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. 2017 Jul 7;3(8):e192.
doi: 10.1097/TXD.0000000000000710. eCollection 2017 Aug.

High Intrapatient Variability of Tacrolimus Levels and Outpatient Clinic Nonattendance Are Associated With Inferior Outcomes in Renal Transplant Patients

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Free PMC article

High Intrapatient Variability of Tacrolimus Levels and Outpatient Clinic Nonattendance Are Associated With Inferior Outcomes in Renal Transplant Patients

Dawn L Goodall et al. Transplant Direct. .
Free PMC article

Abstract

Background: Nonadherence to immunosuppressants is associated with rejection and allograft loss. Intrapatient variability (IPV) of immunosuppression levels is a marker of nonadherence. This study describes the impact of IPV of tacrolimus levels in patients receiving a tacrolimus monotherapy immunosuppression protocol.

Methods: We retrospectively analyzed the outpatient tacrolimus levels of kidney-only transplant patients taken between 6 and 12 months posttransplant. IPV was determined using the coefficient of variance.

Results: Six hundred twenty-eight patients with a mean number of 8.98 ± 3.81 tacrolimus levels and a mean follow-up of 4.72 ± 2.19 years were included. Multivariate analysis showed death was associated with increasing age (1.04 [1.01-1.07], P = 0.0055), diabetes at time of transplant (2.79 [1.44-5.41], P = 0.0024), and rejection (2.34 [1.06-5.19], P = 0.036). Variables associated with graft loss included the highest variability group (2.51 [1.01-6.27], P = 0.048), mean tacrolimus level less than 5 ng/mL (4.32 [1.94-9.63], P = 0.0003), a high clinic nonattendance rate (1.10 [1.01-1.20], P = 0.03), and rejection (9.83 [4.62-20.94], P < 0.0001). Independent risk factors for rejection were de novo donor-specific antibody (3.15 [1.84-5.39], P < 0.0001), mean tacrolimus level less than 5 ng/mL (2.57 [1.27-5.19], P = 0.00860, and a high clinic nonattendance rate (1.11 [1.05-1.18], P = 0.0005).

Conclusions: This study shows that high tacrolimus IPV and clinic nonattendance are associated with inferior allograft survival. Interventions to minimize the causes of high variability, particularly nonadherence are essential to improve long-term allograft outcomes.

Figures

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FIGURE 1
FIGURE 1
Patient survival by COV group. Patient survival was inferior in the HHV group compared with those in the LV group at 83.2% and 92.7%, respectively (P = 0.017), with a trend to inferior survival compared with both the HV and LLV groups with a survival of 93.2% (P = 0.053) and 91.6% (P = 0.08), respectively.
FIGURE 2
FIGURE 2
Death-censored allograft survival by COV group. Censored allograft survival was significantly reduced in patients in the HHV group. Compared with an allograft survival of 77.2% in the HHV group, patients in the HV group had an 89.5% survival (P = 0.011) and in the LV and LLV group allograft survival was 89.4%, P = 0.051 and 93.4%, respectively (P = 0.042).
FIGURE 3
FIGURE 3
Rejection-free survival by COV group. Overall rejection-free survival was inferior in the HHV group compared with the LLV group at 77.7% and 89.7%, respectively (P = 0.023). There was no statistical difference in rejection-free survival between the HHV group and either of the HV or LV groups at 85.0% (P = 0.11) and 85.4% (P = 0.22), respectively.
FIGURE 4
FIGURE 4
Allograft survival by mean tacrolimus and variability level. Allograft survival in the LV less than 5 was significantly lower than the LV 5 to 8 ng/mL group, 49.6% compared with 94.6% (P < 0.0001), and independently lower than allograft survival in the LV greater than 9 ng/mL group at 100.0% (P = 0.019).
FIGURE 5
FIGURE 5
AMR-free survival by mean tacrolimus and variability level. AMR-free survival was also inferior in the LV less than 5 ng/mL group compared with the LV 5 to 8 ng/mL group, with an AMR-free survival of 77.8% and 97.6%, respectively (P < 0.0001).
FIGURE 6
FIGURE 6
Comparison of clinic nonattendances by HV and LV. Patients with a HV of tacrolimus levels were significantly more likely not to attend their outpatient appointments; the median number of nonattendances was 4 (range, 0-22) in the HV group and 2 (range, 0-17) in the LV group (P < 0.0001).

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