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Néphrologie & Thérapeutique

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Middle-molecule uremic toxins: A renewed interest Volume 15, issue 2, Avril 2019

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Background

Although the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG.

Methods

We performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin.

Results

A total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was≤41.66mL/min (OR: 11.29; 95%CI: 7.21–17.61; P<0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26–19.63; P=0.0006).

Conclusion

Our study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment.

La mortalité cardiovasculaire des patients atteints d’une maladie rénale chronique reste un problème majeur. À côté des facteurs de risque traditionnels, les toxines urémiques, dont les molécules de poids moléculaire moyen, participent de façon non négligeable à ce surcroît de mortalité, en générant et en entretenant un état inflammatoire chronique dit de bas grade. Ces molécules sont l’objet d’un intérêt croissant depuis quelques années et une grande partie des toxines urémiques associées à cette surmortalité cardiovasculaire a été identifiée : le FGF23, les cytokines, la pentraxin-3 et récemment les chaînes légères. Plusieurs études épidémiologiques ont mis en évidence l’interaction entre toxines urémiques, inflammation et/ou stress oxydatif, et mortalité cardiovasculaire et globale. L’utilisation des thérapies antioxydantes et/ou des anticorps dirigés contre les toxines ou leur site d’action, n’ont pas jusqu’à ce jour apporté un réel bénéfice sur la morbi-mortalité. Des espoirs se sont tournés récemment vers l’utilisation de nouvelles membranes d’hémodialyse dite medium cut-off (MCO), qui ont l’avantage d’épurer les toxines urémiques de poids moléculaire moyen sans une perte significative d’albumine. Néanmoins, les effets bénéfiques de ces nouvelles membranes sur la morbi-mortalité chez les patients dialysés restent à démontrer.

Cardiovascular mortality in patients with chronic kidney disease remains a major problem. The uremic toxins among which the molecules of middle molecular weight are counted contribute significantly to this high mortality, alongside the traditional risk factors. They generate and maintain a chronic inflammatory state called low-level chronic inflammatory state. A growing interest in these molecules has been noted for some years and the uremic toxins associated with this cardiovascular mortality are currently identified: FGF23, cytokines, pentraxin-3 and recently light chains. The existence of an interaction between uremic toxins, inflammation and/or oxidative stress and cardiovascular mortality is well reported in the various epidemiological studies. While the use of anti-oxidative therapies and/or antibodies against uremic toxins or their site of action have not yet yielded a real benefit, hopes are turning to the use of new hemodialysis membranes medium cut-off (MCO), which have the advantage of purifying the uremic toxin middle molecules without a significant loss of albumin. However, additional works are needed to demonstrate the use of these membranes will lead to modulate the morbi-mortality in the dialysis patients.