Flucloxacillin decreases tacrolimus blood trough levels:a single-center retrospective cohort study

PURPOSE: Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. METHODS: In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, flucloxacillin n = 11 patients). RESULTS: The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4-49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5-51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (p = 0.009) and after flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed. CONCLUSIONS: Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin

Albuminuria and markers for cardiovascular risk in 12-year-olds from the general Dutch population:a cross-sectional study

In adults, albuminuria represents a risk factor for cardiovascular disease and is associated with hypertension and obesity. Pediatric data from the general population are inconsistent and largely based on randomly collected urine. A possible association between antenatal programming and albuminuria at school age has still to be investigated. The purpose of this study is to assess albuminuria in first morning void urine samples in a population-based pediatric cohort and to investigate cross-sectionally the association with factors related to cardiovascular risk. Moreover, we investigate the possible association of antenatal factors with albuminuria. A first morning void urine sample was collected in the population-based GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort at the age of 12 years. We investigated cross-sectionally associations between albuminuria and body mass index (BMI), waist circumference (WC), blood pressure (BP) and antenatal factors. The prevalence of U ACR (urinary albumin-creatinine ratio) ≥ 3 mg/mmol was 3.3% (95%CI 2.3-4.2). In a multivariate linear regression model, U AC was negatively associated with z-BMI (β-0.08, p = 0.013) and positively with z-systolic BP (β 0.09, p = 0.006), model significance p = 0.002. U ACR was negatively associated with z-BMI (β - 0.13, p &lt; 0.001) and positively with z-diastolic BP (β 0.09, p = 0.003), model significance p = 0.001. Albuminuria was not significantly associated with antenatal factors such as gestational age and standardized birth weight. CONCLUSIONS: Albuminuria in first morning void urine in 12-year-olds has a lower prevalence than previously reported by randomly collected samples. A negative association between albuminuria and BMI is confirmed. A positive association with blood pressure, but no association with antenatal factors was found.WHAT IS KNOWN: • While, in adults, albuminuria is a recognized risk factor for cardiovascular disease and is associated with hypertension and obesity, pediatric data are inconsistent and largely based on randomly collected urine. • A possible association between antenatal programming and albuminuria at school age has still to be investigated.WHAT IS NEW: • In this population study on first morning void urine samples from 12-year-olds of the general population, albuminuria is negatively associated with body mass index, and positively associated with blood pressure, while there is no association with antenatal factors. • The prevalence of albuminuria at 12 years is lower than previously reported in studies based on randomly collected urine samples, probably due to elimination of orthostatic proteinuria.</p

Longitudinal relationship between albuminuria in infancy and childhood

Background: Mildly increased albuminuria is common in the general adult population and is a strong predictor for cardiovascular events, even in otherwise healthy individuals. The underlying pathophysiological process could be endothelial dysfunction. Previously, we reported that increased albuminuria can also be found in 2-year-olds from the general population. We hypothesized that some individuals have constitutionally higher levels of albuminuria, possibly as an expression of early or inborn endothelial dysfunction. The aim of this study is to evaluate longitudinal persistence of albuminuria from infancy into school age. Methods: In the population-based GECKO (Groningen Expert Center for Kids with Obesity) cohort, urine was collected from 816 children at the age of 2 years as well as 12 years (random urine and first morning void urine, respectively). We evaluated prevalence and persistence of increased albuminuria (U ACR ≥ 3 mg/mmol) at the two time points. Results: The prevalence of U ACR ≥ 3 mg/mmol at 2 and 12 years of age was 31.9% (95% CI 28.7–35.2) and 3.1% (95% CI 2.0–4.5), respectively. U ACR &lt; 3 mg/mmol at both 2 and 12 years of age was present in 540 children (66.2%). Only 9 children (3.5%) of the 260 children with an U ACR ≥ 3 mg/mmol at 2 years had an U ACR ≥ 3 mg/mmol at 12 years (p &lt; 0.001). Conclusion: Albuminuria in 2-year-olds does largely not persist until the age of 12, indicating that albuminuria at 2 years of age is not a marker for constitutional endothelial dysfunction in this cohort. Graphical abstract: [Figure not available: see fulltext.]</p

