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Potential interactions between uremic toxins and drugs: an application in kidney transplant recipients treated with calcineurin inhibitors.

BACKGROUND: The uremic toxins that accumulate with as renal function deteriorates can potentially affect drug pharmacokinetics. The study's objective was to determine whether plasma concentrations of certain uremic toxins were correlated with blood concentrations of two immunosuppressants.

METHODS: DRUGTOX was a cross-sectional study of 403 adult patients followed up after kidney transplantation and who had undergone therapeutic drug monitoring (TDM) of calcineurin inhibitors (tacrolimus or cyclosporin) between August 2019, and March 2020. For each patient, immunosuppressant trough concentrations (C0) were measured in whole-blood samples and then normalized against the total daily dose: C0/D ratio. The sample was assayed for five uremic toxins (urea, trimethylamine N-oxide (TMAO), indole acetic acid (IAA), para-cresylsulfate (PCS), and indoxylsulfate (IxS)) using liquid chromatography-tandem mass spectrometry.

RESULTS: The median [interquartile range] age was 56 [48-66] and the median eGFR was 41 [30-57] ml/min/1.73 m2. Age, sex, BMI, urea, IxS and PCS were significantly associated with an increment in the tacrolimus C0/D ratio. A multivariate analysis revealed an independent association with IxS (OR [95% CI]: 1.36 [1.00; 1.85], after adjustment for sex, age and BMI, whereas adjustment for age weakened the association for PCS and urea. In a univariate logistic analysis, age, sex, BMI, and the TMAO level (but neither PCS, IxS, IAA nor urea) were significantly associated with an increment in the cyclosporine C0/D ratio.

CONCLUSION: Even though TDM and dose adaptation of immunosuppressants keeps levels within the therapeutic window, elevated exposure to tacrolimus (but not cyclosporine) is associated with an accumulation of PCS, IxS and urea.

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