Reliability of glomerular filtration rate estimating formulas compared to iohexol plasma clearance in critically ill children.

Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CLiohexol) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CLiohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland-Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CLiohexol was measured in 98 patients. Mean CLiohexol (± SD) was 115 ± 54 ml/min/1.73m2. Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC- and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of - 18 ± 51% (95% confidence interval (CI) - 29; - 9), poor precision with 95% LoA from - 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58). CONCLUSION: In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings. CLINICALTRIALS: gov NCT05179564, registered retrospectively on January 5, 2022. WHAT IS KNOWN: • Both acute kidney injury and augmented renal clearance may be present in PICU patients and warrant adaptation of therapy, including drug dosing. • Biomarker-based eGFR formulas are widely used for GFR assessment in critically ill children, although endogenous filtration biomarkers have important limitations in PICU patients and eGFR formulas have never been validated against measured GFR in this population. WHAT IS NEW: • eGFR formulas were found to be largely inaccurate in the PICU population when compared to measured GFR by iohexol clearance. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. • Iohexol plasma clearance could be considered an alternative for accurate GFR assessment in PICU patients.

The Development of a Juvenile Porcine Augmented Renal Clearance Model Through Continuous Infusion of Lipopolysaccharides: An Exploratory Study.

Augmented renal clearance (ARC) as observed in the critically ill (pediatric) population can have a major impact on the pharmacokinetics and posology of renally excreted drugs. Although sepsis has been described as a major trigger in the development of ARC in human critically ill patients, mechanistic insights on ARC are currently lacking. An appropriate ARC animal model could contribute to reveal these underlying mechanisms. In this exploratory study, a state of ARC was induced in 8-week-old piglets. Conscious piglets were continuously infused over 36 h with lipopolysaccharides (LPS) from Escherichia coli (O111:B4) to induce sepsis and subsequently trigger ARC. To study the dose-dependent effect of LPS on the renal function, three different doses (0.75, 2.0, 5.0 µg/kg/h) were administered (two ♂ piglets/dose, one sham piglet), in combination with fluid administration (0.9% NaCl) at 6 ml/kg/h. Single boluses of renal markers, i.e., creatinine [40 mg/kg body weight (BW)], iohexol (64.7 mg/kg BW), and para-aminohippuric acid (PAH, 10 mg/kg BW) were administered intravenously to evaluate the effect of LPS on the renal function. Clinical parameters were monitored periodically. Blood sampling was performed to determine the effect on hematology, neutrophil gelatinase-associated lipocalin, and prostaglandin E2 plasma levels. All piglets that were continuously infused with LPS displayed an elevated body temperature, heart rhythm, and respiratory rate ~1-3 h after start of the infusion. After infusion, considerably higher total body clearances of iohexol, creatinine, and PAH were observed, independent of the administration of LPS and/or its dose. Since also the sham piglet, receiving no LPS, demonstrated a comparable increase in renal function, the contribution of fluid administration to the development of ARC should be further evaluated.

Volumetric absorptive microsampling as alternative sampling technique for renal function assessment in the paediatric population using iohexol.

The glomerular filtration rate (GFR) is considered the best overall index for the renal function. Currently, one of the most promising exogenous markers for GFR assessment is iohexol. In this study, the suitability of volumetric absorptive microsampling (VAMS) as alternative for the conventional blood sampling and quantification of iohexol in paediatric plasma was assessed. Therefore, a new, fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed. Subsequently, the clinical suitability was evaluated in 20 paediatric patients by comparing plasma iohexol concentrations and associated GFR values obtained by the VAMS method with those obtained by conventional blood sampling and quantification of iohexol in plasma. The developed, simple and cost-effective LC-MS/MS-method fulfilled all pre-set validation acceptance criteria. Iohexol could be accurately quantified within a haematocrit range of 20-60% and long-term stability of iohexol in VAMS was demonstrated up to 245 days under different storage temperatures. Both iohexol plasma concentrations (r = 0.98, mean bias: -4.20%) and derived GFR values (r = 0.99; mean bias: 1.31%), obtained by a conventional plasma and the VAMS method, demonstrated good correlation and acceptable bias. The agreement between the two methods was especially good for GFR values higher than 60 mL/min/1.73 m2. Nevertheless, for GFR values <60 mL/min/1.73 m2 the accuracy compared to the plasma method was lower. However, small adjustments to the sampling protocol could probably solve this problem.