Longitudinal relationship between albuminuria in infancy and childhood

Background: Mildly increased albuminuria is common in the general adult population and is a strong predictor for cardiovascular events, even in otherwise healthy individuals. The underlying pathophysiological process could be endothelial dysfunction. Previously, we reported that increased albuminuria can also be found in 2-year-olds from the general population. We hypothesized that some individuals have constitutionally higher levels of albuminuria, possibly as an expression of early or inborn endothelial dysfunction. The aim of this study is to evaluate longitudinal persistence of albuminuria from infancy into school age. Methods: In the population-based GECKO (Groningen Expert Center for Kids with Obesity) cohort, urine was collected from 816 children at the age of 2 years as well as 12 years (random urine and first morning void urine, respectively). We evaluated prevalence and persistence of increased albuminuria (U ACR ≥ 3 mg/mmol) at the two time points. Results: The prevalence of U ACR ≥ 3 mg/mmol at 2 and 12 years of age was 31.9% (95% CI 28.7–35.2) and 3.1% (95% CI 2.0–4.5), respectively. U ACR &lt; 3 mg/mmol at both 2 and 12 years of age was present in 540 children (66.2%). Only 9 children (3.5%) of the 260 children with an U ACR ≥ 3 mg/mmol at 2 years had an U ACR ≥ 3 mg/mmol at 12 years (p &lt; 0.001). Conclusion: Albuminuria in 2-year-olds does largely not persist until the age of 12, indicating that albuminuria at 2 years of age is not a marker for constitutional endothelial dysfunction in this cohort. Graphical abstract: [Figure not available: see fulltext.]</p

Prevalence and distribution of (micro)albuminuria in toddlers

Background. Microalbuminuria is common in the general adult population, with a prevalence of similar to 7%, and is an independent indicator of renal and cardiovascular risks. Whether albuminuria is acquired during life (as a result of hypertension/diabetes) or is congenital and already present at birth is unknown. We studied the prevalence of microalbuminuria in toddlers and compared the distribution of albuminuria with that of the general adult population. In addition, we looked for possible associations between microalbuminuria and antenatal, postnatal and maternal factors.Methods. The urinary albumin concentration (U-AC) was measured in 1352 children and the urinary albumin:creatinine ratio (U-ACR) in 1288 children from the Groningen Expert Center for Kids with Obesity (GECKO) Drenthe cohort (age range 20-40 months). Albuminuria distribution was compared with the albuminuria distribution in 40 854 participants of the general adult cohort of the Prevention of Renal and Vascular End stage Disease (PREVEND) study. Associations between albuminuria (expressed as U-AC and U-ACR) and antenatal, postnatal and maternal factors were tested with linear regression analysis.Results. The median U-AC in the GECKO study was 2.3 mg/L (5th-95th percentiles: 2.1-25.5) and in the PREVEND study it was 6.0 mg/L (2.3-28.6) (P distribution comparison 0.053). The prevalence of U-AC a parts per thousand yen 20 mg/L was 6.9% in the GECKO study and 7.8% in the PREVEND study (P = 0.195). The prevalence of U-ACR a parts per thousand yen 30 mg/g in the GECKO study was 23.4%. U-AC and U-ACR were lower in boys. U-AC was not associated with other determinants, but U-ACR was associated with age and gestational diabetes.Conclusions. The distribution of U-AC and the prevalence of U-AC &gt; 20 mg/L in toddlers and in the young general adult population are comparable. These findings suggest that microalbuminuria is a congenital condition that may predispose to a higher cardiovascular risk later in life.</p

Evaluation of Dosing Guidelines for Gentamicin in Neonates and Children

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children’s Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8–12 mg/L for neonates and 15–20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment