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25
primary care provider should consult with the transplant specialist. Many specialty
centers have medical specialists who have additional expertise in transplant medi-
cine (e.g., Transplant Infectious Disease, Transplant Psychiatry). It is recommended
to review the expertise in one’s local practice area, as well as the preferred consul-
tants of the patient’s transplant team. If there is uncertainty about an aspect of a
patient’s care, it is best to err on the side of communicating with the transplant team.
Most transplant centers have a robust multidisciplinary team to help communicate
and coordinate care.
2.8 Conclusion
Primary care providers have an increasingly vital role in the outpatient care of solid
organ transplant recipients. While care of such patients can be complex, the ability
to review a patient’s prior transplant evaluations and assess the patient’s current
health status prepares the primary care provider to optimize future preventive care
and address acute medical concerns.
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D. Zhong and C. J. Wong
29© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
C. J. Wong (ed.), Primary Care of the Solid Organ Transplant Recipient,
https://doi.org/10.1007/978-3-031-98076-3_3
Chapter 3
Anti-Rejection Medication Therapy
intheAdult Solid Organ Transplant
Recipient
LydiaSun, TyraFainstad, andChristopherKnight
3.1 Introduction
Immunosuppressive medications reduce the risk of graft rejection, and without
them successful organ transplant would be impossible. Unfortunately, these medi-
cations also cause over half of transplant-related deaths, due to infections, cancer,
and other risks related to long-term use [1]. Proper use and early recognition of
adverse effects are crucial to the health and survival of solid organ transplant recipi-
ents. Once a patient is through the acute postoperative setting, primary care clini-
cians often take over care and have primary responsibility for managing interactions
with new and existing medications [2]. It is therefore important for primary care
providers to be comfortable recognizing adverse effects of immunosuppressive
medications in order to provide well-informed, coordinated care with transplant
specialists.
L. Sun (*)
Department of Pharmacy, University of Washington, Seattle, WA, USA
e-mail: lydsun@uw.edu
T. Fainstad
General Internal Medicine, Department of Medicine, University of Colorado School
of Medicine, Aurora, CO, USA
e-mail: tyra.fainstad@cuanschutz.edu
C. Knight
General Internal Medicine, Department of Medicine, University of Washington,
Seattle, WA, USA
e-mail: cknight@uw.edu
30
3.2 Typical Immunosuppressant Course
The goals of immunosuppression are to prevent graft rejection and improve graft
survival, while minimizing adverse effects including metabolic side effects, infec-
tion, and malignancy, in order to improve overall patient survival and quality of life.
Conventional maintenance regimens consist of a combination of immunosuppres-
sive agents that differ by mechanism of action. A multidrug strategy maximizes
overall effectiveness of the immunosuppressants, while also minimizing medication
adverse effects [3].
Patients are typically treated with anti-rejection medications in two phases:
induction and maintenance (see Fig. 3.1). In the induction phase, high doses of
multiple immunosuppressants are given immediately postoperatively until a few
weeks after transplantation. Immunosuppression is usually heavier in this period
when the risk of rejection is higher due to a number of factors, including preserva-
tion injury of the graft and sudden exposure of the recipient immune system to a
load of foreign antigen. The maintenance phase starts several weeks to 3months
later and lasts through the life of the transplanted organ [4].
According to the Scientic Registry of Transplant Recipients (SRTR) data from
2023, the triple regimen of tacrolimus, mycophenolate, and prednisone remains the
most common maintenance regimen at discharge, with use ranging from 67% in
kidney and liver transplant recipients, to 86% of lung and heart transplant recipi-
ents [5].
After 6–12 months, immunosuppression regimens are generally stably main-
tained, unless there is a specic reason, such as infection, malignancy or drug toxic-
ity, to reduce immunosuppression further. The optimal maintenance therapy in solid
organ transplantation is not established, but immunosuppressant levels required to
achieve a state of immune tolerance and graft survival differs between transplanted
organs for reasons that are not completely understood [6]. In general, lung, intes-
tine, and heart transplant recipients require a higher level of immunosuppression
than kidney and liver transplant recipients [6].
