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

ABSTRACT: 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.

SUBMITTER: Mathew SK

PROVIDER: S-EPMC10933594 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Mathew Sumith K SK Chapla Aaron A Venkatesan Padmanaban P Eriyat Vishnu V Aruldhas Blessed Winston BW Prabha Ratna R Neely Michael N MN Rao Shoma V SV Kandasamy Subramani S Mathew Binu Susan BS

Clinical and translational science 20240301 3

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, LR ...[more]

PMID: 38476095

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Project description:Objectives: To assess the association between gentamicin exposure and subclinical signs of nephrotoxicity in school children who were exposed to a high-dose gentamicin regimen in the neonatal period. Methods: Children receiving three or more doses (6 mg/kg) of gentamicin as neonates were invited to a follow-up in school age. We evaluated potential signs of subclinical nephrotoxicity with four validated urine biomarkers: protein-creatinine ratio (PCR), albumin-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and N-acetyl-beta-D-glucosaminidase (NAG) normalized for urine creatinine (NAG-Cr). In addition, blood pressure was measured. The measures of gentamicin exposure were cumulative dose (mg/kg) and highest trough plasma concentration (TPC) in mg/L. We used logistic and linear regression and non-parametric kernel regression to analyze the relationship between gentamicin exposure and the urine biomarkers. Results: A total of 222 gentamicin exposed children were included. As neonates, the children were exposed to a median (interquartile range-IQR) cumulative gentamicin dose of 36 (26-42) mg/kg and the median (IQR) TPC was 1.0 (0.7-1.3) mg/L. At follow-up, 15 children (6.8%) had either one abnormal urine biomarker value (13 children) or two abnormal urine biomarker values (2 children). These 17 biomarker values were all marginally above the suggested upper cutoff, and included the following markers; KIM-1 (n = 2), NAC-Cr (n = 5), ACR (n = 6), and PCR (n = 4). All other 207 children had normal sets of all four urine biomarkers. One child had hypertension. There were no differences in gentamicin exposure, gestational age (GA) at birth or birth weight between the group of 15 children with one or two abnormal urine biomarker values compared to the other 207 children who had normal biomarker values. Using different regression analyses, we did not find any association between gentamicin exposure (cumulative dose and/or TPC) and the urine biomarker values. Conclusions: Exposure to an extended-interval, high-dose gentamicin regimen in the neonatal period was not associated with signs of subclinical nephrotoxicity in schoolchildren. We therefore suggest that the gentamicin treatment regimen evaluated in this study is safe in terms of long-term nephrotoxicity. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03253614.

Dataset Information

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

Publications

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

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