Although acute liver rejection can occur at any time after the transplantation, it is
most commonly experienced within the first 3 to 6 months after transplant and in
approximately 20% to 50% of patients treated with either cyclosporine or tacrolimus
68 Data in patients treated with tacrolimus, mycophenolate, and
prednisone indicate lower rejection rates.
71 Late acute rejections often are a result of
either nonadherence, a reduction in dose, or a discontinuation of immunosuppressive
agents. These rejection episodes, although somewhat common, rarely lead to graft
E.P. presented with some of the subjective complaints of rejection. Commonly,
patients feel poorly and complain of anorexia, abdominal discomfort, and headache.
Other symptoms, such as a low-grade fever, back pain, or respiratory distress, may
rarely occur. With the use of more potent immunosuppression, symptoms are no
longer commonly present with acute rejection and cannot be relied upon for early
indication of rejection. Objective evidence
for rejection in E.P. included an abrupt rise in transaminases and bilirubin and a
liver biopsy that was interpreted as “moderate rejection.” These observations led to
a diagnosis of rejection. Acute rejection is associated with mononuclear cell
infiltration of the graft, edema, and parenchymal necrosis. Rejection should be
diagnosed by biopsy using histologic criteria. Areas commonly damaged by rejection
are the bile ducts, veins, and arteries, known as portal triaditis.
Chronic liver rejection, also called ductopenic rejection, usually develops months to
years after the transplant in less than 5% of recipients. Characteristics of chronic
liver rejection include occlusive arterial lesions, destruction of small intrahepatic
bile ducts (often referred to as vanishing bile duct syndrome), intense cholestasis,
accumulation of foamy macrophages within the portal sinusoids, and fibrosis, which
can lead to the development of cirrhosis.
72 Chronic rejection is almost always
irreversible and unaffected by increased immunosuppressive therapy.
Retransplantation has been considered the only viable alternative. Some patients with
early ductopenic rejection unresponsive to cyclosporine-based therapy have
CASE 34-7, QUESTION 8: Was the treatment of E.P.’s rejection of his transplanted liver appropriate?
E.P. was receiving maintenance immunosuppression with tacrolimus and
prednisone. Double or triple therapy with tacrolimus and prednisone is commonly
used as chronic immunosuppressive therapy. Although E.P.’s tacrolimus
concentration appeared adequate, he was treated with a bolus dose of IV
methylprednisolone because of clinical evidence that supported a diagnosis of graft
rejection. This treatment decision was reasonable because high-dose corticosteroids
reverse the majority of acute rejection episodes.
69 The decision to determine E.P.’s
response to the initial bolus steroid dosage and the severity of rejection by biopsy
also was appropriate before proceeding with further treatment. E.P. had experienced
moderate rejection of his transplanted liver, and the subsequent initiation of rabbit
antithymocyte globulin was reasonable because he did not adequately respond to the
Rejection in adult liver transplant recipients is usually treated with 200 to 1,000
mg/day of IV methylprednisolone and tapered rapidly, similar to E.P. When patients
fail to respond to recycle corticosteroid therapy, several options are available. E.P.
was begun on rabbit antithymocyte globulin therapy; other options include the use of
alemtuzumab. Most centers use rabbit antithymocyte globulin as a second-line agent
if there is no response to high-dose corticosteroids or first line for severe rejection.
The typical dose is 1.5 mg/kg/day given as an infusion for 4 to 6 hours and is
continued for 7 to 14 days. Treatment of corticosteroid-resistant rejection with rabbit
antithymocyte globulin is effective in about 70% to 80% of liver transplant
recipients. Other adjustments in immunosuppression include the addition of
mycophenolate or an mTOR inhibitor.
CASE 34-7, QUESTION 9: After the rejection episode, E.P. is started on MMF. Describe MMF’s
monitoring of MMF in this patient?
In the vast majority of transplant centers, MMF has replaced azathioprine as the
antiproliferative agent used in combination with antibodies, CNI, and prednisone. In
E.P., MMF was not initiated immediately after transplant because he has hepatitis C,
which can recur after transplant, especially with too much immunosuppression.
Therefore, in his case, immunosuppression was initially minimized to limit the
chances of severe hepatitis C recurrence.
Mycophenolate mofetil is a prodrug for the active form, MPA. MMF is well
absorbed (bioavailability 94%) and is rapidly hydrolyzed to MPA. The Cmax
MPA occurs between 1 and 3 hours, and it is hepatically and renally glucuronidated
to inactive MPAG, which is eliminated by the kidney, but mainly excreted into the
bile. Once MPAG is excreted into bile, it then may then undergo enterohepatic
recycling in the GI tract, where it is deconjugated to MPA (which is reabsorbed back
into the systemic circulation). Because of this recycling, a second peak occurs 6 to 12
hours after dosing. MPA has an elimination half-life of 17 hours on average; the
volume of distribution is 4 L/kg, and it is highly protein-bound to albumin (98%).
Protein binding correlates well with albumin, and free MPA concentrations
somewhat correlate with the immunosuppressive effect. Renal impairment, liver
dysfunction, and elevated MPAG concentrations in transplant recipients can reduce
protein binding. This may be a function of low albumin concentrations seen in these
The most commonly reported side effects for MMF are GI (anorexia, nausea,
vomiting and diarrhea, gastritis), hematologic (leukopenia, thrombocytopenia,
anemia), and infections. GI side effects are common, and all side effects are more
common with higher dosages. Patients with GI complaints may respond to
administering the dose without other medications, smaller more frequent doses, or
lowering of the dose and titrating upward as tolerated.
3,000 or absolute neutrophil count is less than 1,300 cells/μL, the MMF dose should
The usual MMF starting dose in adults is 1 to 1.5 g twice daily PO. Some advocate
the higher dosage in high-risk patients (e.g., patients receiving another transplant,
patients with a high PRA, African-Americans). The recommended regimen in patients
with a glomerular filtration rate less than 25 mL/minute is 1 g twice daily PO. In
children, 300 to 600 mg/m2 or 23 mg/kg/day given 2 times a day PO has been
recommended. Due to a drug interaction, doses should be higher when administered
with cyclosporine (1 to 1.5 g) compared to tacrolimus (0.75 to 1 g).
Monitoring MPA plasma concentrations is controversial and not generally
recommended at this time due to the lack of data demonstrating improved outcomes
with TDM. There are a number of studies that have shown some benefit, with others
not showing any clinical improvements with MPA TDM. In kidney transplant
recipients, low MPA AUCs and troughs have been shown to correlate with acute
rejection. In centers routinely performing MPA monitoring, typical AUC 0–12
are 30 to 60 mcg/hour/mL and troughs 1 to 3.5 mcg/mL. MPA monitoring appears to
be more beneficial in protocols where CNI sparing, withdrawal, or minimization is
used. Once started on MMF, E.P. should be monitored for GI and hematologic side
effects, as well as for any signs and symptoms of infection and rejection.
In 2009, the FDA approved the use of generic MMF in solid organ transplantation.
Currently, there are multiple manufacturers with approved generic formulations of
MMF. These products meet FDA standards for bioequivalence and are considered
AB-rated to CellCept 250-mg capsules or 500-mg tablets.
studies demonstrating that generic MMF has produced inferior clinical outcomes or
increased the risk of medication side effects, and most clinicians are comfortable
utilizing the generic formulation of MMF, although frequent changes between
manufacturers are not recommended.
Drug Interactions with Immunosuppressives
QUESTION 1: C.C. is a 42-year-old woman who underwent a liver transplantation 5 days ago. She was
noted to be febrile, with an elevated WBC. Cultures were obtained, and her JP drainage grew Candida
any adjustments in current medication doses?
Because the immunosuppressants have complex and highly variable
pharmacokinetic profiles with relatively narrow therapeutic indexes, drug–drug
interactions represent a significant clinical problem. Drug interactions can be
separated into two main categories: pharmacokinetic and pharmacodynamic.
Pharmacokinetic interactions occur when one medication alters the absorption,
distribution, metabolism, or elimination of the immunosuppressant agent.
34-2 displays the most clinically relevant pharmacokinetic drug interactions that are
likely to be encountered in transplant recipients and how to manage these
interactions. These include drugs that alter either the absorption or metabolism of the
immunosuppressants. Note that this table is not comprehensive.
Pharmacodynamic interactions occur when one medication either potentiates an
adverse effect or alters the pharmacologic effects of the immunosuppressant agent.
Comments
Post a Comment
اكتب تعليق حول الموضوع