Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation

Rahamimov, Ruth; Tifti-Orbach, Hagit; Zingerman, Boris; Green, Hefziba; Schneider, Shira; Chagnac, Avry; Mor, Eytan; Fox, Benjamin D.; Rozen‐Zvi, Benaya

doi:10.1007/s00228-019-02643-y

Cited by 18 publications

(25 citation statements)

References 24 publications

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“…Rahamimov et al published a novel study that approached the issue of long‐term Tac IPV evaluation by calculating cumulative CV across 6‐month time increments for a median follow‐up time of 3.5 years. The results have demonstrated that an increase in cumulative Tac IPV was associated with an increased risk of graft loss 12 . These findings highlight the importance of long‐term Tac IPV calculations as it is related to poorer graft outcomes.…”

Section: Tac Ipv Measurement Methods and Best‐practice Considerationsmentioning

confidence: 67%

“…21 The existing body of evidence satisfies most of Hill's relevant criteria for causality, including strength, consistency, specificity, temporality, biologic gradient, and plausibility. The strong associations observed across several of these studies 5,[7][8][9][10][11][12][13][14][15][16][17][18] in the absence of considerable conflicting evidence or confounding supports the strength of this evidence. Results are consistent across studies analyzing graft outcomes 5,8,11,12,13 and rejection [14][15][16]18 We must also consider the plausibility of the hypothesis that is not a highly variable drug.…”

Section: Tac Ipv and Clini C Al Implic Ati On S For Patient Monitormentioning

confidence: 63%

“…The coefficient of variation (CV) is commonly used by investigators to quantify Tac IPV 7‐13 . The CV is represented by the ratio of the standard deviation ( σ ) to the mean ( μ ).…”

Section: Tac Ipv Measurement Methods and Best‐practice Considerationsmentioning

confidence: 99%

“…Studies have reported the median number of Tac trough concentrations included in the calculation of Tac IPV ranging from 3 to 15 15,18 (see Table 1: IPV Reported). The mean number of levels reported range from 4.6 to 20.7 5,10,11,12,16,17 . Clearly, the more levels that are included, the better confidence a clinician has regarding the accuracy of the Tac IPV estimate.…”

Section: Tac Ipv Measurement Methods and Best‐practice Considerationsmentioning

confidence: 99%

“…Although previous studies estimated Tac IPV at 3 to 12 months after transplantation by calculating either CV or MAD, more recent studies employed a different technique 11,12 (Table 1). Rozen‐Zvi et al was the first to use TWCV to determine whether researchers could identify high‐risk patients in the early posttransplant period.…”

Section: Impact Of Tac Ipv On Clinical Outcomesmentioning

confidence: 99%

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A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

Gonzales

McGillicuddy

Rohan

et al. 2020

American Journal of Transplantation

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Section: Tac Ipv Measurement Methods and Best‐practice Considerationsmentioning

confidence: 67%

Section: Tac Ipv and Clini C Al Implic Ati On S For Patient Monitormentioning

confidence: 63%

“…The coefficient of variation (CV) is commonly used by investigators to quantify Tac IPV 7‐13 . The CV is represented by the ratio of the standard deviation ( σ ) to the mean ( μ ).…”

Section: Tac Ipv Measurement Methods and Best‐practice Considerationsmentioning

confidence: 99%

Section: Tac Ipv Measurement Methods and Best‐practice Considerationsmentioning

confidence: 99%

Section: Impact Of Tac Ipv On Clinical Outcomesmentioning

confidence: 99%

See 3 more Smart Citations

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

Gonzales

McGillicuddy

Rohan

et al. 2020

American Journal of Transplantation

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Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty‐four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV‐directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV‐directed interventions to improve transplant outcomes.

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Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

et al. 2022

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Background Tacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies (dnDSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological risk. Methods This was a single-center retrospective study including 48 pediatric kidney transplant recipients. TacIPV was calculated based on coefficient of variation (CV%) 6–12 months posttransplant. TacIPV cutoff was set at the median (25%). Outcome parameters were dnDSA development and rejection episodes. Results In total, 566 Tac levels were measured with median 11.0 (6.0–17.0) measurements per patient. The cutoff of 25% corresponded to the median CV% in our study cohort (25%, IQR 18–35%) and was comparable to cutoffs determined by receiver operating characteristic (ROC) curve analysis. High TacIPV was associated with higher risk of dnDSA development (HR 3.4, 95% CI 1.0–11.1, P = 0.047; Kaplan–Meier analysis P = 0.018) and any kind of rejection episodes (HR 4.1, 95% CI 1.1–14.8, P = 0.033; Kaplan–Meier analysis P = 0.010). There was a clear trend towards higher TacIPV below the age of 6 years. TacIPV (CV%) was stable over time. A TacIPV (CV%) cutoff of 30% or IPV quantification by mean absolute deviation (MAD) showed comparable results. Conclusions High TacIPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile. Therefore, in patients with high TacIPV, potential causes should be addressed, and if not resolved, changes in immunosuppressive therapy should be considered. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

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Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation

Cited by 18 publications

References 24 publications

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

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