Transplantation Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Transplantation Reviews
journal homepage: www.elsevier.com/locate/trre

Pharmacokinetics and pharmacodynamics of immunosuppressive drugs

in elderly kidney transplant recipients
Yun-Ying Shi a,b, Dennis A. Hesselink c, Teun van Gelder a,c,⁎
a
Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
b
Department of Nephrology, West China Hospital of Sichuan University, Chengdu, China
c
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

a b s t r a c t

Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate
and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of
acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age,
donor age is associated with a higher incidence of acute rejection.
Pharmacokinetic studies in renal transplant recipients show that CNI troughs are N 5% higher in elderly compared
to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacro-
limus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relative-
ly high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same
whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for
other immunosuppressive drugs.
Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of
immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell
(NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of
immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and
non-melanoma skin cancer in elderly patients.
Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient popula-
tion, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to in-
vestigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to
decide on the optimal regimen and target levels for elderly transplant recipients.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction: aging in transplant recipients and donors
In the past decades, the number of elderly patients (those
≥ 65 years) with end-stage renal disease (ESRD) has grown rapidly
[1,2]. Like in younger patients, renal transplantation provides a survival
benefit and improves quality of life compared with dialysis, and is
therefore the optimal renal replacement therapy for the elderly suffer-
ing from ESRD [3]. Since 2002, the total number of kidney transplants
in patients ≥ 65 years old has doubled in the U.S. (Fig. 1) [1,4]. In
Europe, the increase in the proportion of kidney transplant recipients
≥65 years between 1991 and 2007 is over 5-fold, from 3.6 to 19.7% [2].
⁎ Corresponding author at: Department of Hospital Pharmacy, Clinical Pharmacology
Unit, Erasmus MC, University Medical Center Rotterdam, Room Na-210, P.O. Box 2040,
3000 CA Rotterdam, The Netherlands. Tel.: +31 10 703 3202; fax: +31 10 703 2400.
E-mail address: t.vangelder@erasmusmc.nl (T. van Gelder).
Meanwhile, the imbalance between donor organ shortage and the
growing waiting list has led to the increased utilization of kidneys
from older living donors (OLD) and expanded criteria deceased donors
(ECDs) [5,6]. Furthermore, the likelihood of receiving an OLD or ECD
kidney increases with recipient age [7,8]. In the Eurotransplant Senior
Program (ESP) kidneys from donors of 65 years or more were allocated
to local transplant candidates above 65 years of age, without matching
for HLA antigens. The rationale behind this policy was to expedite the
change of the elderly to receive a transplant and to reduce cold ischemia
time to prevent ischemic injury and hereby delayed graft function and
the increased risk of rejection [9].
Transplantation of elderly recipients is more complicated compared
to young transplant recipients because their graft function is often less
than ideal, they have more comorbidities and a different immune re-
sponse, suffer more from immunosuppression-related adverse events,
and use more co-medication resulting in more frequent drug–drug in-
teractions [10].

http://dx.doi.org/10.1016/j.trre.2015.04.007
0955-470X/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
2 Y-Y. Shi et al. / Transplantation Reviews xxx (2015) xxx–xxx
Fig. 1. 1.1 The number of deceased donor kidney transplants by age in the US. Includes kid-
ney-alone and kidney–pancreas transplants. 1.2 The number of living donor kidney trans-
plants by age in the US. Includes kidney-alone and kidney–pancreas transplants. Figure 1.1
and 1.2 are reproduced from the US Renal Data System. The data reported here have been
supplied by the United States Renal Data System (USRDS). The interpretation and
reporting of these data are the responsibility of the author(s) and in no way should be
seen as an official policy or interpretation of the U.S. government [1].
In this paper, we will review the evidence that elderly patients differ
from younger patients in pharmacokinetics (PK) and pharmacodynam-
ics (PD) of immunosuppressive medications. Studies performed in adult
kidney transplant patients are the main focus in this review.
2. Immunosuppression in elderly patients
2.1. Aging and immune response
The immune response, like the function of all organs and biological
systems in the human body, is significantly affected by aging [11].
Both innate and adaptive immunity decrease with age but cell-
mediated immunity is most clearly affected [11–13]. Thymic output of
naive T cells decreases exponentially, resulting in a decline of T-cell di-
versity and a low CD4/CD8 ratio in the older immune system [14–16].
Experimental transplantation models indicate that CD4+ T-cell function
and proliferation is impaired, while regulatory T-cell responses remain
intact in older recipients [17]. Other changes include increased numbers
of memory T-cells and overproduction of pro-inflammatory cytokines
[11,13,18].
Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
Fig. 2. Acute rejection rate and death from infection by age categories. Reproduced from
Meier-Kriesche and colleagues with permission of Wolters Kluwer Health [19].
2.2. Aging and rejection
The age-related decline in immune reactivity is believed to contrib-
ute to the lower acute rejection risk of elderly transplant recipients.
Studies from individual centers and registry data analyses show that
the incidence of acute rejection decreases steadily with increasing re-
cipient age (Fig. 2) [19–22]. In a recent analysis of more than 100,000
renal transplant recipients from the United Network for Organ Sharing
(UNOS) database, Tullius and Milford [23] confirmed these findings.
Acute rejection rates in patients above 65 years of age were about 10%
lower than those in patients between 20 and 30 years [23]. Older
renal transplant recipients may therefore benefit from a less aggressive
immunosuppressive regimen.
However, this lower risk of acute rejection may not apply when
grafts are transplanted from older donors. Organs from elderly donors
are particularly susceptible to ischemia–reperfusion injury and associat-
ed with a higher incidence of acute rejection and delayed graft function
(DGF) [11,24]. De Fijter et al. [25,26] reported that the cumulative inci-
dence of biopsy-proven acute rejection (BPAR) was significantly higher
in older than in younger donor (b 50 years of age) kidneys, a phenome-
non that was observed in both younger and elderly recipients. Interest-
ingly, the increased rejection incidence in older donor kidneys was
largely due to an increase in rejections of the tubulo-interstitial type,
whereas the incidence of acute vascular rejection was not different
from younger donor kidneys [26]. Using the recent data from UNOS,
Tullius and Milford [23] confirmed that higher donor age is associated
with more frequent acute rejection. Wiebe et al. [27] studied the devel-
opment of de novo donor-specific antibodies and the risk factors for its
development in 315 consecutive renal transplants without pre-
transplant donor-specific antibodies. A stepwise logistic regression
analysis identified HLA-DR mismatches and non-adherence, but not
donor or recipient age, to be predictors of de novo donor-specific anti-
bodies [27].
