809318

research-article2018
AOPXXX10.1177/1060028018809318Annals of PharmacotherapyDagenais et al

Special Contribution
Annals of Pharmacotherapy

Common Questions and Misconceptions

1­–11
© The Author(s) 2018
Article reuse guidelines:
in the Management of Renal Transplant sagepub.com/journals-permissions
DOI: 10.1177/1060028018809318
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Patients: A Guide for Health Care journals.sagepub.com/home/aop

Providers in the Posttransplant Setting

Renée Dagenais, PharmD1, Marianna Leung, PharmD1, Krishna Poinen, MD1,

and David Landsberg, MD1

Abstract
Once renal transplant recipients are stabilized and require less frequent follow-up with their transplant team, health care
providers outside of the transplant setting play an integral role in patients’ ongoing medical care. Given renal transplant
recipients’ inherent complexity, these health care providers often seek consult regarding decisions that may affect
transplant-related medications or outcomes. In this review, we discuss answers to 10 of the questions commonly posed to
our renal transplant team by other health care providers.

Keywords
renal transplant, drug interactions, drug safety, urinary tract infection, herpes zoster, angiotensin converting enzyme
inhibitors, angiotensin II receptor blockers, fluoroquinolones, immunosuppressant medications, HMG-CoA reductase
inhibitors, sodium-glucose cotransporter 2 inhibitors, skin malignancy, immunizations, antidepressants

Introduction within our transplant program, which is based out of an aca-

When compared with dialysis, renal transplantation has
been associated with reduced mortality, lower rates of car-
diovascular events, and improved quality of life.1 The
annual number of renal transplants continues to rise, and the
transplants (also known as grafts) themselves are function-
ing longer because of advancements in therapies and moni-
toring.2 Together, this has resulted in a higher prevalence of
renal transplant recipients being followed in the posttrans-
plant setting.2
Once patients are stabilized in the acute postoperative
phase and require less frequent follow-up with their trans-
plant team, health care providers outside of the transplant
setting play an integral role in their ongoing medical care.
Given the complexity of patients’ transplant-related medi-
cations and comorbidities, these health care providers are
encouraged to contact the transplant providers regarding
decisions that may affect transplant-related outcomes and to
ensure appropriate continuity of care.
Our goal is to present 10 common, pragmatic scenarios that
occur frequently in the post–renal transplant course and to pro-
vide recommendations to help nontransplant clinicians in
tackling these in their own practice. We drew from experiences
demic facility in an urban city center, and services a diverse
adult patient population. Our program performs between 150
to 180 renal transplants each year, and upward of 1000 patients
are actively followed as outpatients. Presented in this review
are answers to 10 of the more common questions posed to our
renal transplant team (Table 1).
Questions
1. How Should a Patient With Asymptomatic
Bacteriuria Be Managed? Does This Change if
Pyuria Is Present?
Urinary tract infections (UTIs), including asymptomatic
bacteriuria, cystitis, and pyelonephritis, are the most com-
mon type of infections among renal transplant recipients.3
1
St Paul’s Hospital, Vancouver, BC, Canada
Corresponding Author:
Renée Dagenais, St Paul’s Hospital, 1081 Burrard St, 6th Floor, Unit 6D,
Vancouver, BC V6Z 1Y6, Canada.
Email: rdagenais1@providencehealth.bc.ca
2 Annals of Pharmacotherapy 00(0)

Table 1. Summary of Responses to 10 Commonly Posed Questions.

