African-American Race Modifies the Influence of

Tacrolimus Concentrations on Acute Rejection and

Toxicity in Kidney Transplant Recipients
David J. Taber,1,2,* Mulugeta G. Gebregziabher,3 Titte R. Srinivas,4 Kenneth D. Chavin,1 Prabhakar K.
Baliga,1 and Leonard E. Egede5
1
Division of Transplant Surgery, College of Medicine Medical University of South Carolina, Charleston, South
Carolina; 2Department of Pharmacy, Ralph H. Johnson VAMC, Charleston, South Carolina; 3Department of
Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, South Carolina;
4
Division of Transplant, Nephrology, College of Medicine, Medical University of South Carolina, Charleston,
South Carolina; 5Veterans Affairs HSR&D Health Equity and Rural Outreach Innovation Center (HEROIC),
Ralph H. Johnson VAMC, Charleston, South Carolina

STUDY OBJECTIVE To determine the effect of tacrolimus trough concentrations on clinical outcomes in
kidney transplantation, while assessing if African-American (AA) race modifies these associations.
DESIGN Retrospective longitudinal cohort study of solitary adult kidney transplants.
SETTING Large tertiary care transplant center.
PATIENTS Adult solitary kidney transplant recipients (n=1078) who were AA (n=567) or non-AA
(n=511).
EXPOSURE Mean and regressed slope of tacrolimus trough concentrations. Subtherapeutic concentra-
tions were lower than 8 ng/ml.
MEASUREMENTS AND MAIN RESULTS AA patients were 1.7 times less likely than non-AA patients to
achieve therapeutic tacrolimus concentrations (8 ng/ml or higher) during the first year after kidney
transplant (35% vs 21%, respectively, p<0.001). AAs not achieving therapeutic concentrations were
2.4 times more likely to have acute cellular rejection (ACR) as compared with AAs achieving thera-
peutic concentrations (20.8% vs 8.5%, respectively, p<0.01) and 2.5 times more likely to have anti-
body-mediated rejection (AMR; 8.9% vs 3.6%, respectively, p<0.01). Rates of ACR (8.3% vs 6.7%)
and AMR (2.0% vs 0.9% p=0.131) were similar in non-AAs compared across tacrolimus concentra-
tion groups. Multivariate modeling confirmed these findings and demonstrated that AAs with low
tacrolimus exposure experienced a mild protective effect for the development of interstitial fibrosis/
tubular atrophy (IF/TA; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.47–1.32) with the
opposite demonstrated in non-AAs (HR 2.2, 95% CI 0.90–5.1).
CONCLUSION In contradistinction to non-AAs, AAs who achieve therapeutic tacrolimus concentrations
have substantially lower acute rejection rates but are at risk of developing IF/TA. These findings
may reflect modifiable time-dependent racial differences in the concentration-effect relationship of
tacrolimus. Achievement of therapeutic tacrolimus trough concentrations, potentially through geno-
typing and more aggressive dosing and monitoring, is essential to minimize the risk of acute rejec-
tion in AA kidney transplant recipients.
KEY WORDS kidney transplantation, African-American, tacrolimus, therapeutic drug monitoring, acute
rejection.
(Pharmacotherapy 2015;35(6):569–577) doi: 10.1002/phar.1591
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
570 PHARMACOTHERAPY Volume 35, Number 6, 2015