Acute rejection has a stronger negative impact on long-term graft
survival of older renal transplant recipients compared with younger re-
cipients [28]. In an analysis of 48,821 transplant recipients from the
United States Renal Data System (USRDS) database, Meier-Kriesche
et al. found that acute rejection had a strong negative impact on
death-censored graft survival in older renal transplant recipients [28].
This strong effect of acute rejection could not be explained by the fact
that more marginal and therefore more vulnerable grafts are
transplanted in the elderly [29].
2.3. Aging and infection
While the risk of acute rejection is reduced, the risk of death due to
an infection is increased in elderly transplant recipients [30,31].
Meier-Kriesche et al. showed that the risk of death due to infectious
complications increases with age (Fig. 2) [19,32]. Both opportunistic,
as well as non-opportunistic infections are more frequent with
 Y-Y. Shi et al. / Transplantation Reviews xxx (2015) xxx–xxx
increasing age [19]. Studies from single centers have documented
similar results [33,34].
In view of the decreased allo-response and the increased risk of
infections in elderly transplant recipients, it might be beneficial for
these patients to be treated with lower dosages of immunosuppressive
drugs or to aim for lower target concentrations [35,36]. However, this
may not apply to elderly recipients receiving kidneys from elderly
donors [31].
3. General considerations of pharmacokinetics and pharmacody-
namics in the elderly recipients
Despite the considerable increase in the number of kidney trans-
plants performed in elderly patients, there is surprisingly little data re-
garding the optimal immunosuppressive drug combination therapy
for this population. Clinical trials to evaluate the safety and efficacy of
immunosuppression regimens in this specific patient population,
which is underrepresented in published trials, are lacking. In general,
the majority of elderly transplant recipients are treated with the same
regimens as younger recipients. Given the above-mentioned consider-
ations, elderly patients would possibly be better off with alternative im-
munosuppressive treatment.
3.1. Age-related changes in immunosuppressive drug pharmacokinetics
The physiologic changes associated with aging lead to changes in
drug disposition, including drug absorption and bioavailability, hepatic
metabolism, and renal clearance. With increasing age the absorption
of drugs decreases. This may be due to a reduced splanchnic blood
flow, diminished gastric acid secretion or reduced intestinal epithelium
surface area [37–41]. No studies have reported a discernible effect of age
on intestinal cytochrome P450 (CYP) 3A or ABCB1 expression [42–46]
or intestinal UDP-glucuronosyltransferase (UGT) enzyme expression
and/or activity among adults. It seems that age-related changes in ab-
sorptive capacity only have a minor influence on the variability in expo-
sure to the currently used immunosuppressant drugs.
As in the elderly the percentage of body fat increases, and body
water decreases, the volume of distribution (Vd) for lipophilic drugs
can increase with age and vice versa for hydrophilic drugs [38]. The
elimination half-life of lipophilic drugs such as tacrolimus and cyclo-
sporine can thus increase with age through a larger Vd, irrespective of
the drugs' (enzymatic) clearance [39].
The age-related decrease in liver mass and hepatic blood flow could
result in reduced hepatic metabolism [38,47]. In a review of in vivo stud-
ies comparing the clearance of different CYP3A substrates, a general
trend to a reduction in clearance with older age was observed, especially
in male subjects [48,49]. Schwartz et al. however reported no effect of
age on oxidative clearance as measured by the erythromycin breath
test among 60 individuals aged 65–101 years [50].
3.2. Age-related changes in immunosuppressive drug pharmacodynamics
Age-associated changes in pharmacodynamics may occur at the re-
ceptor or signal-transduction level. Age can affect responses to medica-
tion, resulting in altered toxicity or drug-drug interactions [51]. The
increased susceptibility observed in elderly liver recipients for calcine-
urin inhibitor (CNI)-associated neurotoxicity could be associated with
age-related changes in the brain such as reduced ABCB1 expression or
activity [52]. Similarly, age-related changes are observed in kidney and
liver, which could theoretically explain the increased organ susceptibil-
ity for drug-related toxicity [53,54]. However, no data or formal studies
have been published on elderly subjects [55]. With regard to immuno-
suppressive effect, Sugiyama et al. found no influence of age on sensitiv-
ities of peripheral-blood lymphocytes (PBMCs) to immunosuppressive
drugs using the lymphocyte immunosuppressant-sensitivity test
procedure [56].
Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
3
Meanwhile, elderly transplant recipients may often have various
pre-existing chronic diseases, such as hypertension, coronary artery or
peripheral vascular disease, congestive heart failure, chronic kidney in-
sufficiency, hepatic insufficiency or cirrhosis, cerebrovascular disease,
history of malignancy, chronic obstructive pulmonary disease or diabe-
tes, which are all associated with an increased risk of complications and
mortality after transplantation [55]. Old age per se has been reported as
a risk factor for many drug-related adverse effects, including nephrotox-
icity, infections and malignancy [55]. Thus, in elderly patients in general
lower drug doses and/or lower target concentrations should be aimed
for. CNI minimization and steroid withdrawal may be especially benefi-
cial for elderly patients [36,55]. Such modifications must be individual-
ized and fully consider the specific needs of each recipient.