Question Response
1 Asymptomatic bacteriuria with or without pyuria does not require antimicrobial management in posttransplant
recipients, unless in the context of pregnancy, urological intervention, or otherwise unexplained acute deterioration
of kidney function. Asymptomatic patients should not have surveillance urine cultures.
2 ACE inhibitors or ARBs are best avoided 3 to 6 months posttransplant to minimize the risk of prerenal kidney injury
and to avoid potential confounding when interpreting abrupt serum creatinine changes early posttransplant.
3 Concomitant administration of calcineurin inhibitors/sirolimus and statins may result in a significant increase in statin
serum concentrations; therefore, the indication and dosing of statins must be evaluated when considering initiation
or reinitiation of statin therapy.
4 SGLT-2 inhibitors should be prescribed with caution in renal transplant recipients because of the increased risk for
mycotic and bacterial urinary tract infections, urosepsis, and osmotic diuresis with subsequent volume depletion.
5 Concomitant use of tacrolimus and ciprofloxacin is unlikely to result in clinically significant QTc prolongation in the
absence of additional risk factors.
6 Despite the well-documented increased risk of skin cancers in renal transplant recipients, there still exists a gap in
patients’ knowledge and understanding of this risk as well as patients’ implementation of precautionary measures to
mitigate this risk. Routine screening and routine use of sun protection measures will help lower their risk of skin
cancers.
7 Fluoroquinolone-associated tendinopathy is an important safety consideration, especially in patients 60 years and older
and/or who are concomitantly taking oral corticosteroids.
8 Recommended management of herpes zoster infections in renal transplant recipients is the same as for
immunocompetent patients, except possibly for longer duration. If more than 72 hours has passed since the onset of
cutaneous symptoms, it is still appropriate to initiate antivirals in immunocompromised patients.
9 If all routine scheduled vaccinations have not been received prior to transplantation, all outlying inactivated vaccines
should be administered per the appropriate catch-up schedule. Live-attenuated vaccines are generally contraindicated
posttransplant. Though guidelines vary, it is generally recommended that vaccines be postponed until after 2 or 3 to
6 months posttransplant and 6 months following treatment with rituximab or antithymocyte globulin. The inactivated
influenza vaccine can be administered after 1 month posttransplant if during influenza season.
10 Few clinically relevant pharmacokinetic interactions have been reported between antidepressant medications
and immunosuppressant medications. Antidepressant safety profiles may help guide selection, based on
immunosuppressant- and patient-specific factors. St John’s wort increases metabolism of immunosuppressant
medications, which has resulted in cases of renal graft rejection; its use should be discouraged.

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; PCV13, pneumococcal 13-valent conjugate; PPV23,
pneumococcal 23-valent polysaccharide; SGLT-2, sodium-glucose transport protein 2.

