Augmented renal clearance of aminoglycosides using population-based pharmacokinetic modelling with Bayesian estimation in the paediatric ICU.

OBJECTIVE: To evaluate augmented renal clearance (ARC) using aminoglycoside clearance (CLAMINO24h) derived from pharmacokinetic (PK) modelling. METHODS: A retrospective study at two paediatric hospitals of patients who received tobramycin or gentamicin from 1999 to 2016 was conducted. Compartmental PK models were constructed using the Pmetrics package, and Bayesian posteriors were used to estimate CLAMINO24h. ARC was defined as a CLAMINO24h of ≥130 mL/min/1.73 m2. Risk factors for ARC were identified using multivariate logistic regression. RESULTS: The final population model was fitted to 275 aminoglycoside serum concentrations. Overall clearance (L/h) was=CL0×(TBW/70)0.75×AGEH/(TMH + AGEH) + CL1 (0.5/SCr), where TBW is total body weight, H is the Hill coefficient, TM is a maturation term and SCr is serum creatinine. Median CLAMINO24h in those with versus without ARC was 157.36 and 93.42 mL/min/1.73 m2, respectively (P<0.001). ARC was identified in 19.5% of 118 patients. For patients with ARC, median baseline SCr was lower than for those without ARC (0.38 versus 0.41 mg/dL, P=0.073). Risk factors for ARC included sepsis [adjusted OR (aOR) 3.77, 95% CI 1.01-14.07, P=0.048], increasing age (aOR 1.11, 95% CI 1-1.23, P=0.04) and low log-transformed SCr (aOR 0.16, 95% CI 0.05-0.52, P=0.002). Median 24 h AUC (AUC24h) was significantly lower in patients with ARC at 45.27 versus 56.95 mg·h/L, P<0.01. CONCLUSIONS: ARC was observed in one of every five patients. Sepsis, increasing age and low SCr were associated with ARC. Increased clearance was associated with an attenuation of AUC24h in this population. Future studies are needed to define optimal dosing in paediatric patients with ARC.

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase.

The Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O-GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a.