For the purposes of this chapter, we will focus on maintenance medications as
these are primarily what the primary care physician will encounter.
• First few weeks postop
• Higher doses
• Starts after induction, usually several
weeks to 3 months postop
• Lower doses
• Continues for life
Induction
Maintenance
Fig. 3.1 Phases of anti-rejection medication use in transplant recipients
L. Sun et al.
31
3.3 Overview ofClasses ofAnti-rejection Medications
The main classes of anti-rejection medications that are used for maintenance
include: calcineurin inhibitors, anti-proliferative/anti-metabolites, corticosteroids,
and mammalian target of rapamycin (mTOR) inhibitors. High doses of corticoste-
roids are used early after transplantation but are generally tapered as quickly as
possible because of their long-term toxicity [7]. Mechanisms of action are given in
Table3.1. Dosing, pharmacokinetics, and side effects are given in Table3.2.
Table 3.1 Mechanism of action of common anti-rejection medications [1, 2, 7, 8]
Immunosuppressant General mechanism of action Specic mechanism of action
Calcineurin inhibitors
Tacrolimus (Prograf
®
)
Cyclosporine (Neoral
®
,
Sandimmune
®
)
Inhibitors of T-cell activation
(early)
Block IL-2 production
Anti-metabolites
Mycophenolate (Cellcept
®
,
Myfortic
®
)
Azathioprine (Imuran
®
)
Inhibitors of T-cell
production
Block DNA (nucleotide)
synthesis
Corticosteroids
Prednisone
Methyl-prednisolone
Non-specic inhibitors of
immune function
Block IL-1 production
mTOR inhibitors
Sirolimus (Rapamune
®
)
Everolimus (Anitor
®
)
Inhibitors of T-cell activation
(late)
Inhibit IL-2 activity and
activation of cell cycle
IL interleukin
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
32
Table 3.2 Dosing, pharmacokinetics, and adverse effects of common immunosuppressant medications [1, 2, 7, 8]
Immunosuppressant
Dosing
Monitoring
Pharmacokinetics:
Half-life (t
1/2
)
Bioavailability (F) Adverse effects Comments
Calcineurin
inhibitors
Tacrolimus
(FK-506, Prograf
®
)
Dosing:
0.025–0.1mg/kg PO
Q12h
Monitoring:
Target levels 5–15ng/
mL (trough)
t
1/2
≈8h
F=15–30% (more
predictable than
cyclosporine)
Nephrotoxicity (related to dose and duration)
• Acute nephrotoxicity is reversible
• Chronic progressive renal disease is irreversible
Electrolyte disturbance (related to reduction in
renal blood ow)
• Hyperkalemia
• Hypomagnesemia
Neurologic side effects
• Headache
• Tremor, paresthesias
• Rare/serious: PRES (posterior reversible
encephalopathy syndrome)
Post-transplant diabetes
Gastrointestinal toxicity
• Diarrhea
• Dyspepsia
• Nausea, vomiting
Metabolic/endocrine side effects
• Hypertension
• Hypercholesterolemia
Neurologic side effects, gastrointestinal side
effects, alopecia, and diabetes are more common
with tacrolimus than cyclosporine
Generic forms are bioequivalent
The extended release formulation Envarsus
®
is not
equivalent—Dosing should be adjusted only by the
transplant team
Cyclosporine
(Gengraf
®
, Neoral
®
,
Sandimmune
®
)
Dosing:
4–5mg/kg PO Q12h
(IBW)
Monitoring: Target
levels 75–250ng/mL
(trough)
t
1/2
≈8–18h Nephrotoxicity (related to dose and duration)
• Acute nephrotoxicity is reversible
• Chronic progressive renal disease is irreversible
Electrolyte disturbance (related to reduction in
renal blood ow)
• Hyperkalemia
• Hypomagnesemia
Metabolic/endocrine side effects
• Hypertension
• Hypercholesterolemia
• Hirsutism
Hypertension, hypercholesterolemia, and hirsutism
are more common with cyclosporine than
tacrolimus
Generic formulations of Gengraf
®
and Neoral
®
are
also called “cyclosporine modied”
Sandimmune
®
(cyclosporine non-modied):
