Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Autor: Mathew SK; Department of Pharmacology and Clinical Pharmacology, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Chapla A; Department of Endocrinology, Diabetes & Metabolism, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Venkatesan P; Department of Biochemistry, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Eriyat V; Department of Pharmacology and Clinical Pharmacology, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Aruldhas BW; Department of Pharmacology and Clinical Pharmacology, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Prabha R; Department of Pharmacology and Clinical Pharmacology, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Neely MN; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.; Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, California, USA., Rao SV; Surgical Intensive Care Unit and Division of Critical Care, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Kandasamy S; Surgical Intensive Care Unit and Division of Critical Care, Christian Medical College & Hospital, Vellore, Tamilnadu, India., Mathew BS; Department of Pharmacology and Clinical Pharmacology, Christian Medical College & Hospital, Vellore, Tamilnadu, India.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2024 Mar; Vol. 17 (3), pp. e13764.
DOI: 10.1111/cts.13764
Abstrakt: Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.
(© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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