4. Specific pharmacokinetic considerations for immunosuppressive
drugs in the elderly recipients
4.1. Tacrolimus
Theoretically, age-dependent changes in the pharmacokinetics of
immunosuppressive drugs may contribute to changes in dose require-
ment in elderly transplant recipients. However, no significant age-
dependent reduction in drug absorption is observed among most
drugs that are absorbed through passive diffusion [57], which is also
likely to be the case with tacrolimus (Tac). After absorption, changes
in drug distribution in the elderly could be due to the strong protein
binding and due to the lipophilic character of Tac. Although in the elder-
ly plasma albumin concentrations are slightly lower and the adipose tis-
sue mass are increased, no convincing data of age-related changes in the
distribution of Tac have been reported [51,55]. More studies are needed
to better understand the impact of aging on CYP and ABCB1 activity and
expression [58,59].
Staatz and Tett [58] summarized the available studies on pharmaco-
kinetics of tacrolimus in elderly transplant recipients. They did not find
a significant influence of age on tacrolimus bioavailability, Vd, or clear-
ance, in contrast to other covariates such as liver function, hepatic
graft weight, post transplantation time and haematocrit [58]. Some
studies of tacrolimus pharmacokinetics in liver and kidney recipients
found changes in tacrolimus clearance in case of hepatitis C infection
and diarrhea but no age-associated variability in drug exposure
[60–62]. Miura et al. also found no impact of age on the dose/
bodyweight-adjusted pharmacokinetic parameters of tacrolimus [63].
However, the number of elderly patients included in the studies men-
tioned above was either not documented or very small. A recent study
found that bioavailability increased with age in both genders towards
a common value at age N 55 years, while age was one of the covariates
influencing the tacrolimus individual dose requirement [64].
A single nucleotide polymorphism (SNP) in the CYP3A5 gene
(6986A N G) has been consistently studied and was strongly associated
with tacrolimus dose requirement [59]. The dose requirement of pa-
tients expressing CYP3A5 (those carrying the A nucleotide, defined as
the *1 allele) is around 50 % higher than that of non-expressers (those
homozygous for the G nucleotide, defined as the *3 allele) [59]. The
study that has up until now provided the best available evidence for
age-related differences in Tac exposure among renal transplant recipi-
ents is the one conducted by Jacobson et al. This study showed that
the dose/bodyweight-normalized tacrolimus predose concentrations
in elderly recipients (65–84 years) were 17% higher than middle aged
(35–64 years) adults and 68% higher than young (18–34 years) adults,
with age and CYP3A5 genotype having the largest effect [65]. In addition,
the effect of age within a given genotype was still substantial. In recipi-
ents with the CYP3A5∗3/∗3 genotype (CYP3A5 non-expressers), dose and
weight normalized predose concentrations were 45% higher in the elder
subjects compared to the younger adults; meanwhile, a similar increase
in predose concentration with increasing age was also observed in indi-
viduals with the CYP3A5∗1/∗ 1 or ∗ 1/∗ 3 genotype (CYP3A5 expressers)
4 Y-Y. Shi et al. / Transplantation Reviews xxx (2015) xxx–xxx
[65]. These data suggest that the dose requirement of tacrolimus in el-
derly patients might be much less than the younger patients when
aiming for the same target concentration range. More clinical studies
with larger sample size and specifically comparing the pharmacokinet-
ics of tacrolimus across different patient age groups are needed.
4.2. Cyclosporine
Han et al. [66] reviewed the studies of covariates on pharmacokinet-
ics of cyclosporine, showing a significant decrease in CL/F, Vd/F and ab-
sorption rate constant (ka) [67] of cyclosporine with increasing age
[67,68]. However, early pharmacokinetic studies focusing on age-
dependent influence on cyclosporine disposition have all failed to iden-
tify a clinically relevant effect of age on drug exposure [55,69]. Falck
et al. studied pharmacokinetic data of 25 renal transplant recipients
on cyclosporine A (CsA) treatment, and showed that elderly patients
(age ≥65 years) achieved 2-hour post-dose cyclosporine target concen-
trations with lower doses than younger individuals (18–64 years) due
to a 34% lower clearance of cyclosporine [70]. In addition, elderly pa-
tients had a 44% higher intracellular T-lymphocyte-to-whole blood
cyclosporine concentration ratio than younger patients [70], which
may explain why older recipients not only have a lower frequency of
acute rejection but also suffer more frequently from the toxic effects of
cyclosporine [21,25,30]. Jacobson et al. [65] also found a similar trend.
Elder recipients had higher normalized cyclosporine pre-dose concen-
trations than middle aged or young adults, despite receiving median
doses that were 100 mg/day lower, and recipient age had the largest
effect on cyclosporine troughs [65]. These data suggest that in the
elderly patient it might be better to reduce the starting dosage and
aim at lower whole blood cyclosporine target concentrations.
4.3. Mycophenolate mofetil
Mycophenolate mofetil (MMF) is the pro-drug of mycophenolic acid
(MPA). There is a wide inter-individual variability in dose requirements
to achieve therapeutic MPA exposure [71,72]. Age could theoretically
influence MPA disposition through alterations in protein binding, he-
patic glucuronidation capacity and renal function [31,40,73,74]. Wang
et al. [75] studied the impact of age on pharmacokinetic parameters in
Chinese renal transplant recipients. They found that when giving the
same dose of MMF, the MPA area under the curve (AUC) was signifi-
cantly lower in the elderly group (n = 24, 65.6 ± 3.6 years old) than
in the younger control group (n = 24, 39.6 ± 14.3 years old), while
there was no significant difference in peak concentrations or time to
Cmax[75]. Conflicting result were reported by Miura et al. [63] who
found no impact of age on dose-adjusted AUC0–12, Cmax, C0, and CL/F of
MPA. Both studies were limited by small sample size in elderly patients.
In our own study we could not find a significant effect of age on
clearance of MPA [74].
4.4. Mammalian target of rapamycin inhibitors
Pharmacokinetic studies of everolimus (EVR) and sirolimus (SRL)
have shown no significant impact of the recipient's age on drug expo-
sure [55,76–79]. Although an inverse relationship was found between
SRL clearance and age in a population pharmacokinetic study of 25
kidney transplant recipients, patients aged N50 years in this study
only made up 25% of the total sample size [80]. With the dramatic in-
crease in the number of elderly transplant recipients in the last decade,
more pharmacokinetic studies of mammalian target of rapamycin
(mTOR) inhibitors with sufficient number of elderly transplant
patients are needed, so as to better understand the role of age in
drug variability.
Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
4.5. Belatacept
Between-patient variability in belatacept pharmacokinetics is low
(b30%), and the effects of demographic covariates (age, gender, and
race) is not statistically significant, or the magnitude of the effect is of
minimal clinical relevance (within 80–125%) [81]. Belatacept was ap-
proved in 2011 based on two phase III clinical trials [82,83]. In these
two trials 15% (n = 60) of patients were older than 65 years, and 3%
(n = 12) were above 75 years of age. Clinical outcome in the elderly pa-
tients was similar to those below 65 years of age, although the small
sample size lacks statistical power to conclude definitively that no dif-
ference exists [84].
5. Specific pharmacodynamic considerations for immunosuppres-
sive drugs in the elderly recipients
PD monitoring examines the biological effects of a drug rather than
the surrogate marker of drug concentration. The PD effect can reflect
inter-individual differences in the susceptibility to a drug. There are
two different types of pharmacodynamic strategies applied for immu-
nosuppressant drug monitoring: (1) enzymatic strategies, which direct-
ly measure the enzyme activity that is selectively targeted by one class
of immunosuppressive agents; (2) immunologic strategies, which mea-
sure the general inhibition of cellular immune responses at different
levels, including cytokine mRNA, expression of surface activation
markers, cytokine-producing cells, extracellular cytokine concentration,
and cell proliferation [85].
5.1. Calcineurin inhibitors
Van Rossum et al. [85] reviewed studies on monitoring of calcineurin
activity in transplant recipients. In patients treated with either Tac or
CsA, a clear inverse relationship between drug concentration and en-
zyme activity in whole blood, leukocytes, and PBMCs fraction was ob-
served [85]. Among 22 renal transplant recipients with CsA-based
immunosuppressive treatment, baseline calcineurin inhibition was sig-
nificantly lower in patients with biopsy-proven acute rejection (BPAR)
[86]. Although CNI activity measurements have been shown to be a
promising biomarker, data in the elderly are lacking.
The inhibition of calcineurin would lead to a decrease in nuclear fac-
tor of activated T-cell (NFAT)-regulated gene expression (RGE) [85,87].
Several clinical studies monitoring NFAT RGE in transplant recipients
treated with either CsA or Tac, found that there is a strong inverse cor-
relation between drug concentration and the residual expression of
NFAT-regulated genes [87,88]. Patients with lower NFAT RGE may
have increased risks of recurrent infections and non-melanoma skin
cancer [87–89], while patients with insufficient inhibition of NFAT-
regulated genes would be at risk for acute rejection [87,89,90]. Pharma-
codynamic data of NFAT RGE among elderly patients are limited. In a
prospective observational study, Sommerer et al. [91] measured the re-
sidual NFAT RGE in 36 elderly renal allograft recipients (≥65 years). CsA
peak concentrations correlated significantly with the inhibition of gene
expression, while renal allograft function correlated inversely with the
inhibition of NFAT RGE [91]. NFAT RGE in patients with opportunistic in-
fections was lower compared with that in patients without infections,
whereas the daily CsA dosage, CsA C0, and CsA C2 concentrations
were comparable [91]. Compared to younger transplant patients,
NFAT RGE is significantly lower in elderly recipients (Sommerer C., per-
sonal communication).
5.2. MMF
MPA is a selective and reversible inhibitor of inosine
monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in
purine synthesis. IMPDH activity is highly variable between transplant
recipients [92–94]. Staatz and Tett [71,95] reviewed studies measuring
 Y-Y. Shi et al. / Transplantation Reviews xxx (2015) xxx–xxx
IMPDH activity in transplant patients. Results showed that higher
IMPDH activity pre-transplant as well as post-transplant might be asso-
ciated with the increased risk of acute rejection [71]. Sombogaard et al.
found that IMPDH mRNA levels do not correlate with IMPDH activity
but are significantly associated with the incidence of acute rejection
[96]. Again, no data are available for comparison of IMPDH baseline ac-
tivity or of the degree of inhibition of IMPDH activity in elderly versus
non-elderly transplant recipients.
5.3. mTOR inhibitors
Several studies have assessed the exposure-response relationships
for EVR and SRL. When EVR is used with either CsA or Tac, risk of
acute rejection is reduced as EVR C0 is ≥3 ng/mL [78]. For SRL used in
combination with CsA, a SRL C0 range of 5–15 ng/mL provides the opti-
mal balance between sufficient immunosuppression and acceptable tol-
erance [78,79]. However, predose concentrations of mTORi might not
necessarily correlate with the biological effects of the drug on immune
cells. mTOR inhibition results in the dephosphorylation and inactivation
of the downstream effector p70 S6 kinase (p70S6K). The phosphoryla-
tion status at the Thr389 site of the p70S6K was previously assessed in
PBMCs of renal transplant recipients using Western blot [97,98], while
recent studies explored other quantitative and applicable methods
such as commercial enzyme-linked immunosorbent assay (ELISA) kit
and phosphoflow cytometry [99,100]. Results showed that mTOR inhi-
bition was associated with marked reduction of p70S6K phosphoryla-
tion but failed to correlate with mTOR inhibitor trough levels
[97,98,100]. Nevertheless, pharmacology data in elderly transplant pa-
tients are quite limited and the same therapeutic range of mTOR inhib-
itors is applied in this population.