Observational studies have reported 48% to 58% of patients
to have had at least 1 episode of bacteriuria, and up to 33%
to 85% of episodes may be asymptomatic.4-7 Whether or not
to treat asymptomatic bacteriuria in renal transplant recipi-
ents is an area of controversy.
The latest Infectious Diseases Society of America guide-
lines regarding asymptomatic bacteriuria state that recom-
mendations cannot be made for the screening or treatment of
asymptomatic bacteriuria in renal or other solid organ trans-
plant recipients.8 The Kidney Disease, Improving Global
Outcomes guidelines regarding the care of renal transplant
recipients do not make mention of this topic.9 Frequent epi-
sodes of asymptomatic bacteriuria have been associated
with increased risk of symptomatic UTIs5,10,11 and acute
graft pyelonephritis,4,12 with the latter being associated with
decreased renal graft functioning.6,13 Given this and renal
transplant recipients’ immunocompromised state, it is under-
standable why practitioners are inclined to screen for bacte-
riuria and treat regardless of whether patients have
accompanying symptoms. However, the overall results from
observational studies and a randomized controlled trial indi-
cate that treatment of asymptomatic bacteriuria with or with-
out pyuria does not significantly decrease the risk of
subsequent symptomatic UTI14-17 or affect outcomes related
to renal graft functioning.12,14,16,17 Whether asymptomatic
bacteriuria occurring early post–renal transplant may affect
the observed outcomes was not addressed in these studies.
Spontaneous bacterial clearance rates of up to 70% have
been reported in untreated patients and are often comparable
to (or, in some cases, greater than) clearance rates reported
for treated patients.15,17,18
Treatment of asymptomatic bacteriuria also has the
potential to confer harm. Observational studies have
reported selection of resistant organisms in up to 47% to
78% of renal transplant recipients treated for asymptomatic
bacteriuria.15,18 Use of antibiotics within the prior 6 months
has also been associated with a 3-fold increase in the risk
for resistant or extended spectrum β-lactamase-producing
uropathogens.7 Accordingly, the prevalence of antibiotic-
resistant microorganisms isolated from the urine of renal
Dagenais et al
transplant recipients has significantly increased over time.19
One retrospective study reported increased risk of subse-
quent symptomatic UTI in patients treated for asymptom-
atic bacteriuria.16 Treated patients are also subjected to the
adverse effects associated with the selected antimicrobial
therapy.
Unless in the context of pregnancy or a urological inter-
vention with anticipated mucosal bleeding,8 or if there is an
otherwise unexplained acute deterioration in renal func-
tion, the risks associated with treating asymptomatic bacte-
riuria (with or without pyuria) likely outweigh the lack of
demonstrated benefit. There is no indication for surveil-
lance urine cultures in the post-transplant period if patients
are asymptomatic.
2. When Is It Safe to Initiate or Restart Therapy
With an Angiotensin-Converting Enzyme (ACE)
Inhibitor or Angiotensin II Receptor Blocker
(ARB) Post–Renal Transplant?
Although ACE inhibitors and ARBs are widely used in
patients with chronic kidney disease to treat hypertension
and slow the progression to end-stage renal disease20; they
are generally avoided early post–renal transplant. This is
because of the potential for reduced graft perfusion and an
increased risk of prerenal acute kidney injury.
A double-blind randomized controlled trial conducted in
clinically stable renal transplant recipients evaluated the
safety of initiating enalapril at 1 month posttransplant.21
Compared with placebo, patients receiving enalapril experi-
enced significantly higher rates of the combined end point
of serum creatinine elevation to more than 30% above base-
line and hyperkalemia over the course of the 6-month treat-
ment period.21 Retrospective analyses of recipients did not
show a difference in the observed serum creatinine, potas-
sium, or hemoglobin when initiating an ACE inhibitor or
ARB within the first 3 to 6 months posttransplant versus
initiating after 6 months22 or versus instead initiating a cal-
cium channel blocker.23 A systematic review suggested that
it may be appropriate for clinicians to consider initiating an
ACE inhibitor or ARB within the first 12 weeks posttrans-
plant in patients with a functional graft, hypertension, and a
compelling indication (eg, heart failure, diabetes).24
Despite evidence to suggest that early initiation of an
ACE inhibitor or ARB may be appropriate in select patients,
we generally wait until 3 to 6 months posttransplant at our
center. This stems from the myriad potential etiologies for a
rise in serum creatinine in the early posttransplant period.
Postponing initiation of an ACE inhibitor or ARB during
this time ensures that they are not a potential confounder
when working through the differential diagnoses. If an ACE
inhibitor or ARB is initiated after the 3 to 6 months post-
transplant, monitoring of serum creatinine and potassium
within 1 to 2 weeks is recommended.
3
3. Is It Safe to Use Statins Concomitantly With