Tacrolimus (TAC) is the most commonly used Methods

immunosuppressant in transplantation and con-
sidered the cornerstone of contemporary mainte- Study Design
nance immunosuppressive therapy. Therapeutic This was a single-center longitudinal cohort
drug monitoring (TDM) of TAC in kidney trans- study of a large sample of racially diverse adult
plantation, using 12-hour trough concentrations solitary kidney recipients transplanted between
to approximate total exposure, is advocated 2005 and 2012 at the Medical University of
in national guidelines and utilized in most South Carolina in Charleston, South Carolina.
transplant centers.1, 2 Despite this commonly Data were retrospectively collected, starting at
accepted practice,3 evidence to support TAC the time of transplant (baseline data) and longi-
TDM in improving clinical outcomes, either tudinally following patients through graft loss,
through reduction in acute rejection rates or death, or end of follow-up (July 2013). For the
toxicities, is conflicting. Recent data, pooled initial univariate comparisons, cohorts were
from three randomized controlled trials and con- delineated based on TAC 12-hour trough con-
ducted in a predominantly low-risk cohort of centrations during the first year posttransplant
kidney transplant recipients, suggests that (lower than 8 ng/ml vs 8 ng/ml or higher). This
achieving therapeutic TAC trough concentra- cutoff was chosen to be consistent with previous
tions early posttransplant is not associated with U.S. studies. Once it was established that AA
reduced rejection rates.4 However, other studies race significantly modifies the impact of TAC
have demonstrated that TAC trough concentra- exposure on acute rejection, cohorts were then
tions are associated with improved efficacy in stratified across recipient race, and final multi-
higher risk patients.5–7 variate modeling is displayed in this context.
It is well established that African-Americans Local institutional review board approval was
(AAs) are at substantially higher risk of acute obtained before conducting this study.
rejection and graft loss following transplant.8–10
In addition, AAs require significantly higher
doses of TAC to achieve therapeutic trough con- Patients
centrations,11, 12 which is likely a reflection of
differences in gene variants associated with drug Patients were considered eligible for inclusion
absorption and metabolism.13 Outside of phar- in this study if they received a kidney transplant
macokinetic issues, AA patients are also at from the study institution between 2005 and
higher immunologic risk, which may be related 2012 and were adults at the time of transplant
to differences in the pharmacodynamics of im- (18 years or older). Patients were excluded if
munosuppressants including TAC.8, 14, 15 they received a nonrenal organ transplant before,
Despite these data, a paucity of studies have with, or after the kidney transplant, received a
assessed if AA race modifies the impact of TAC maintenance immunosuppression regimen that
trough concentrations on clinical outcomes in did not consist of TAC, mycophenolate, and cor-
kidney transplantation. This is likely because of ticosteroids, had graft loss within 3 months of
an underrepresentation of AA patients in previ- transplant, or were lost to follow-up.
ous studies analyzing associations between TAC
trough concentrations and clinical outcomes in Outcomes
transplantation.4–6, 16–19 Thus the objectives of
this study were to determine the overall impact Outcome measurements were time to develop-
of TAC trough concentrations on clinical out- ment of acute rejection and interstitial fibrosis/
comes in kidney transplantation while assessing tubular atrophy (IF/TA) based on the 12-hour
if AA race modifies these associations. trough concentrations of TAC. Histology was
obtained from both for cause and protocol biop-
sies that were scored using Banff criteria by a
single pathologist. Time to these events was
This research was presented at the 2014 ASN Kidney computed as the number of years starting at the
Week, as an oral presentation, in Philadelphia, PA. time of transplant to the development of acute
*Address for correspondence: David J. Taber, Division of rejection and IF/TA or to graft loss, death, or
Transplant Surgery, Medical University of South Carolina,
96 Jonathan Lucas Street, MSC 611, Charleston, SC 29425; end of follow-up (July 2013). Data from patients
e-mail: [email protected]. who did not develop any of these events were
Ó 2015 Pharmacotherapy Publications, Inc. censored.
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TACROLIMUS TDM IN AFRICAN-AMERICANS Taber et al 571