5.4. Induction agents
In the KDIGO guidelines interleukin 2 receptor antagonists (IL2RA)
are recommended as first-line induction agents, while lymphocyte-
depleting agents including anti-thymocyte globulin (ATG) are sug-
gested for high immunologic risk recipients [101]. No specific recom-
mendations regarding dose or treatment duration are made for elderly
transplant recipients [101]. There are no studies to suggest that in elder-
ly patients following a standard IL2RA dose or a standard ATG dose the
lymphocytopenia in peripheral blood lasts for a longer duration than in
younger patients. Considering the lower immunologic risk but in-
creased risk of post-transplant complications among elderly recipients,
IL2RA have been propagated as a preferable choice for them with a bet-
ter safety [31]. Using United Network of Organ Sharing data from 2003
to 2008, Gill et al. [102] analyzed the use of different induction agents in
elderly (≥60 years) deceased-donor kidney transplant recipients. Re-
sults showed that IL2RA is associated with increased risk of acute rejec-
tion, suggesting that ATG might be the preferred induction agent only
for high-risk elderly recipients with a high-risk donor organ [36,102].
Recent studies showed that in comparison to younger patients, low-
dose rabbit ATG (rATG) induction therapy could achieve equivalent ef-
ficacy without inducing excess morbidity in patients older than 65,
which provide a therapeutic option for this specific population
[103,104].
5.5. Co-medication
Kuypers [55] reviewed studies on interactions between immuno-
suppressant drugs and concomitant medication in elderly transplant re-
cipients. Elderly patients are typically treated with several other drugs,
and as a result of drug–drug interactions outcome may be impaired.
CNI and mTOR inhibitors are metabolized by the CYP3A family and are
substrates of P-gp, therefore dose adjustments should be made when
administered with CYP3A inhibitors or inducers [55].
Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
5
6. Conclusions
Elderly transplant recipients have a decreased incidence of acute re-
jection but an increased risk of infectious death. Based on this review of
the literature it seems most likely that this observation is due to the fact
that both innate and adaptive immune reactivity decrease with in-
creased age. Cell-mediated immunity is most clearly affected. Possibly
also the pharmacokinetics and/or the pharmacodynamics of immuno-
suppressive drugs are different in elderly patients. A clinically relevant
impact of age on the pharmacokinetics of immunosuppressive drugs
has been shown for CNI. The dose/bodyweight-normalized CNI troughs
are more than 50% higher in older recipients than in younger patients
[65]. Therapeutic drug monitoring will easily correct for the lower
dose requirement for these drug. Furthermore, a significantly higher in-
tracellular T-lymphocyte-to-whole blood CsA concentration ratio in el-
derly transplant recipients has been reported. As monitoring
intracellular concentrations is not routinely performed this can go un-
noticed, and is not corrected by therapeutic drug monitoring. If the
higher intracellular CsA concentrations can be confirmed this would
suggest that lower whole blood target concentrations should be aimed
for in elderly patients. Pharmacodynamic monitoring of immunosup-
pressive drugs is in its infancy. There is no biomarker that has been
shown to be predictive of the reduced allo-reactivity in elderly trans-
plant recipients, with sufficient sensitivity and specificity that it can be
used in clinical practice.
In view of the increasing numbers of elderly patients in our trans-
plant programs there is a clear need for studies investigating the opti-
mal target concentrations for the immunosuppressive drugs in this
population. Patients studied in clinical trials should reflect the popula-
tion in whom the drug is intended to be used. Systematically studying
the safety and efficacy of immunosuppressive drugs in elderly trans-
plant patients is encouraged by registration authorities [84]. For the
time being it seems wise to administer the currently used drugs in
lower dosages, or aim for lower targets, in an attempt to avoid death
due to infectious complications [36]. We would favor the avoidance of
T-cell depleting antibodies in low-risk elderly recipients, to rapidly
taper and discontinue corticosteroids and to aim for low-CNI targets.
Conflicts of interest
Y.Y.S. has no conflicts of interest to declare.
D.A.H. has received lecture and consulting fees, as well as grant sup-
port from Astellas Pharma, Fresenius Medical Care, Novartis, MSD, and
Bristol-Myers Squibb.
T.vG. has received lecture and consulting fees from Astellas, Roche,
Teva, and Chiesi, as well as grant support from Pfizer.
Funding
Yun-Ying Shi was supported by a research grant from Sichuan
University.
References
[1] USRDS 2013 Annual Data Report: Atlas of chronic kidney disease and end-stage
renal disease in the United States. U.S. Renal Data System. Bethesda, MD: National
Institutes of Health, National Institute of Diabetes and Digestive and Kidney Dis-
eases; 2013.
[2] De Fijter JW. Counselling the elderly between hope and reality. Nephrol Dial Trans-
plant 2011;26:2079–81.
[3] Tonelli M, Wiebe N, Knoll G, et al. Systematic review: kidney transplantation com-
pared with dialysis in clinically relevant outcomes. Am J Transplant 2011;11:
2093–109.
[4] Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: kidney.
Am J Transplant; 2014. p. 11–44.
[5] Excell LMV, Russ G. ANZOD Registry Report 2013. ANZOD Registry Report. Ade-
laide: ANZDATA Registry and ANZOD Registry; 2013.
[6] Hourmant M, Lerat L, Karam G. Donation from old living donors: how safe is it?
Nephrol Dial Transplant 2013;28:2010–4.
6 Y-Y. Shi et al. / Transplantation Reviews xxx (2015) xxx–xxx
[7] Huang E, Poommipanit N, Sampaio MS, et al. Intermediate-term outcomes associ-
ated with kidney transplantation in recipients 80 years and older: an analysis of
the OPTN/UNOS database. Transplantation 2010;90:974–9.
[8] Segev DL. Evaluating options for utility-based kidney allocation. Am J Transplant
2009;9:1513–8.
[9] De Fijter JW. An old virtue to improve senior programs. Transpl Int 2009;22:
259–68.
[10] Hilmer SN, Gnjidic D. The effects of polypharmacy in older adults. Clin Pharmacol
Ther 2009;85:86–8.
[11] Martins PN, Pratschke J, Pascher A, et al. Age and immune response in organ trans-
plantation. Transplantation 2005;79:127–32.
[12] Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune sys-
tem. Curr Opin Immunol 2010;22:507–13.
[13] Abecassis M, Bridges ND, Clancy CJ, et al. Solid-organ transplantation in older
adults: current status and future research. Am J Transplant 2012;12:2608–22.
