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The measurement of glomerular filtration rate (GFR) is essential to understanding renal physiology, including the monitoring of disease progression and treatment effectiveness. Transdermal measurement of glomerular filtration rate (tGFR) using a miniaturized fluorescence monitor in combination with a fluorescent exogenous GFR tracer has become a common technique to measure GFR in the preclinical setting, especially in rodent models. It allows for close to real-time measurement of GFR in conscious unrestrained animals and overcomes several limitations of other GFR measures. Its widespread use is reflected by published research articles and conference abstracts from different research fields, including in the assessment of new and existing kidney therapeutics, evaluation of nephrotoxicity, screening of novel chemical or medical agents, and fundamental understanding of kidney function., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Accurate prediction of pharmacokinetic parameters, such as renal clearance, is fundamental to the development of effective and safe new treatments for patients. However, conventional renal models have a limited ability to predict renal drug secretion, a process that is dependent on transporters in the proximal tubule. Improvements in microphysiological systems (MPS) have extended our in vitro capabilities to predict pharmacokinetic parameters. In this study a kidney-MPS model was developed that successfully recreated renal drug secretion. Human proximal tubule cells grown in the kidney-MPS, resem­bling an in vivo phenotype, actively secreted the organic cation drug metformin and organic anion drug cidofovir, in contrast to cells cultured in conventional culture formats. Metformin and cidofovir renal secretory clearance were predicted from kid­ney-MPS data within 3.3- and 1.3-fold, respectively, of clinically reported values by employing a semi-mechanistic drug distribution model using kidney-MPS drug transport parameters together with in vitro to in vivo extrapolation. This approach introduces an effective application of a kidney-MPS model coupled with pharmacokinetic modelling tools to evaluate and predict renal drug clearance in humans. Kidney-MPS renal clearance predictions can potentially complement pharma-cokinetic animal studies and contribute to the reduction of pre-clinical species use during drug development.

Development of peptide drugs is challenging but also quite rewarding. Five blockbuster peptide drugs are currently on the market, and six new peptides received first marketing approval as new molecular entities in 2012. Although peptides only represent 2% of the drug market, the market is growing twice as quickly and might soon occupy a larger niche. Natural peptides typically have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Strategies have been developed to improve peptide drugability through enhancing permeability, reducing proteolysis and renal clearance, and prolonging half-life. In vivo, in vitro, and in silico tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability. [ABSTRACT FROM AUTHOR]

Abstract: Probe substrates for, and inhibitors of, specific transporters are desired to evaluate quantitatively the in vivo functions of transporters in humans. Based on published data, adefovir and benzylpenicillin were selected as organic anion transporter (OAT) 1- and OAT3-selective probe substrates, respectively. In human kidney slices, probenecid potently inhibited the uptake of both adefovir and benzylpenicillin with inhibition constant (K i) values of 18.6±5.1 and 12.6±4.2μM, respectively, whereas p-aminohippurate (PAH) preferentially inhibited adefovir uptake. A clinical drug-interaction study involving healthy subjects was performed to investigate the dose-dependent inhibition potencies of probenecid and PAH on the renal clearance of the probe substrates. Adefovir or benzylpenicillin was coadministered with different oral doses of probenecid (500, 750, or 1500mg) or intravenous PAH infusion rates (70, 120, or 210mg/min/person) to the same subject using a crossover design. The renal clearance of adefovir was reduced by 45% and 46% in the subjects treated with the maximum dose of probenecid and PAH, respectively, which was in accordance with the results of in vitro inhibition study. On the other hand, renal clearance of benzylpenicillin was reduced by 78% in the subjects treated with the maximum dose of probenecid (1500mg), which could be explained by its in vitro K i values. However, PAH unexpectedly increased the renal clearance of benzylpenicillin by 47%. These results suggest that adefovir and benzylpenicillin can be used as probe drugs for OAT1 and OAT3, respectively, and that PAH can be used to investigate the role of OAT1 in the urinary excretion of drugs in humans, whereas it may modulate other transport processes in the kidney. [Copyright &y& Elsevier]

Dabigatran etexilate represents a possible improved alternative to warfarin for anticoagulation in hemodialysis patients with atrial fibrillation (AF). The objective was to determine dabigatran plasma concentrations and anticoagulant effects following administration of a single 110 mg oral dose of dabigatran etexilate to 10 adult patients immediately prior to starting hemodialysis. Mass spectrometry and the Hemoclot® assay were used, respectively, to determine free (unconjugated) dabigatran concentrations and thrombin time (TT) in plasma samples collected intermittently over 48 hours. The median time (tmax) to reach the maximum plasma-free dabigatran concentration (Cmax) was 2 hours (range 1-3 hours). The mean free dabigatran Cmax was 95.5 ± 33.4 ng/mL. The mean elimination half-lives on and off hemodialysis were, respectively, 2.6 ± 1.3 and 30.2 ± 7.8 hours. Hemodialysis effectively removed dabigatran with an extraction ratio of 0.63 ± 0.07. The maximal TT ratio was 2.1 and the TT ratio demonstrated a strong linear dependence on free dabigatran concentration (r2 = 0.741). A 110 mg oral dabigatran dose prior to hemodialysis was rapidly absorbed and achieved therapeutic concentrations. Hemodialysis effectively removed dabigatran from the plasma and may be an effective means of accelerating the elimination of dabigatran in circumstances of excessive anticoagulation. [ABSTRACT FROM AUTHOR]