Data Variables and Study Definitions Statistical Analysis

Data were collected in a retrospective longitu- For the initial analysis, cohorts were divided
dinal manner using both paper and electronic into an exposure groups with TAC mean trough
medical records. Baseline information was col- concentrations lower than 8 ng/ml and an expo-
lected at the time of transplant and included sure group with concentrations of 8 ng/ml or
recipient sociodemographics and past medical higher (defined as concentrations within the first
history as well as donor and transplant charac- year and prior to acute rejection or IF/TA
teristics. Following transplant, clinical data events). Univariate comparisons between cohorts
including laboratory values, medication regi- for baseline and follow-up data were made using
mens, and vital signs were collected at prespeci- the Pearson v2 test for categorical data and the
fied time points in relation to transplant date: Student t test for continuous variables; nonpara-
day 3, 5, 7, and 14, month 1, 3, and 6, and metric analyses were made using the Mann-
yearly thereafter. All documented posttransplant Whitney U test when applicable.
events were captured including acute rejections, Multivariable modeling, using Cox regression,
hospitalizations, graft failures, and deaths. was used to study the association between time
Graft failure was defined as a documented to development of acute rejection and IF/TA and
return to chronic dialysis or death. Acute rejec- 12-hour trough concentrations of TAC in AAs
tion was defined as biopsy proven and at least and non-AAs. In this time-to-event analysis, vari-
Banff grade of 1A per the 1997 staging criteria. IF/ ables were included in the model based on their
TA was considered to be a biopsy-proven devel- univariate association or if they were known to
opment of at least mild IF/TA that occurred at influence the clinical outcomes of acute rejection
least 1 month after transplant. IF/TA present on or IF/TA. AA race effect modification was deter-
biopsies taken at the time of transplant or within mined in a multiplicative fashion by including an
1 month of transplant was considered donor dis- interaction term (AA race 9 TAC concentration
ease. Delayed graft function was defined as the [both mean and trajectory]) within the models.
need for dialysis within 7 days following trans- Statistical significance was defined as a p value
plant. Cytomegalovirus (CMV) infection was <0.05. Statistical analyses were performed using
defined as the presence of CMV viremia of any SPSS v. 22 (IBM Corp., Armonk, NY) and SAS
detectable level (200 copies/ml or more) or any v.9.4 (SAS Institute Inc., Cary, NC).
CMV viremia with signs and symptoms consistent
with infection. BK infection was defined as BK
Results
viremia of any detectable level (200 copies/ml or
more) and/or biopsy-proven BK nephropathy.
Patients and Baseline Characteristics
Intrapatient TAC concentrations were assessed
using two methods, means and trajectories. For Between January 1, 2005, and December 31,
the mean comparisons, trough concentrations 2012, a total of 1501 kidney transplants were
were averaged for each patient during the first performed in our institution. Of these trans-
year posttransplant (or up until having acute plants, 423 patients were excluded because of
rejection or IF/TA), and cohorts were assigned nonkidney transplant (n=185), age younger than
based on a cutoff of 8 ng/ml. This cutoff trough 18 years at time of transplant (n=79), adminis-
concentration was chosen because our center tration of a non-TAC/mycophenolate mofetil
considers this protocol to be therapeutic, as maintenance immunosuppression regimen at
shown by previous studies conducted in the baseline (n=63), graft loss within 3 months of
United States.4 For the trajectory analysis, each transplant (n=38), and lost to follow-up (n=58),
patient had a slope determined using linear leaving 1078 patients who were included in the
regression. Both the mean and trajectory data final analyses. The mean time of follow-up was
were used as variables within multivariable mod- 3.8  2.1 years, which was similar between
eling. These two methods of assessing TAC TAC exposure cohorts (3.8  2.2 years in the
trough concentrations were chosen because they TAC 8 ng/ml group or higher vs 3.7  2.1 years
provide different information, with the mean in the TAC lower than 8 ng/ml group; p=0.524).
analysis serving as a proxy for the average expo- Baseline recipient demographics, past medical
sure prior to the event and the trajectory analy- history, donor demographics, and transplant
sis informing assessment of the direction the characteristics were reported across exposure
concentrations were headed prior to the event. cohorts (mean TAC 8 ng/ml or higher [n=767]
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
572 PHARMACOTHERAPY Volume 35, Number 6, 2015

vs < 8 ng/ml [n=311]) (Table 1). The groups Univariate Analysis for Outcomes Based on
were fairly similar for baseline information, Mean TAC Concentrations
except that the low TAC exposure cohort was
more likely to be AA (65% vs 48%, p<0.001), to Table 2 displays the clinical outcomes com-
have received an expanded criteria donor kidney pared across TAC exposure cohorts. Patients with
(18% vs 12%, p=0.011), and to develop delayed a mean TAC concentration lower than 8 ng/ml
graft function (19% vs 11%, p=0.001). Because had 2.2 (95% confidence interval [CI] 1.5–3.1,
these factors influence the outcomes of acute p<0.001) times the risk of developing acute cellular
rejection and IF/TA, they were controlled for in rejection and antibody-mediated rejection (AMR)
the multivariable modeling. The study popula- (95% CI 1.2–4.1, p=0.010). The risk of developing
tion was racially diverse and contained a bal- de novo IF/TA was also significantly higher in the
anced number of AA (n=567) and non-AA low TAC exposure cohort (relative risk 1.6, 95%
(n=511) patients. CI 1.1–2.2, p=0.010). In multivariable modeling,
Good delineation was noted between exposure the interaction term between recipient race and
cohorts for TAC trough concentrations during TAC exposure was statistically significant for acute
the first year posttransplant, with those in the rejection (p<0.05), which was consistent for mod-
mean of lower than 8 ng/ml group having els that included the intrapatient mean TAC trough
roughly a 2 ng/ml lower TAC concentration concentration as well as those including the intra-
across all time points during the first year post- patient TAC trajectory. The interaction term for
transplant (Figure 1). AA recipients in both the outcome of IF/TA was not statistically signifi-
TAC exposure cohorts had a delay in achieving cant (p=0.192, 0.197) for either model.
therapeutic trough concentrations of ~2 days Because of the significant interaction between
(median days to therapeutic: 7 days in AA vs recipient race and TAC exposure for the outcome
5 days in non-AA, p<0.001) and had 1.7 times of acute rejection, the data were stratified across
the risk of not achieving a mean TAC trough race (Table 3). Among AAs, acute rejection
concentration of at least 8 ng/ml (p<0.001) dur- (p<0.001) and AMR (p=0.007) rates were signifi-
ing the first year posttransplant. cantly higher in those with mean TAC concentra-
tions lower than 8 ng/ml. This was not