[14] Naylor K, Li G, Vallejo AN, et al. The influence of age on T cell generation and TCR
diversity. J Immunol 2005;174:7446–52.
[15] Czesnikiewicz-Guzik M, Lee WW, Cui D, et al. T cell subset-specific susceptibility to
aging. Clin Immunol 2008;127:107–18.
[16] Smith C, Miles JJ, Khanna R. Advances in direct T-cell alloreactivity: function, avid-
ity, biophysics and structure. Am J Transplant 2012;12:15–26.
[17] Denecke C, Bedi DS, Ge X, et al. Prolonged graft survival in older recipient mice is
determined by impaired effector T-cell but intact regulatory T-cell responses.
PLoS One 2010;5:e9232.
[18] Lo DJ, Weaver TA, Stempora L, et al. Selective targeting of human alloresponsive
CD8+ effector memory T cells based on CD2 expression. Am J Transplant 2011;
11:22–33.
[19] Meier-Kriesche HU, Ojo A, Hanson J, et al. Increased immunosuppressive vulnera-
bility in elderly renal transplant recipients. Transplantation 2000;69:885–9.
[20] Cecka JM. The OPTN/UNOS renal transplant registry. Clin Transpl 2004:1–16.
[21] Friedman AL, Goker O, Kalish MA, et al. Renal transplant recipients over aged 60
have diminished immune activity and a low risk of rejection. Int Urol Nephrol
2004;36:451–6.
[22] Mendonca HM, Dos Reis MA, De Castro De Cintra Sesso R, Camara NO, Pacheco-
Silva A. Renal transplantation outcomes: a comparative analysis between elderly
and younger recipients. Clin Transplant 2007;21:755–60.
[23] Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J
Med 2011;364:1369–70.
[24] Terasaki PI, Gjertson DW, Cecka JM, Takemoto S, Cho YW. Significance of the donor
age effect on kidney transplants. Clin Transplant 1997;11:366–72.
[25] De Fijter JW. The impact of age on rejection in kidney transplantation. Drugs Aging
2005;22:433–49.
[26] De Fijter JW, Mallat MJ, Doxiadis Ii, et al. Increased immunogenicity and cause of
graft loss of old donor kidneys. J Am Soc Nephrol 2001;12:1538–46.
[27] Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic cor-
relations of de novo donor-specific HLA antibody post kidney transplant. Am J
Transplant 2012;12:1157–67.
[28] Meier-Kriesche HU, Srinivas TR, Kaplan B. Interaction between acute rejection and re-
cipient age on long-term renal allograft survival. Transplant Proc 2001;33:3425–6.
[29] Meier-Kriesche HU, Ojo AO, Cibrik DM, et al. Relationship of recipient age and de-
velopment of chronic allograft failure. Transplantation 2000;70:306–10.
[30] Knoll GA. Kidney transplantation in the older adult. Am J Kidney Dis 2013;61:
790–7.
[31] Danovitch GM, Gill J, Bunnapradist S. Immunosuppression of the elderly kidney
transplant recipient. Transplantation 2007;84:285–91.
[32] Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B. Exponentially increased risk of in-
fectious death in older renal transplant recipients. Kidney Int 2001;59:1539–43.
[33] Trouillhet I, Benito N, Cervera C, et al. Influence of age in renal transplant infections:
cases and controls study. Transplantation 2005;80:989–92.
[34] Mohamed Ali AA, Abraham G, Khanna P, et al. Renal transplantation in the elderly:
South Indian experience. Int Urol Nephrol 2011;43:265–71.
[35] Ladriere M. What is the best immunosuppression for the elderly kidney transplan-
tation patient? Nephrol Ther 2008;4:S179–83.
[36] Heldal K, Midtvedt K. Managing transplant rejection in the elderly: the benefits of
less aggressive immunosuppressive regimens. Drugs Aging 2013;30:459–66.
[37] Turnheim K. Drug therapy in the elderly. Exp Gerontol 2004;39:1731–8.
[38] Shi S, Morike K, Klotz U. The clinical implications of ageing for rational drug thera-
py. Eur J Clin Pharmacol 2008;64:183–99.
[39] Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacody-
namics: basic principles and practical applications. Br J Clin Pharmacol 2004;57:6–14.
[40] Meier-Kriesche HU, Kaplan B. Immunosuppression in elderly renal transplant re-
cipients: are current regimens too aggressive? Drugs Aging 2001;18:751–9.
[41] Bernardo JF, Mccauley J. Drug therapy in transplant recipients: special consider-
ations in the elderly with comorbid conditions. Drugs Aging 2004;21:323–48.
[42] Paine MF, Ludington SS, Chen ML, Stewart PW, Huang SM, Watkins PB. Do men and
women differ in proximal small intestinal CYP3A or P-glycoprotein expression?
Drug Metab Dispos 2005;33:426–33.
[43] Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in
interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol
Ther 1997;62:248–60.
[44] Canaparo R, Finnstrom N, Serpe L, et al. Expression of CYP3A isoforms and P-
glycoprotein in human stomach, jejunum and ileum. Clin Exp Pharmacol Physiol
2007;34:1138–44.
[45] Uesugi M, Masuda S, Katsura T, Oike F, Takada Y, Inui K. Effect of intestinal CYP3A5
on postoperative tacrolimus trough levels in living-donor liver transplant recipi-
ents. Pharmacogenet Genomics 2006;16:119–27.
Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
[46] Fukudo M, Yano I, Yoshimura A, et al. Impact of MDR1 and CYP3A5 on the oral
clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-
donor liver transplant patients. Pharmacogenet Genomics 2008;18:413–23.
[47] Zeeh J, Platt D. The aging liver: structural and functional changes and their conse-
quences for drug treatment in old age. Gerontology 2002;48:121–7.
[48] Cotreau MM, Von Moltke LL, Greenblatt DJ. The influence of age and sex on the
clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 2005;44:33–60.