Patients’ Immunosuppressive Medications? If
So, When Is It Safe to Initiate or Restart Statin
Therapy Post–Renal Transplant?
Dyslipidemia is highly prevalent in renal transplant recipi-
ents and contributes to cardiovascular disease as the leading
cause of mortality in this population.25 In addition to gen-
eral risk factors (eg, genetic predisposition, diet, obesity,
diabetes), calcineurin inhibitors, mTOR inhibitors, and cor-
ticosteroids further increase renal transplant recipients’ risk
of dyslipidemia.25 Statins are considered first-line in the
management of dyslipidemia and cardiovascular disease
and have demonstrated potential benefit in decreasing the
risk of major cardiovascular events in renal transplant
recipients.26,27 The risk for interactions between statins and
immunosuppressant medications must be considered if
statin therapy is to be initiated posttransplant.
The American Heart Association (AHA) established
guidelines regarding how to appropriately manage important
drug-drug interactions with statin medications.28 Through
inhibition of CYP3A4, P-glycoprotein, and OATP1B1, cal-
cineurin inhibitors may increase exposure of concomitantly
administered statins; 2- to 20-fold increases in the area-
under-the-concentration-time curve have been reported
when administered concomitantly with cyclosporine.28,29
mTOR inhibitors may also increase statin exposure via inhi-
bition of CYP3A4 and P-glycoprotein. The AHA guidelines
do not recommend the concomitant administration of lovas-
tatin, simvastatin, or pitavastatin with calcineurin inhibitors
or mTOR inhibitors.28 If fluvastatin, atorvastatin, pravas-
tatin, or rosuvastatin are prescribed, the maximum daily
doses should be limited.28 These recommendations are pri-
marily derived from evidence with cyclosporine, as limited
evidence exists with other alternatives. If a patient’s previ-
ous dose of statin exceeds that recommended by the AHA
guidelines, clinical judgment should be exercised and con-
sideration be made to reduce the statin dose if or when it is
reinitiated.
The timing posttransplant after which it may be consid-
ered safe to initiate or restart statins has not been established
in the literature. In a review of studies regarding the use of
statins in renal transplant recipients, timing of statin initia-
tion varied from within the first 3 to 7 days to at least 6 to 12
months posttransplant.26 At our center, patients who were
receiving a statin for secondary prevention prior to trans-
plantation will generally be continued on therapy. Patients
taking a statin for primary prevention prior to transplantation
will generally have cessation of therapy until reassessment
once stable renal function and immunosuppressant therapy
is established. Canadian Consensus Working Group guide-
lines recommend assessing creatine kinase at baseline and if
symptoms of myopathy occur.30 Assessment of liver trans-
aminases is recommended at baseline, at 6 to 12 weeks after
4 Annals of Pharmacotherapy 00(0)
initiation, and if patients present with signs or symptoms of
liver toxicity.30 Monitoring of these parameters is routinely
performed at our center because the aforementioned interac-
tions increase the risk for statin toxicity.
4. Are Sodium-Glucose Cotransporter 2 (SGLT-
2) Inhibitors Safe to Administer in Renal
Transplant Recipients?
Whereas some renal transplant recipients may have a preex-
isting diagnosis of diabetes, others may develop what is
termed new-onset diabetes after transplantation.31
Regardless of the etiology, appropriate diabetes manage-
ment is necessary to optimize patient outcomes. Use of
SGLT-2 inhibitors have become more common, especially
with the statistically significant decrease in the composite
of cardiovascular-related mortality, nonfatal myocardial
infarction, and nonfatal stroke reported for empagliflozin
and canagliflozin in the EMPA-REG OUTCOME and
CANVAS trials, respectively.32,33 However, the adverse
effect profile of SGLT-2 inhibitors must be carefully evalu-
ated in the context of renal transplant recipients prior to use.
For example, SGLT-2 inhibitors in the general popula-
tion have been associated with an increased risk of mycotic
genital tract infections, UTIs, and urosepsis when compared
with placebo and alternative antidiabetic medications.32-35
This is notable for renal transplant recipients, who are
already prone to UTIs and infection-related morbidities
because of their immunocompromised state.3 SGLT-2
inhibitors’ osmotic diuretic effect has been associated with
an increased risk of volume depletion.33,35 This may be of
concern in renal transplant recipients, especially in the early
post-transplant period because volume depletion has the
potential to negatively affect perfusion of the kidney graft.
Canagliflozin has been reported to be well tolerated in a
case series of 10 renal transplant recipients36; however,
larger and longer studies are needed to better establish the
safety and efficacy of SGLT-2 inhibitors in this patient pop-
ulation before their routine use can be recommended.
5. Are Ciprofloxacin and Tacrolimus Safe to
Take Concomitantly?
As a result of increasing rates of antimicrobial-resistant uro-
pathogens among renal transplant recipients,7,19 ciprofloxacin