Table 1. Baseline Characteristics Compared Across Tacrolimus Exposure Cohorts

Mean TAC ≥ Mean TAC
Variables 8 ng/ml (n=767) < 8 ng/ml (n=311) p value
Recipient demographics
Median age (IQR) 53.4 (42.5–62.4) 50.9 (40.1–61.7) 0.154
Female, % 41.0 42.1 0.634
African-American, % 47.6 65.0 < 0.001
Medicare insurance, % 70.8 74.0 0.297
Recipient medical history
Primary cause of end-stage renal disease
Diabetes, % 25.4 28.3 0.332
Hypertension, % 28.9 31.2 0.464
Heart disease, % 19.2 18.3 0.750
Dialysis, % 77.6 81.4 0.170
Median years on dialysis (IQR) 2 (0.5–4) 2.5 (1–4) 0.023
Previous kidney transplant, % 9.6 9.0 0.743
Donor characteristics
Deceased donor, % 82.5 84.6 0.419
African-American, % 23.1 28.9 0.043
Expanded criteria donor, % 11.7 18.2 0.011
Median age (IQR) 38 (24–47) 39 (24–49) 0.213
Transplant characteristics
Cytolytic induction, % 40.0 48.6 0.097
Median panel reactive antibody (IQR) 0 (0–27) 0 (0–21) 0.334
Panel reactive antibody > 20%, % 30.7 28.2 0.539
Median HLA mismatch (IQR) 4 (3–5) 5 (4–5) 0.053
Median cold time, hrs (IQR) 16.6 (9.1–23.1) 17.3 (11.7–23.5) 0.256
Median warm time, min (IQR) 36 (30–41) 36 (30–40) 0.723
Delayed graft function, % 11.2 18.6 0.001
IQR = interquartile range; HLA = human leukocyte antigen; TAC = tacrolimus.
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TACROLIMUS TDM IN AFRICAN-AMERICANS Taber et al 573

Figure 1. Tacrolimus trough concentrations compared over time across exposure cohorts, stratified by race.