[49] Ginsberg G, Hattis D, Russ A, Sonawane B. Pharmacokinetic and pharmacodynamic
factors that can affect sensitivity to neurotoxic sequelae in elderly individuals. En-
viron Health Perspect 2005;113:1243–9.
[50] Schwartz JB. Erythromycin breath test results in elderly, very elderly, and frail el-
derly persons. Clin Pharmacol Ther 2006;79:440–8.
[51] Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynam-
ics in the elderly. Exp Gerontol 2003;38:843–53.
[52] Dimartini A, Fontes P, Dew MA, Lotrich FE, De Vera M. Age, model for end-stage
liver disease score, and organ functioning predict posttransplant tacrolimus neuro-
toxicity. Liver Transpl 2008;14:815–22.
[53] Zhou XJ, Rakheja D, Yu X, Saxena R, Vaziri ND, Silva FG. The aging kidney. Kidney
Int 2008;74:710–20.
[54] Schmucker DL. Age-related changes in liver structure and function: implications for
disease? Exp Gerontol 2005;40:650–9.
[55] Kuypers DR. Immunotherapy in elderly transplant recipients: a guide to clinically
significant drug interactions. Drugs Aging 2009;26:715–37.
[56] Sugiyama K, Isogai K, Toyama A, et al. Pharmacodynamic parameters of immuno-
suppressive drugs are not correlated with age, duration of dialysis, percentage of
lymphocytes or lymphocyte stimulation index in renal transplant recipients. Biol
Pharm Bull 2008;31:2146–9.
[57] Turnheim K. Drug dosage in the elderly. Is it rational? Drugs Aging 1998;13:357–79.
[58] Staatz CE, Tett SE. Pharmacokinetic considerations relating to tacrolimus dosing in
the elderly. Drugs Aging 2005;22:541–57.
[59] Hesselink DA, Bouamar R, Elens L, Van Schaik RH, Van Gelder T. The role of pharma-
cogenetics in the disposition of and response to tacrolimus in solid organ trans-
plantation. Clin Pharmacokinet 2014;53:123–39.
[60] Op Den Buijsch RA, Christiaans MH, Stolk LM, et al. Tacrolimus pharmacokinetics
and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1
(ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol
2007;21:427–35.
[61] Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus
in solid organ transplantation. Clin Pharmacokinet 2004;43:623–53.
[62] Wei-Lin W, Jing J, Shu-Sen Z, et al. Tacrolimus dose requirement in relation to
donor and recipient ABCB1 and CYP3A5 gene polymorphisms in Chinese liver
transplant patients. Liver Transpl 2006;12:775–80.
[63] Miura M, Satoh S, Kagaya H, et al. No impact of age on dose-adjusted pharmacoki-
netics of tacrolimus, mycophenolic acid and prednisolone 1 month after renal
transplantation. Eur J Clin Pharmacol 2009;65:1047–53.
[64] Storset E, Holford N, Midtvedt K, Bremer S, Bergan S, Asberg A. Importance of he-
matocrit for a tacrolimus target concentration strategy. Eur J Clin Pharmacol
2014;70:65–77.
[65] Jacobson PA, Schladt D, Oetting WS, et al. Lower calcineurin inhibitor doses in older
compared to younger kidney transplant recipients yield similar troughs. Am J
Transplant 2012;12:3326–36.
[66] Han K, Pillai VC, Venkataramanan R. Population pharmacokinetics of cyclosporine
in transplant recipients. AAPS J 2013;15:901–12.
[67] Falck P, Midtvedt K, Van Le TT, et al. A population pharmacokinetic model of
ciclosporin applicable for assisting dose management of kidney transplant recipi-
ents. Clin Pharmacokinet 2009;48:615–23.
[68] Wu KH, Cui YM, Guo JF, et al. Population pharmacokinetics of cyclosporine in clin-
ical renal transplant patients. Drug Metab Dispos 2005;33:1268–75.
[69] Kovarik JM, Koelle EU. Cyclosporin pharmacokinetics in the elderly. Drugs Aging
1999;15:197–205.
[70] Falck P, Asberg A, Byberg KT, et al. Reduced elimination of cyclosporine A in elderly
(N65 years) kidney transplant recipients. Transplantation 2008;86:1379–83.
[71] Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ trans-
plant recipients: an update. Arch Toxicol 2014;88:1351–89.
[72] Shaw LM, Korecka M, Venkataramanan R, Goldberg L, Bloom R, Brayman KL. Myco-
phenolic acid pharmacodynamics and pharmacokinetics provide a basis for ratio-
nal monitoring strategies. Am J Transplant 2003;3:534–42.
[73] Kaplan B, Meier-Kriesche HU, Friedman G, et al. The effect of renal insufficiency on
mycophenolic acid protein binding. J Clin Pharmacol 1999;39:715–20.
[74] Van Hest RM, Mathot RA, Pescovitz MD, Gordon R, Mamelok RD, Van Gelder T.
Explaining variability in mycophenolic acid exposure to optimize mycophenolate
mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic
acid in renal transplant recipients. J Am Soc Nephrol 2006;17:871–80.
[75] Wang CX, Meng FH, Chen LZ, et al. Population pharmacokinetics of mycophenolic
acid in senile Chinese kidney transplant recipients. Transplant Proc 2007;39:
1392–5.
[76] Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de
novo renal transplant recipients over the first post-transplant year: pharmacoki-
netics, exposure-response relationships, and influence on cyclosporine. Clin
Pharmacol Ther 2001;69:48–56.
[77] Kovarik JM, Hsu CH, Mcmahon L, Berthier S, Rordorf C. Population pharmacokinet-
ics of everolimus in de novo renal transplant patients: impact of ethnicity and
comedications. Clin Pharmacol Ther 2001;70:247–54.
[78] Shihab F, Christians U, Smith L, Wellen JR, Kaplan B. Focus on mTOR inhibitors and
tacrolimus in renal transplantation: pharmacokinetics, exposure–response rela-
tionships, and clinical outcomes. Transpl Immunol 2014;31:22–32.