is commonly utilized for symptomatic UTIs. When filling a
ciprofloxacin prescription for patients on a tacrolimus-based
regimen, drug interaction software often prompt a warning
regarding the risk of QTc prolongation and torsades de pointes
(TdP) with this combination.37
Tacrolimus has been categorized by one database as hav-
ing “possible risk of TdP.”38 A proposed mechanism by
which tacrolimus may cause QTc prolongation is via binding
to FK506 binding protein (FKBP)12 in cardiac myocytes.39
This affects function of voltage-gated sodium channels
involved in arrhythmogenesis.39 The first case of tacrolimus-
associated dysrhythmia was reported in 1992, wherein intra-
venous tacrolimus was implicated in causing QTc
prolongation and TdP post–liver transplantation.40 A similar
case was reported in a post–renal transplant patient thereaf-
ter.41 In both cases, congenital long QT syndrome could not
be ruled out. Subsequent reports of tacrolimus-associated
QTc prolongation have been in the context of concomitant
administration of one or more medications with known pro-
pensity to prolong the QTc interval (eg, amiodarone, levo-
floxacin, itraconazole, or metoclopramide).42-44 Tacrolimus
did not demonstrate a greater propensity to cause QTc pro-
longation in renal transplant recipients when compared with
cyclosporine, everolimus, and azathioprine.45 Also, although
mean QTc intervals were significantly longer posttransplant
when compared with pretransplant in all 4 treatment groups,
none exceeded 500 ms (the longest mean QTc interval post-
transplant was 455 ms).45
Fluoroquinolones have been categorized as having
“known risk of TdP,”38 with blockade of hERG potassium
channels in the cardiac myocytes being the likely mecha-
nism of QTc prolongation.46 When compared with alterna-
tive fluoroquinolones, ciprofloxacin has a lower propensity
to inhibit hERG channels46 and is less likely to cause clini-
cally significant QTc prolongation when given at therapeu-
tic doses.46,47 This was reflected in a recent European cohort
study, which found no difference in the incidence of arrhyth-
mia when comparing oral fluoroquinolones (82.6% cipro-
floxacin) with oral penicillin V.48 One case report of a renal
transplant recipient describes elevated tacrolimus levels fol-
lowing initiation of ciprofloxacin; QTc prolongation was
not reported to occur.49
Overall, currently available evidence suggests that con-
comitant administration of tacrolimus and ciprofloxacin is
unlikely to result in clinically relevant prolongation of the
QTc interval in the majority of patients. This suggestion
may not apply to patients with additional factors that may
increase their risk of QTc prolongation (eg, electrolyte
abnormalities, congenital long QT syndromes, bradycardia,
cardiomyopathy, or concomitant administration of addi-
tional QTc-prolonging medications). The risks and benefits
of this combination must be carefully weighed in these
patients.
6. What Is the Incidence of Skin Cancer in
Renal Transplant Recipients, and How Can This
Risk Be Mitigated?
Immunosuppressive therapy puts transplant recipients at an
elevated risk of developing cancer when compared with the
general population.50 The reported risk is highest for viral-
associated cancers (eg, lymphoma, Kaposi sarcoma) and
Dagenais et al
skin cancers, especially nonmelanocytic skin cancers (ie,
squamous-cell carcinoma and basal-cell carcinoma).50 In
regard to skin cancer, the incidence in solid organ transplant
recipients increases markedly over time. For example, non-
melanoma skin cancer has cumulative incidence rates
reported as 5%, 10% to 27%, and 40% to 60%, at 2, 10, and
20 years posttransplant, respectively.50
Despite the well-documented increased risk of skin can-
cers in renal transplant recipients, there is still a gap in
patients’ knowledge and understanding of this risk and the
importance of precautionary measures. In one study,
although 75% of patients reported being informed about the
necessity of sun protection, only 40% understood that
development of skin cancer is related to sun exposure, and
only 11% could explain what sun protection factor (SPF)
means.51 Another study found that only 52% of renal trans-
plant recipients considered themselves to be at higher risk
of skin cancer.52 Sunscreen was reportedly used “never” or
“sometimes” in 81% of these patients when sun tanning,52
whereas 26% of another group of renal transplant recipients
admitted to never using sunscreen on sunny days.53
In nontransplant populations, regular and appropriate
use of sunscreen has been associated with reduced rates of
skin cancer.54-56 Although health care providers outside of
the transplant team are not expected to independently man-
age transplant recipients’ skin lesions, they may identify
abnormal lesions during a physical exam and initiate refer-
ral to a dermatologist. They are also instrumental in provid-
ing patient education and ensuring patients continue to take
the appropriate precautions to minimize the risk of skin can-
cer. Useful patient resources and recommended sunscreens
are accessible online.57,58
7. What Is the Risk of Fluoroquinolone-
Associated Tendinopathy in Renal Transplant
Recipients?
In 2008, the Food and Drug Administration issued a black-