Table 2. Clinical Outcomes Compared across Tacrolimus fied by race for the outcomes of acute rejection
Exposure Cohorts (Figure 2A, 2B) and IF/TA (Figure 2C, 2D) for
Mean TAC ≥ Mean TAC
the mean TAC exposure analysis. The figure
8 ng/ml < 8 ng/ml demonstrates that AA patients with FK lower
Clinical outcomes (n=767), % (n=311), % p value than 8 ng/ml experienced a significantly higher
Acute rejection 7.6 16.4 < 0.001 risk of acute rejection (adjusted hazard ratio
Borderline rejection 11.1 14.1 0.16 [HR] 2.8, 95% CI 1.7–4.8; Figure 2B), which
Antibody-mediated 2.7 6.1 0.008 was not demonstrated in non-AAs (adjusted HR
rejection 0.7, 95% CI 0.15–3.2; Figure 2A). The multivar-
Interstitial fibrosis/ 9.6 15.1 0.01
tubular atrophy
iate modeling also revealed that AA patients
Any BK infection 13.3 14.1 0.712 with FK lower than 8 ng/ml experienced a mild
BK nephropathy 5.1 5.1 0.968 protective effect for developing IF/TA (HR 0.78,
Any 16.8 15.1 0.492 95% CI 0.47–1.32; Figure 2D), whereas non-
cytomegalovirus AAs with FK lower than 8 ng/ml were at higher
infection
Graft loss 10.0 12.2 0.294
risk of IF/TA (HR 2.2, 95% CI 0.90–5.1; Fig-
Death 6.4 6.8 0.826 ure 2C).
TAC = tacrolimus. For the outcome of IF/TA, the multivariate
modeling revealed differences as compared with
demonstrated for either acute rejection (p=0.577) the univariate analysis. AA patients with low
or AMR (p=0.450) among non-AAs. The rates of TAC exposure experienced a mild protective
IF/TA were similar in those with low TAC expo- effect (HR 0.78, 95% CI 0.47–1.32; Figure 2D),
sure among both AAs (p=0.138) and non-AAs whereas non-AAs with low TAC exposure were
(p=0.112). Graft loss rates were similar across at higher risk of IF/TA (HR 2.2, 95% CI 0.90–
TAC exposure cohorts, regardless of race as well. 5.1; Figure 2C); however, neither of these
adjusted HR estimates reached statistical signifi-
Multivariate Analyses cance, although the trends were in the opposite
direction. Acute rejection (adjusted HR 24–87)
Figure 2 displays the Cox regression models was the predominant risk factor for developing
adjusted event-free survival plot estimates, strati- IF/TA in both AAs and non-AAs.
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
574 PHARMACOTHERAPY Volume 35, Number 6, 2015
Table 3. Clinical Outcomes Compared across Tacrolimus Exposure Cohorts, Stratified by Race
African-Americans Non–African-Americans
Mean TAC ≥ Mean TAC Mean TAC ≥ Mean TAC
Clinical outcomes 8 ng/ml (n=365), % < 8 ng/ml (n=202), % 8 ng/ml (n=402), % < 8 ng/ml (n=109)
Acute rejection 8.5 20.8a 6.7 8.3b
Borderline rejection 12.3 14.4b 10.0 13.8b
Antibody-mediated rejection 3.6 8.9a 2.0 0.9b
Interstitial fibrosis/tubular atrophy 12.3 16.8b 7.2 11.9b
Graft loss 10.7 12.4b 9.5 11.9b
Death 6.6 5.9b 6.2 8.3b
TAC = tacrolimus.
a
p<0.05.
b
p>0.05.

Figure 2. Cox regression event-free survival plots for acute rejection and interstitial fibrosis/tubular atrophy (IF/TA),
compared across FK exposure cohorts and stratified by race. CI = confidence interval; DGF = delayed graft function;
ECD = expanded criteria donor; HLA = human leukocyte antigen; HR = hazard ratio; PRA = panel reactive antibody.

Multivariate modeling using Cox regression substantially larger effect seen in AAs (HR 16.6)
was performed using intrapatient TAC trajecto- as compared with non-AAs (HR 4.6). Con-
ries as a continuous covariate for the outcomes versely, the intrapatient TAC trajectory was not
of acute rejection and graft loss (Table 4). These statistically significantly associated with IF/TA
results demonstrated a similar pattern for effect in either AAs (HR 7.9) or non-AAs (0.3),
modification of race on the association of TAC although, similar to the mean TAC lower than
exposure for acute rejection (interaction term 8 ng/ml model, the effect trend was in opposite
p<0.001) but not for IF/TA (p=0.182). The in- directions: AAs with increasing intrapatient TAC
trapatient TAC trajectory was significantly and trajectories were at higher risk of IF/TA,
positively associated with acute rejection, with a whereas non-AAs with increasing intrapatient
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TACROLIMUS TDM IN AFRICAN-AMERICANS Taber et al 575
Table 4. Multivariate Modeling Output for Intrapatient Tacrolimus Trajectory for Acute Rejection and Interstitial Fibrosis/
Tubular Atrophy, Stratified by Race
Outcomea Cohort Parameter estimate Standard error Adjusted HR 95% CI p value
Acute rejection b
African-American 2.81 0.42 16.60 7.3–37.9 < 0.0001
Non–African-American 1.54 0.30 4.65 2.58–8.36 < 0.0001
IF/TAc African-American 2.07 1.81 7.91 0.23–275.3 0.2534
Non–African-American 1.21 3.89 0.30 0.00–609.3 0.7560
CI = confidence interval; HLA = human leukocyte antigen; HR = hazard ratio; IF/TA = interstitial fibrosis/tubular atrophy.
a
Model adjusted for gender, age, diabetes, insurance, donor type, HLA mismatch, panel reactive antibody, retransplant, and induction.
b
Interaction term p=0.0003.
c
Interaction term p=0.1823.