 Y-Y. Shi et al. / Transplantation Reviews xxx (2015) xxx–xxx
[79] Kahan BD, Napoli KL, Podbielski J, Hussein I, Katz SH, Van Buren CT. Therapeutic
drug monitoring of sirolimus for optimal renal transplant outcomes. Transplant
Proc 2001;33:1278.
[80] Dansirikul C, Morris RG, Tett SE, Duffull SB. A Bayesian approach for population
pharmacokinetic modelling of sirolimus. Br J Clin Pharmacol 2006;62:420–34.
[81] Zhou Z, Shen J, Hong Y, Kaul S, Pfister M, Roy A. Time-varying belatacept exposure
and its relationship to efficacy/safety responses in kidney-transplant recipients.
Clin Pharmacol Ther 2012;92:251–7.
[82] Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-
based immunosuppression regimens versus cyclosporine in renal transplant recip-
ients (BENEFIT study). Am J Transplant 2010;10:535–46.
[83] Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cy-
closporine in kidney transplants from extended criteria donors (BENEFIT-EXT
study). Am J Transplant 2010;10:547–57.
[84] Meyer JM, Archdeacon P, Albrecht R. FDA perspective: enrolment of elderly trans-
plant recipients in clinical trials. Transplantation 2013;95:916–8.
[85] Van Rossum HH, De Fijter JW, Van Pelt J. Pharmacodynamic monitoring of calcine-
urin inhibition therapy: principles, performance, and perspectives. Ther Drug
Monit 2010;32:3–10.
[86] Brunet M, Crespo M, Millan O, et al. Pharmacokinetics and pharmacodynamics in
renal transplant recipients under treatment with cyclosporine and Myfortic. Trans-
plant Proc 2007;39:2160–2.
[87] Sommerer C, Meuer S, Zeier M, Giese T. Calcineurin inhibitors and NFAT-regulated
gene expression. Clin Chim Acta 2012;413:1379–86.
[88] Sommerer C, Zeier M, Czock D, Schnitzler P, Meuer S, Giese T. Pharmacodynamic
disparities in tacrolimus-treated patients developing cytomegalus virus viremia.
Ther Drug Monit 2011;33:373–9.
[89] Sommerer C, Zeier M, Meuer S, Giese T. Individualized monitoring of nuclear factor
of activated T cells-regulated gene expression in FK506-treated kidney transplant
recipients. Transplantation 2010;89:1417–23.
[90] Steinebrunner N, Sandig C, Sommerer C, et al. Pharmacodynamic monitoring of nu-
clear factor of activated T cell-regulated gene expression in liver allograft recipients
on immunosuppressive therapy with calcineurin inhibitors in the course of time
and correlation with acute rejection episodes—a prospective stud. Ann Transplant
2014;19:32–40.
[91] Sommerer C, Schnitzler P, Meuer S, Zeier M, Giese T. Pharmacodynamic monitoring
of cyclosporin A reveals risk of opportunistic infections and malignancies in renal
transplant recipients 65 years and older. Ther Drug Monit 2011;33:694–8.
Please cite this article as: Shi Y-Y, et al, Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant
recipients, Transplant Rev (2015), http://dx.doi.org/10.1016/j.trre.2015.04.007
7
[92] Weimert NA, Derotte M, Alloway RR, Woodle ES, Vinks AA. Monitoring of inosine
monophosphate dehydrogenase activity as a biomarker for mycophenolic acid ef-
fect: potential clinical implications. Ther Drug Monit 2007;29:141–9.
[93] Saeves I, Line PD, Bremer S, et al. Tacrolimus exposure and mycophenolate phar-
macokinetics and pharmacodynamics early after liver transplantation. Ther Drug
Monit 2014;36:46–53.
[94] Van Gelder T. Mycophenolate mofetil: how to further improve using an already
successful drug? Am J Transplant 2005;5:199–200.
[95] Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of
mycophenolate in solid organ transplant recipients. Clin Pharmacokinet
2007;46:13–58.
[96] Sombogaard F, Peeters AM, Baan CC, et al. Inosine monophosphate dehydrogenase
messenger RNA expression is correlated to clinical outcomes in mycophenolate
mofetil-treated kidney transplant patients, whereas inosine monophosphate dehy-
drogenase activity is not. Ther Drug Monit 2009;31:549–56.
[97] Hartmann B, Schmid G, Graeb C, et al. Biochemical monitoring of mTOR inhibitor-
based immunosuppression following kidney transplantation: a novel approach for
tailored immunosuppressive therapy. Kidney Int 2005;68:2593–8.
[98] Leogrande D, Teutonico A, Ranieri E, et al. Monitoring biological action of
rapamycin in renal transplantation. Am J Kidney Dis 2007;50:314–25.
[99] Hartmann B, He X, Keller F, Fischereder M, Guba M, Schmid H. Development of a
sensitive phospho-p70 S6 kinase ELISA to quantify mTOR proliferation signal inhi-
bition. Ther Drug Monit 2013;35:233–9.
[100] Hoerning A, Wilde B, Wang J, et al. Pharmacodynamic monitoring of mammalian
target of rapamycin inhibition by phosphoflow cytometric determination of
p70S6 kinase activity. Transplantation 2015;99:210–9.
[101] Kidney disease: improving global outcomes transplant work G. KDIGO clinical
practice guideline for the care of kidney transplant recipients. Am J Transplant
2009;9:S1–S155.
[102] Gill J, Sampaio M, Gill JS, et al. Induction immunosuppressive therapy in the elderly
kidney transplant recipient in the United States. Clin J Am Soc Nephrol 2011;6:
1168–78.
[103] Laftavi MR, Patel S, Soliman MR, et al. Low-dose thymoglobulin use in elderly renal
transplant recipients is safe and effective induction therapy. Transplant Proc 2011;
43:466–8.
[104] Khanmoradi K, Knorr JP, Feyssa EL, et al. Evaluating safety and efficacy of rabbit
antithymocyte globulin induction in elderly kidney transplant recipients. Exp Clin
Transplant 2013;11:222–8.