box warning regarding the risk of tendinitis and tendon rup-
ture secondary to systemic fluoroquinolone use.59 The
majority of cases have involved the Achilles tendon, but
other tendons may also be affected.60 A suggested mecha-
nism of fluoroquinolone-associated tendinopathy includes
mitochondrial damage and degenerative changes in tendon
tissues secondary to the production of reactive oxygen spe-
cies.61 Delays in tendon healing may also play a role.61
Observational data suggest that ofloxacin is associated with
a higher risk compared with other fluoroquinolones.62,63
Ciprofloxacin and norfloxacin have also been implicated,60,62
and cases with levofloxacin have been reported.64
Although the prevalence of fluoroquinolone-associated
tendinopathy is estimated to be only 0.14% to 0.4 % in the
general population,60 factors such as age of 60 years and
older and concomitant use of systemic corticosteroids may
5
increase this risk.62,65-68 In one population-based case-con-
trol study, the adjusted odds ratio for Achilles tendon rup-
ture within 30 days of fluoroquinolone exposure increased
from 4.3 (95% CI = 2.4-7.8) in the overall population to 6.4
(95% CI = 3.0-13.7) and 20.4 (95% CI = 4.6-90.1) in
patients aged 60 to 79 years and 80 years or older, respec-
tively.62 In patients with concomitant oral corticosteroid
use, the adjusted odds ratio increased to 17.5 (95% CI =
5.0-60.9).62 Other potential risk factors include renal failure
and diabetes mellitus.60,67,68 Many renal transplant recipi-
ents have one or more of the aforementioned risk factors for
fluoroquinolone-associated tendinopathy. This is important
to consider when deciding between antimicrobial alterna-
tives. Indeed, cases of fluoroquinolone-associated tendi-
nopathies have occurred at our center.
The reported lag time between fluoroquinolone exposure
and the onset of tendinopathy varies but is a median of 6
days.60,68 Although the majority of cases occur within 1
month,60 cases up to 6 months following completion of flu-
oroquinolone therapy have been reported.68 Tendinopathy
may be unilateral or bilateral and may present as pain and
inflammation of the tendon area. Tendon rupture is abrupt
and may lead to joint immobility.60 For patients presenting
with these signs and symptoms, we recommend cessation of
the fluoroquinolone, minimizing use of the affected joint,
and physical therapy.60 Early recognition of fluoroquino-
lone-associated tendinopathy by clinicians may allow early
intervention and prevention of tendon rupture.
8. How Should Herpes Zoster Infections
(Shingles) Be Managed in Renal Transplant
Recipients?
By nature of being immunocompromised, renal transplant
recipients who are seropositive for varicella zoster virus
are at risk of viral reactivation and resultant shingles
infection.69,70 The incidence of shingles in these patients
has been reported to vary between 3.5% and 9%.69
Although immunocompromised, the approach to treating
shingles in renal transplant recipients is similar to that for
the general population.
Initiation of antivirals within 72 hours of cutaneous
symptom onset is recommended to optimize effectiveness of
therapy,69,71 but it is appropriate to initiate therapy after 72
hours in immunocompromised patients.69 In the case of
localized, dermatomal presentations of shingles that do not
involve the eye, recommendations for oral acyclovir, valacy-
clovir, or famciclovir in solid organ transplant recipients are
the same as for the general population.69-71 Management
with oral agents can take place in the outpatient setting. One
subtle difference is in the recommended duration of therapy.
In immunocompetent patients, a 7-day course is often suffi-
cient.71 In renal transplant recipients, the minimum duration
of therapy in localized infection is 7 days or until all lesions
6 Annals of Pharmacotherapy 00(0)
have crusted over, whichever is longest.70 If the shingles
presents as herpes zoster ophthalmicus (ie, affecting the eye)
or as disseminated or invasive infection, patients require
treatment with at least 7 days of intravenous acyclovir.70 It is
prudent to assess patients’ renal function and whether dose
adjustments are necessary when prescribing antiviral agents.
9. Which Vaccines Are Safe and Recommended
for Renal Transplant Recipients, and at What
Time in the PostTransplant Period Are They
Most Appropriate to Administer?
Infection remains a significant cause of morbidity and mor-
tality in renal transplant recipients, and ensuring patients are
immunized against vaccine-preventable diseases is an essen-
tial element in their care.72 Practice guidelines and immuni-
zation schedules detail recommendations for patients who
are immunocompromised.73-75 Ideally, patients will have
received all routine scheduled vaccines recommended for
immunocompetent patients based on their individual age
and risk prior to transplantation. If not, all outlying inacti-
vated vaccines should be administered per the appropriate
catch-up schedule.73-75 Live-attenuated vaccines are gener-
ally contraindicated posttransplant because of the risk for
disseminated infection.73-76 Although limited evidence does
suggest that live vaccines may potentially be safe in immu-