TAC trajectories were at a lower risk of devel- included was low risk, with 12% black, 40%
oping IF/TA. living donor, and 92% with a panel reactive anti-
body less than 15%.4 In contradistinction, two
recent analyses demonstrated that early post-
Discussion
transplant tacrolimus trough concentrations
The results of this analysis provide novel were significantly lower in patients who subse-
insights into the markedly different impact of quently developed acute rejection. Both of these
TAC exposure on outcomes across recipient studies contained smaller sample sizes (n=57
race. AA kidney transplant recipients have a and 216), but patients appeared to be at higher
70% higher risk of not achieving mean therapeu- immunologic risk compared with the Bouamer
tic TAC trough concentrations during the first analysis.5, 7 However, to date, very limited stud-
year posttransplant. Importantly, low TAC expo- ies have assessed the association between TAC
sure substantially increases the risk of acute trough concentrations and acute rejection that
rejection in AAs, which was not demonstrated in contain a significant number of AA patients.
non-AAs. Conversely, AA recipients with thera- Most recent studies analyzing the association
peutic TAC concentrations may be at a some- between TAC concentrations and outcomes are
what higher risk of developing IF/TA, which, from the United Kingdom, Australia, or Europe.
after confounder adjustment, appears to be a Studies from the United States are either dated
mildly protective factor in non-AAs. (use much higher target TAC trough concentra-
Intrapatient TAC trajectory analysis, which was tions than conventional strategies) or have a
used as a surrogate measure for the direction that small sample size.6, 16–20 There are data clearly
TAC concentrations are trending prior to the demonstrating that AA recipients require higher
event, also demonstrate that AA patients have sig- TAC doses to achieve therapeutic concentra-
nificantly higher trajectories (slopes) prior to tions, but these analyses have not correlated this
acute rejection as compared with non-AAs. AAs to acute rejection.11, 12 Thus the data presented
with increasing trajectories are also at mildly within this analysis are the first to provide statis-
higher risk of developing IF/TA, with the opposite tically and clinically significant associations
effect seen in non-AAs. These analyses, taken in between TAC concentrations and clinical out-
entirety, provide evidence that enhanced monitor- comes within a large AA population (n=567).
ing and manipulation of TAC trough concentra- There is a robust biologic explanation why
tions may provide one mechanism to mitigate AA patients have a significantly stronger associa-
racial disparities in kidney transplantation. tion between TAC concentrations and clinical
Evidence supporting the use of TAC TDM to outcomes when compared with non-AAs. First,
improve outcomes or reduce toxicities is con- AAs are less likely to achieve therapeutic TAC
flicting.3 The most recent study, published in concentrations, which is likely a reflection of
2013, was a secondary analysis of pooled data pharmacogenomics.14, 15 AA patients are sub-
from three randomized controlled clinical trials. stantially more likely to be CYP 3A5 expressors,
The analysis failed to find a relationship between a known factor that strongly influences TAC
TAC troughs at five time points (day 3, 10, 14 dosing requirements.21, 22 Second, AAs are at
and month 1 and 6 posttransplant) and biopsy- higher immunologic risk due to a number of
proven acute rejection. Although this was a large potential etiologies including more HLA mis-
analysis (n=1304), none of the three trials were matching,23, 24 more marginal donors,25 and
originally designed to study this association, and immune functionality differences.26–28 Thus
the population of kidney transplant recipients achieving therapeutic TAC concentrations early
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
576 PHARMACOTHERAPY Volume 35, Number 6, 2015

