALT and
ALP, which typically precede clinical symptoms of jaundice and fever.
High dose corticosteroids are usually first line therapy for acute cellular rejection.
Approximately 70 to 80% of episodes of acute cellular rejection resolve after a course of high
dose corticosteroids, and a second course is effective in many of the remaining cases.
Management of acute cellular rejection in patients with HCV infection requires special
consideration. Treatment with corticosteroids or with T cell depletion is associated with
acceleration of HCV progression and increased mortality.
10% or less of patients with acute cellular rejection develops steroid-resistant rejection.
Agents including OKT3, thymoglobulin, MMF, anti-interleukin receptor antibodies, sirolimus,
and tacrolimus have been used as rescue agents to treat such patients. Although the largest
experience in treating steroid-resistant rejection is with OKT3, use of the other agents should
be considered, particularly in patients with HCV.