nocompromised patients, reports of serious adverse events
and fatalities associated with live vaccines in this population
preclude routine use.77 In cases where patients are deemed
high risk for the wild-type infection (eg, during a measles
outbreak), potential risks versus benefits of immunizing
with a live vaccine must be weighed on a patient-by-patient
basis.73-76 Live vaccines include the following: measles,
mumps, rubella (MMR); varicella zoster (chicken pox); her-
pes zoster (shingles) subcutaneous injection; influenza nasal
spray; Bacille Calmette-Guérin (BCG); yellow fever; small-
pox; oral rotavirus; oral polio; and oral typhoid.
Two pairs of vaccines merit further discussion, the first
being the herpes zoster live-attenuated and inactive recom-
binant subunit vaccines. Prior to the inactive recombinant
subunit vaccine against herpes zoster, only the live-attenu-
ated formulation was available. This posed a barrier to
immunocompromised patients receiving immunization
against this potentially fatal infection.69,73-76 The inactive
vaccine has shown promise as a safe alternative in immuno-
compromised patient populations. Preliminary data from a
phase III clinical trial conducted in adult renal transplant
recipients suggest that the inactive vaccine elicits satisfac-
tory humoral and cellular immune responses by 1 month fol-
lowing the second dose.78 Whether this results in clinical
protection from herpes zoster infection was not assessed.
Pain, redness, and swelling at the injection site occurred at a
higher frequency with the vaccine when compared with pla-
cebo.78 There was no difference in other safety parameters,
including generalized symptoms (eg, fatigue, myalgia,
fever), potential immune-mediated diseases, serious adverse
events, or allograft rejection.78 Phase 1/2 randomized con-
trolled trials conducted in autologous hematopoietic stem-
cell transplant recipients79 and patients infected with HIV80
also suggest satisfactory immunogenicity and safety profile
of the vaccine in immunocompromised patients.
The pneumococcal 23-valent polysaccharide (PPV23)
and 13-valent conjugate (PCV13) are another pair of vac-
cines subject to many inquiries. In immunocompetent
patients, a 3 to 4 dose series of the PCV13 is recommended
in the scheduled childhood vaccinations, and a 2-dose series
of the PPV23 is recommended in adults ⩾65 years old.73,81
In solid organ transplant recipients, recommendations vary
based on patients’ age and history of pneumococcal immu-
nization. Patients who have not received the PCV13 vac-
cine as part of their routine childhood immunizations are
recommended to receive one lifetime dose.73-75 Two doses
of the PPV23 vaccine administered at least 5 years apart are
also recommended. If the second dose was given before the
age of 65 years, then a third dose is recommended once
patients are ⩾65 years old, also spaced at least 5 years from
the previous.73-75 Importantly, if the PCV13 and PPV23
vaccine are both indicated in a patient, they should not be
administered on the same day; the PPV23 should be given
at least 8 weeks following the PCV13, and at least 1 year
should separate the vaccines if given in the reverse
order.73,74,82 Although the number and timing of these vac-
cines may seem confusing, the aforementioned recommen-
dations are described by the Centers for Disease Control
and Prevention.82 A “prime-boost” strategy (ie, PPV booster
given after PCV priming dose) has been proposed to
enhance patients’ sero-responsiveness to the vaccines; how-
ever, current evidence does not support this strategy in solid
organ transplant recipients.83
As immunosuppressants have the potential to blunt vac-
cine immunogenicity and effectiveness, the timing of vaccine
administration is key.73-76 Posttransplant, it is recommended
that vaccines be postponed until after 2 or 3 to 6 months fol-
lowing transplantation, when the intensity of immunosuppres-
sion is decreased.74-76 An exception to this is the inactivated
influenza vaccine, which may be administered after 1 month
posttransplant if it is during the influenza season.75,76 If a
patient receives rituximab or antithymocyte globulin for the
treatment of rejection, it is recommended that vaccinations be
postponed until 6 months after treatment.75
10. Which Antidepressant Medications Are
Safe to Use in Renal Transplant Recipients? Are
There Preferred Agents?
Reported prevalence of depression among renal transplant
recipients ranges from 5% to greater than 20%.84,85
Depression has been identified as a risk factor for medica-
tion noncompliance86,87 and is associated with increased
Dagenais et al
risk of renal allograft failure and mortality in the posttrans-
plant setting.84,85,88 Management of depression in this popu-
lation is, therefore, advisable. In selecting an antidepressant
medication, the interaction and side effect profile of avail-
able alternatives must be considered in the context of
patients’ immunosuppressant regimen.
Tacrolimus, cyclosporine, and sirolimus are substrates of
CYP3A4 isoenzyme and P-glycoprotein,89 whereas the
majority of antidepressant medications are substrates and/or
inhibitors of cytochrome P450 enzymes.90 Despite this, few
clinically relevant interactions have been reported.