Conventional Pig as Animal Model for Human Renal Drug Excretion Processes: Unravelling the Porcine Renal Function by Use of a Cocktail of Exogenous Markers.

Over recent years, pigs have been promoted as potential animal model due to their anatomical and physiological similarities with humans. However, information about the contribution of distinct renal elimination processes [glomerular filtration rate (GFR), effective renal plasma flow (ERPF), tubular secretion, and reabsorption] in pigs is currently limited. Therefore, a cocktail of renal markers, consisting of iohexol (GFR), para-aminohippuric acid (ERPF and net tubular anion secretion), pindolol (net tubular cation secretion), and fluconazole (net tubular reabsorption) was administered intravenously to 7-week-old male conventional pigs. Plasma and urinary concentrations were determined using validated analytical methods. The clearance of iohexol (GFR) was 97.87 ± 16.05 ml/min/m² (mean ± SD). The ERPF, calculated as the renal clearance of PAH, was 226.77 ± 62.45 ml/min/m², whereas the net tubular secretion of PAH was 130.28 ± 52.62 ml/min/m². The net tubular secretion of R-pindolol and S-pindolol was 13.53 ± 12.97 and 18.01 ± 39.23 ml/min/m², respectively. The net tubular reabsorption of fluconazole was 78.32 ± 13.52 ml/min/m². Overall, this cocktail of renal markers was considered to be safe for use in pigs since no adverse effects were observed. Iohexol, PAH and fluconazole were considered suitable renal marker to assess the porcine renal function. Pindolol seems less appropriate due to the high degree of nonrenal clearance in pigs. The values of GFR, ERPF, and anion secretion are within the same range for both human and pig. Regarding the tubular reabsorption of fluconazole, slightly higher values were obtained for pigs. Nevertheless, these results indicate the conventional pig could be an appropriate animal model to study renal drug elimination processes in humans.

Simultaneous Measurement of Glomerular Filtration Rate, Effective Renal Plasma Flow and Tubular Secretion in Different Poultry Species by Single Intravenous Bolus of Iohexol and Para-Aminohippuric Acid.

The aim of the current study was to investigate the simultaneous measurement of plasma p-aminohippuric acid (PAH) clearance as a potential marker to assess effective renal plasma flow (eRPF) and tubular secretion (TS), and the plasma clearance of iohexol (IOH) as a marker of the glomerular filtration rate in poultry species. The PAH was administered intravenously (IV) to broiler chickens, layers, turkeys, Muscovy ducks, and pigeons. Each animal received successively a single bolus dose of 10 mg PAH/kg bodyweight (BW) and 100 mg PAH/kg BW to assess the eRPF and TS, respectively. Simultaneously with both PAH administrations, a single IV bolus of 64.7 mg/kg BW of IOH was administered. A high linear correlation (R2 = 0.79) between eRPF, based on the clearance of the low dose of PAH, and BW was observed for the poultry species. The correlation between TS, based on the clearance of the high dose of PAH, and BW was moderate (R2 = 0.50). Finally, a moderate correlation (R2 = 0.68) was demonstrated between GFR and eRPF and between GFR and TS (R2 = 0.56). This presented pharmacokinetic approach of the simultaneous administration of IOH and PAH enabled a simultaneous evaluation of eRPF/TS and GFR, respectively, in different poultry species.

Unraveling the Contribution of Fluid Therapy to the Development of Augmented Renal Clearance in a Piglet Model.