posttransplant in AAs is less common yet may ABCB1 gene variant analysis, in conjunction
be more crucial to preventing acute rejection with other known donor and recipient risk fac-
when compared with non-AAs. Finally, AAs are tors, may provide the ability to predict which
more likely to receive deceased donor organs,25 patients are at greater risk of CNI-associated
which due to their increased marginal status as nephrotoxicity.32 It is clear that the predominant
compared with living donors, may be more risk of developing IF/TA is acute rejection,
prone to TAC-related nephrotoxicity, leading to regardless of race. Thus improving early TAC
higher rates of IF/TA in patients achieving thera- dosing accuracy in AAs, which will likely lead to
peutic TAC concentrations.29–31 lower rejection rates, may, in fact, be the most
Moving forward, a number of potential inter- successful intervention to improve all posttrans-
ventions have the strong potential to improve plant outcomes.
TAC medication therapy management and moni- A number of limitations to this study should
toring in AA recipients. First, prospective geno- be discussed. First, this was a retrospective
typing of potential recipients for CYP3A5 and study, and as such, it is prone to bias, misclassi-
ABCB1 would potentially allow clinicians the fication, and confounders. We attempted to limit
ability to develop individualized initial dosing bias by specifying minimum predefined exclu-
strategies for TAC at the time of transplantation. sions. Indeed, very few patients were excluded
Because AAs are known to predominantly due to missing data or lost to follow-up. Mis-
express the CYP3A5 gene variant, this alone classification is also a possibility because a num-
could lead to dramatic improvements in early ber of methods were used to assess TAC
TAC dosing accuracy. The literature demonstrat- exposure. To minimize misclassification, we uti-
ing a strong association between ABCB1 gene lized two methods (intrapatient mean and trajec-
variants and tacrolimus pharmacokinetics and tory) to conduct a robust assessment of
dynamics is less compelling and somewhat con- exposure. We chose not to use single-time point
tradictory. A number of studies have found that measurements as previous studies have done,
ABCB1 gene variants are associated with tacroli- which are limited by a high degree of both intra-
mus dosing requirements and risk of toxicity and interpatient variability. Because this was a
(calcineurin inhibitor [CNI] nephrotoxicity longitudinal cohort study, we were able to clas-
through accumulation in the allograft); others sify outcomes in a time-to-event manner (rejec-
have failed to find such associations.3, 13, 15, 32 tion and IF/TA), which allowed us to fully
Thus further research is needed in this area. In establish temporality, because only the TAC con-
addition, the interactions and convergence of centrations that were drawn prior to the event
CYP3A5 and ABCB1 gene variants on TAC phar- were included in the exposure calculations. Con-
macokinetics and dynamics is not well studied, founding was minimized by collecting detailed
particularly as it relates to racial disparities in baseline and follow-up data and including
transplantation.3, 13, 15, 32 The data presented in known risk factors in multivariate models.
this analysis suggest that improved understand- Because we had access to a large sample size
ing of CYP3A5 and ABCB1 genotyping may allow with significant event rates, we were able to
for more accurate dosing and monitoring of include all important confounders in models,
TAC therapy and provide clinicians better infor- which was a limitation of previous studies. A
mation to conduct risk-benefit assessment of this number of limitations that we cannot fully
highly efficacious, yet significantly toxic immu- address due to the retrospective nature of this
nosuppressant therapy. This is particularly the study include assessment of gene variants,
case in AA patients.32 assessment of medication adherence to TAC
In terms of the association between therapeu- therapy, and discerning if all concentrations
tic TAC concentrations and the development of were true 12-hour predose troughs. The 7-year
IF/TA, the path forward is not as well defined. time period of the study, which may have cap-
Two studies have demonstrated good success tured significant evolutions in donor and recipi-
with CNI minimization or withdrawal regimens, ent characteristics and/or clinical practice
using therapy based on mammalian target of ra- standards was also a limitation. However, using
pamycin in AA recipients.33, 34 Perhaps develop- this time period did allow for a large sample of
ing a method to identify which AA recipients are patients, which increased the power and external
at high likelihood to develop significant post- validity of this study.
transplant IF/TA may be the first step toward In conclusion, these results provide novel evi-
individualizing immunosuppression regimens. dence to support that AA kidney transplant
 18759114, 2015, 6, Downloaded from https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.1591 by Medical University Of South, Wiley Online Library on [17/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TACROLIMUS TDM IN AFRICAN-AMERICANS Taber et al 577

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did not observe this association in non-AAs. increased risk of early acute rejection in adult renal transplan-
tation. Nephrol Dial Transplant 2001;16:1905–9.
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centrations may be at higher risk of developing crolimus whole blood concentrations correlate closely to side-
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ported by the National Institute of Diabetes and open-label, concentration-ranging trial of FK506 in primary
Digestive and Kidney Diseases of the National Insti- kidney transplantation: a report of the United States multicen-
ter FK506 kidney transplant group. Transplantation
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