Nefazodone, a potent CYP3A4 inhibitor, has the most con-
sistent evidence for significantly increasing levels of cyclo-
sporine and tacrolimus.91,92 However, it is neither commonly
used nor available on all drug markets because of its risk of
hepatotoxicity.91,92 Of the selective serotonin reuptake
inhibitors (SSRIs), fluvoxamine is associated with the
greatest inhibitory effect on CYP3A4.90,91 In one case
report, a patient’s cyclosporine dose had to be decreased by
33% in order to achieve target levels following initiation of
fluvoxamine.93 Case reports, case series, and retrospective
comparisons in organ transplant recipients have otherwise
not identified consistent or notable impacts of paroxetine,
sertraline, fluoxetine, or citalopram on cyclosporine94-96 or
tacrolimus97 levels. One case report associated a decrease in
cyclosporine levels with the initiation of bupropion,98 but
no definitive mechanism could explain the finding.
Mirtazapine, trazodone, serotonin norepinephrine reuptake
inhibitors (SNRIs), vortioxetine, and tricyclic antidepres-
sants (TCAs) have not been reported to significantly affect
the measured levels of cyclosporine, tacrolimus, or siroli-
mus and are unlikely to do so based on their proposed cyto-
chrome P450 profiles.90-92 Regardless, it is justifiable to
monitor immunosuppressant levels following initiation of
an antidepressant if there are any concerns for potential
interactions (eg, fluoxetine and its active metabolite are
associated with mild-moderate CYP3A4 inhibition, so may
warrant immunosuppressant drug level monitoring despite
lack of clinical data to support an interaction).90-92
Safety profiles of antidepressant medications may also
guide selection. As previously discussed, tacrolimus has
been associated with causing prolongation of the QTc inter-
val.38 Citalopram, escitalopram, and TCAs have the poten-
tial to cause clinically significant increases in the QTc
interval38,99,100; caution and appropriate monitoring would
be warranted if used concomitantly with tacrolimus. Other
SSRIs, though flagged as increasing risk for QTc prolonga-
tion,38 are less likely to be of concern. Corticosteroids have
been associated with weight gain and hyperlipidemia, while
cyclosporine and sirolimus may also cause the latter.91,92
Mirtazapine, paroxetine, and TCAs contribute to weight
gain, and mirtazapine may trigger elevations in cholesterol
and triglyceride levels.91,92 Therefore, these antidepressants
may not be first-line in transplant recipients already
7
struggling with these metabolic changes. Corticosteroids
and calcineurin inhibitors are also notorious for causing
secondary hypertension. If a patient’s hypertension is diffi-
cult to manage, the potential for venlafaxine and bupropion
to also increase blood pressure should be considered with
these agents.91,92
Cases of serotonin syndrome have been reported when
venlafaxine and sertraline were initiated in patients receiv-
ing tacrolimus or cyclosporine.101,102 A proposed mecha-
nism in the case of venlafaxine is the inhibition of
P-glycoprotein by tacrolimus and cyclosporine, which may
result in supratherapeutic levels of venlafaxine and its
metabolite within the central nervous system.101 Given its
rarity, this should not preclude the use of SSRIs or SNRIs in
the posttransplant setting. Signs and symptoms of serotonin
syndrome could instead be incorporated into patient coun-
seling and follow-up monitoring.
The use of St John’s wort (Hypericum perforatum) as a
natural alternative to antidepressants is not uncommon. St
John’s wort is a known inducer of CYP3A4 and P-glycoprotein,
reportedly decreasing tacrolimus and cyclosporine levels by
up to 50% to 70% when used concomitantly.91,103 This has
resulted in cases of renal graft rejection.91,103 Similar out-
comes can be expected for sirolimus because it too is a sub-
strate of CYP3A4 and P-glycoprotein.89 Although health care
providers cannot bar patients from electing to self-treat with
St John’s Wort, its use should be discouraged because of the
risk for negative outcomes.
There may be fewer first-line antidepressant options in
the posttransplant setting because of potential interactions
with concomitant immunosuppressants. For remaining
alternatives, the risks and benefits of each agent must be
weighed in every individual patient.
Conclusion
With the increasing prevalence of renal transplant recipi-
ents, the importance of health care providers in the ongoing
care of posttransplant patients will only continue to grow.
Transplant recipients’ immunosuppressant medications and
comorbidities are complex and warrant careful consider-
ation in all clinical decisions. We encourage health care pro-
viders to seek advice from patients’ transplant team if ever
unsure of how a clinical decision may affect transplant-
related outcomes. It is with this open communication that
we can collaborate and optimize the care of these patients.
Authors’ Note
This manuscript has not been submitted to any other journal and is
not under consideration for publication elsewhere.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
8 Annals of Pharmacotherapy 00(0)
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
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