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Significant Correlations between p-Cresol Sulfate and Mycophenolic Acid Plasma Concentrations in Adult Kidney Transplant Recipients

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Abstract

Background and Objectives

Mycophenolic acid (MPA) is a commonly prescribed life-long immunosuppressant for kidney transplant recipients. The frequently observed large variations in MPA plasma exposure may lead to severe adverse outcomes; therefore, characterizations of contributing factors can potentially improve the precision dosing of MPA. Our group recently reported the potent inhibitory effects of p-cresol (a protein-bound uremic toxin that can be accumulated in kidney transplant patients) on the hepatic metabolism of MPA in human in vitro models. Based on these data, the hypothesis for this clinical investigation was that a direct correlation between p-cresol and MPA plasma exposure should be evident in adult kidney transplant recipients.

Methods

Using a prospective and observational approach, adult kidney transplant recipients within the first year after transplant on oral mycophenolate mofetil (with tacrolimus ± prednisone) were screened for recruitment. The exclusion criteria were cold ischemia time > 30 h, malignancy, pregnancy, severe renal dysfunction (i.e., estimated glomerular filtration rate, eGFR, < 10 mL/min/1.73 m2), active graft rejection, or MPA intolerance. Patients’ demographic and biochemistry data were collected. Total and free plasma concentrations of MPA, MPA glucuronide (MPAG), and total p-cresol sulfate (the predominant, quantifiable form of p-cresol in the plasma) were quantified using validated assays. Correlational and categorical analyses were performed using GraphPad Prism.

Results

Forty patients (11 females) were included: donor type (living/deceased: 20/20), induction regimen (basiliximab/thymoglobulin/basiliximab followed by thymoglobulin: 35/3/2), post-transplant time (74 ± 60 days, mean ± standard deviation), age (53.7 ± 12.4 years), bodyweight (79.8 ± 18.5 kg), eGFR (51.9 ± 18.0 mL/min/1.73 m2), serum albumin (3.6 ± 0.5 g/dL), prednisone dose (18.5 ± 13.2 mg, n = 33), and tacrolimus trough concentration (9.4 ± 2.4 µg/L). Based on Spearman analysis, significant control correlations supporting the validity of our dataset were observed between total MPA trough concentration (C0) and total MPAG C0 (correlation coefficient [R] = 0.39), ratio of total MPAG C0-to-total MPA C0 and post-transplant time (R = − 0.56), total MPAG C0 and eGFR (R = − 0.35), and p-cresol sulfate concentration and eGFR (R = − 0.70). Our primary analysis indicated the novel observation that total MPA C0 (R = 0.39), daily dose-normalized total MPA C0 (R = 0.32), and bodyweight-normalized total MPA C0 (R = 0.32) were significantly correlated with plasma p-cresol sulfate concentrations. Consistently, patients categorized with elevated p-cresol sulfate concentrations (i.e., ≥ median of 3.2 µg/mL) also exhibited increased total MPA C0 (by 57 % vs those below median), daily dose-normalized total MPA C0 (by 89 %), and bodyweight-normalized total MPA C0 (by 62 %). Our secondary analyses with MPA metabolites, unbound concentrations, free fractions, and MPA metabolite ratios supported additional potential interacting mechanisms.

Conclusion

We have identified a novel, positive association between p-cresol sulfate exposure and total MPA C0 in adult kidney transplant recipients, which is supported by published mechanistic in vitro data. Our findings confirm a potential role of p-cresol as a significant clinical variable affecting the pharmacokinetics of MPA. These data also provide the justifications for conducting subsequent full-scale pharmacokinetic-pharmacodynamic studies to further characterize the cause-effect relationships of this interaction, which could also rule out potential confounding variables not adequately controlled in this correlational study.

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Acknowledgements

We thank Alberta Health Services and study participants as the data sources for this manuscript. To maintain the blinding of the investigative team, independent data extraction was contracted to Prime Site Research Solutions Inc (Edmonton, Alberta, Canada).

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Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Room 3-142D, 11361-87 Avenue, Edmonton, AB, T6G 2E1, Canada

    Yan Rong & Tony K. L. Kiang

  2. Alberta Precision Laboratories (Alberta Health Services), University of Alberta Hospital, Edmonton, AB, Canada

    Penny Colbourne

  3. Kidney Transplant Services, Faculty of Medicine and Dentistry, University of Alberta Hospital, University of Alberta, Edmonton, AB, Canada

    Sita Gourishankar

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  1. Yan Rong
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Correspondence to Tony K. L. Kiang.

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Funding

This study was funded by a start-up grant provided by the University of Alberta to Dr. Tony Kiang (RES0036916).

Conflict of interest

Yan Rong, Penny Colbourne, Sita Gourishankar, and Tony Kiang declare that they have no conflict of interest.

Availability of data and material

Original data are available from the corresponding author on reasonable request.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the University of Alberta Research Ethics Board (date: December 21, 2020; study ID: Pro00105082).

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Not required as recommended/approved by the University of Alberta Research Ethics Board (Pro00105082). This was based on the study being non-invasive and non-interventional (i.e., no deviation from routine clinical care). The investigative team had no contact with the participants and was totally blinded from their identities.

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Authors’ contributions

All authors contributed to the study conception and design. Material preparation, data collection, analytical measurements, and data analyses were performed by Yan Rong and Dr. Tony Kiang. The first draft of the manuscript was written by Yan Rong. All authors commented on the final version of the manuscript, which was edited by Dr. Tony Kiang.

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Rong, Y., Colbourne, P., Gourishankar, S. et al. Significant Correlations between p-Cresol Sulfate and Mycophenolic Acid Plasma Concentrations in Adult Kidney Transplant Recipients. Clin Drug Investig 42, 207–219 (2022). https://doi.org/10.1007/s40261-022-01121-1

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  • DOI: https://doi.org/10.1007/s40261-022-01121-1

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