Augmented renal clearance (ARC) observed in the critically ill pediatric population has received an increased attention over the last years due to its major impact on the disposition and pharmacokinetics of mainly renally excreted drugs. Apart from an important inflammatory trigger, fluid administration has been suggested to contribute to the development of ARC. Therefore, the primary objective of this study was to evaluate the effect of continuous intravenous fluid administration on renal function using a conventional piglet animal model and to quantify the impact of fluid administration on the pharmacokinetics of renally excreted drugs. At baseline, twenty-four piglets (12 treatment/12 control; 7 weeks old, all ♂) received the marker drugs iohexol (64.7 mg/kg body weight (BW)) and para-aminohippuric acid (10 mg/kg BW) to quantify glomerular filtration rate and effective renal plasma flow, respectively. In addition, the hydrophilic antibiotic amikacin (7.5 mg/kg BW) was administered. Following this baseline measurement, the treatment group received fluid therapy as a constant rate infusion of 0.9% saline at 6 mL/kg/h over 36 h. After 24 h of fluid administration, the marker drugs and amikacin were administered again. When comparing both groups, a significant effect of fluid administration on the total body clearances of iohexol (p = 0.032) and amikacin (p = 0.0014) was observed. Clearances of iohexol and amikacin increased with on average 15 and 14%, although large interindividual variability was observed. This led to decreased systemic exposure to amikacin, which was manifested as decrease in area under the plasma concentration-time curve from time 0 h to infinity from 34,807 to 30,804 ng.h/mL. These results suggest that fluid therapy is a key factor involved in the development of ARC and should be taken into account when administering mainly renally excreted drugs. However, further research is necessary to confirm these results in children.

Development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of iohexol, p-aminohippuric acid and creatinine in porcine and broiler chicken plasma.

In order to study the renal function, in terms of glomerular filtration and effective renal plasma flow, in broiler chickens and pigs, an ultra-high performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of iohexol, p-aminohippuric acid (PAH) and exogenously administered creatinine in plasma was developed and validated. Sample preparation consisted of a deproteinization step using methanol for porcine plasma and an Ostro™ Protein Precipitation & Phospholipid Removal Plate was used for broiler chicken plasma. Chromatographic separation was achieved on a Hypersil Gold aQ column using 0.1% formic acid in water and 0.1% formic acid in methanol as mobile phases. The total run time was limited to 10 min. Matrix-matched calibration curves for iohexol and PAH were prepared and good linearity (r ≥ 0.9973; gof ≤ 6.17%) was achieved over the concentration range tested (0.25-90 µg/mL). Limits of quantification were 0.25 µg/mL for iohexol and PAH. Water was used as surrogate matrix for analysis of creatinine in plasma. This surrogate calibration curve showed good linearity over the concentration range tested (0.25-90 µg/mL) (r ≥ 0.9979; gof ≤ 5.66%). For creatinine, the relative lower limit of quantification was 201.03 ±â€¯49.20% and 60.14 ±â€¯7.64% for chicken and porcine plasma, respectively. The results for within-day and between-day precision and accuracy fell within the specified ranges. This straightforward, cost-effective and rapid method, determining iohexol, PAH and creatinine within one single chromatographic run, has been successfully used for the analysis in porcine and broiler chicken plasma samples in order to determine the renal function of these species.

Comparative population pharmacokinetics and absolute oral bioavailability of COX-2 selective inhibitors celecoxib, mavacoxib and meloxicam in cockatiels (Nymphicus hollandicus).

Selective COX-2 inhibitors are non-steroidal anti-inflammatory drugs which directly target cyclooxygenase-2 (COX-2), an enzyme mainly responsible for induction of inflammation, pyresis and pain. Although commonly used in avian medicine, limited pharmacokinetic (PK) data in domestic and companion birds are available. In this study, PK parameters and absolute oral bioavailability expressed as percentage (F%) of celecoxib (10 mg/kg BW), mavacoxib (4 mg/kg BW) and meloxicam (1 mg/kg BW) were determined following single oral (PO) and intravenous (IV) administration to cockatiels (Nymphicus hollandicus). The drugs were quantified in plasma by liquid chromatography-tandem mass spectrometry. Data were processed using the nonlinear mixed effects (NLME) approach. In contrast to celecoxib (T1/2el = 0.88 h) and meloxicam (T1/2el = 0.90 h), mavacoxib has a prolonged elimination half-life (T1/2el = 135 h) following oral administration of a commercial formulation (CF). High to complete oral absorption was observed following oral administration of celecoxib (F% = 56-110%) and mavacoxib (F% = 111-113%), CF and standard solutions, respectively. In contrast, the F% of meloxicam was low (F% = 11%). Based on the presented results, a less frequent dosing of mavacoxib is proposed compared to celecoxib and meloxicam. However, pharmacodynamic and safety studies are necessary to further investigate the use of these NSAIDs in cockatiels.