• Sandimmune
®
is NOT bioequivalent or
interchangeable with Gengraf
®
/Neoral
®
• Most transplant recipients are started on
Gengraf
®
/Neoral
®
. Only those patients
transplanted prior to release of Gengraf
®
/Neoral
®
formulation are maintained on Sandimmune
®
L. Sun et al.
33
Immunosuppressant
Dosing
Monitoring
Pharmacokinetics:
Half-life (t
1/2
)
Bioavailability (F) Adverse effects Comments
Anti-
metabolites
Mycophenolate
(Cellcept, Myfortic
®
)
Dosing:
Mycophenolate mofetil
(MMF) or Cellcept
®
1000mg PO Q12hrs
Mycophenolate
sodium/mycophenolic
acid (MPA) or
Myfortic
®
720mg PO
Q12hrs
Monitoring:
General routine use of
mycophenolate
therapeutic drug
monitoring is not
recommended on the
basis of available
evidence
a
t
1/2
≈18h Gastrointestinal toxicity
• Nausea, vomiting
• Diarrhea (40%)
• Abdominal pain
Hematologic side effects
• Leukopenia, anemia, thrombocytopenia
Contraindicated in pregnancy
Use Cellcept
®
(MMF) for feeding tube
administration because it is available in a liquid
form. (Mycophenolate tablets should not be split,
crushed, or chewed.)
Cellcept
®
(MMF) is a prodrug, and the rst
mycophenolate-based product developed
Myfortic
®
(MPA) is active form
Conversion:
Cellcept
®
(MMF) 250mg=Myfortic
®
(MPA)
180mg
While diarrhea is common, mycophenolate may
rarely cause an illness similar to inammatory
bowel disease
Azathioprine (Imuran
®
) Dosing:
1–2mg/kg PO daily
Associated with more hematological toxicities than
mycophenolate
Gastrointestinal toxicity
• Nausea, vomiting
• Anorexia
• Hepatoxicity: Increased transaminases, bilirubin,
alkaline phosphatase
Hematologic side effects
• Leukopenia, anemia, thrombocytopenia
Older anti-proliferative agent used for maintenance
therapy
Rarely used due to increased rates of acute
rejection vs. mycophenolate
Disrupts DNA synthesis of de novo and salvage
pathways
May be used when:
• Pregnancy is desired
• Intolerable adverse effects with mycophenolate
• Cost is an issue—Approximately $40/month vs.
$70–1000/month with mycophenolate
• Patient has inammatory bowel disease (IBD) or
auto-immune hepatitis (AIH)
(continued)
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
34
Immunosuppressant
Dosing
Monitoring
Pharmacokinetics:
Half-life (t
1/2
)
Bioavailability (F) Adverse effects Comments
Corticosteroids Prednisone,
Methyl-prednisolone
Dosing:
Varies by organ
transplanted and
transplant center
protocol
Maintenance dosing is
usually tapered to
prednisone 5mg daily
or every other day
Short term (high dose) side ef
fects
• Emotional lability, hallucinations
• Insomnia
• Heartburn, gastrointestinal bleeding
• Hypertension
• Hyperglycemia
• Fluid retention
• Facial swelling (moon facies)
• Blurred vision
Long-term (low dose) side effects
• Muscle/joint weakness
• Hyperglycemia
• Weight gain (increased appetite)
• Osteoporosis
• Thinning of the skin
• Rounded shoulders
• Cataracts
• Hypercholesterolemia
• Acne
Tapering too quickly may lead to are of
underlying condition, or precipitate an episode of
rejection
Some centers will use steroid-free maintenance
regimens in select patients, typically only in liver
transplantation and less commonly kidney
transplantation
For select patients at high risk of adverse outcomes
with any antibody induction, an induction using
only corticosteroids may be used.
Table 3.2 (continued)
L. Sun et al.