Purpose: This study employed a mouse model to evaluate the effects of diabetic nephropathy on the pharmacokinetics of 8C2, a murine monoclonal antibody (mAb). Methods: Streptozotocin (STZ) was administered to mice to induce diabetic nephropathy (125 mg/kg/day × 2). Mice were grouped ( n = 8-10) based on time after STZ-treatment (control, 1, 2, 3, 4, or 6 weeks), and injected intravenously with 10 mg/kg 8C2. Blood samples were collected up to 7 days, and 8C2 plasma concentrations were determined via immunoassay. Inulin clearance and urinary albumin excretion rate (UAE) were determined to assess renal function. Results: UAE, inulin clearance, and 8C2 clearance increased significantly following STZ. Comparing control and 6 week STZ-treatment groups, UAE and inulin clearance increased from 25.7 ± 3.3 to 99.3 ± 13.7 μg/day, and from 421 ± 31 to 584 ± 78 μl/min. 8C2 clearance increased from 121 ± 12.5 to 228 ± 61 μl/hr/kg ( p < 0.01). 8C2 clearance was highly correlated with UAE (r: 0.731). Inclusion of UAE as a covariate in population modeling explained significant residual variability in 8C2 clearance. Conclusions: The clearance of 8C2 increased significantly in STZ-treated mice. Population pharmacokinetic modeling suggests that UAE has potential for use in predicting mAb clearance in subjects with diabetic nephropathy, possibly assisting in the individualization of mAb dosing. [ABSTRACT FROM AUTHOR]

Purpose: Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin. Methods: Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance. Results: A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty). Conclusions: Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration. [ABSTRACT FROM AUTHOR]

Renal clearance is a key determinant of the elimination of drugs. To date, only few in vitro- in vivo extrapolation ( IVIVE) approaches have been described to predict the renal organ clearance as the net result of glomerular filtration, tubular secretion, and tubular reabsorption. In this study, we measured in LLC- PK1 cells the transport of 20 compounds that cover all four classes of the Biopharmaceutical Drug Disposition System. These data were incorporated into a novel kidney model to predict all renal clearance processes in human. We showed that filtration and secretion were main contributors to the renal organ clearance for all compounds, whereas reabsorption was predominant for compounds assigned to classes 1 and 2. Our results suggest that anionic drugs were not significantly secreted in LLC- PK1 cells, resulting in under-predicted clearances. When all study compounds were included a high overall correlation between the reported and predicted renal organ clearances was obtained ( R2 = 0.83). The prediction accuracy in terms of percentage within twofold and threefold error was 70% and 95%, respectively. In conclusion, our novel IVIVE method allowed to predict the human renal organ clearance and the contribution of each underlying process. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:994-1001, 2014 [ABSTRACT FROM AUTHOR]

Bisphenol A diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE), and their derivatives are frequently used in food packaging materials. Some toxicological studies have shown that the endocrine-disrupting activities of these compounds are similar to or higher than those of bisphenol A (BPA), which may also adversely affect the growth and development of children and adolescents. Here, we investigated nine bisphenol-diglycidyl ethers (BDGEs) in 181 paired urine and serum samples from children and adolescents from Beijing to determine their partitioning, clearance and exposure levels. The results showed that nine BDGEs were detected in 181 urine and serum samples from children and adolescents from Beijing. Bisphenol A bis(2,3-dihydroxypropyl) glycidyl ether (BADGE·2H 2 O) was the primary pollutant. The daily intake of ∑BDGEs was 15.217 ng/kg bw/day among children and adolescents in Beijing. The ranking of BDGEs in terms of renal clearance rate (CL renal) in this study population was BADGE > BADGE·2H 2 O > BFDGE > bisphenol F bis(3-chloro-2-hydroxypropyl) glycidyl ether (BFDGE·2HCl) > bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) glycidyl ether (BADGE·HCl·H 2 O). In addition, the serum and urine ratios (S/U ratios) of BFDGE·2HCl, BADGE·2H 2 O, BFDGE, BADGE, and BADGE·HCl·H 2 O were higher than 1, indicating that these contaminants have a higher enrichment capacity in human blood. To our knowledge, this is the first study on the partitioning and renal clearance rate of BDGEs in paired urine and serum samples from children and adolescents. [Display omitted] • BADGE·2H 2 O was the primary contaminant in the urine and serum of adolescents in Beijing. • The enzymolysis strategy can lead to significant overestimation of BADGE·2H 2 O exposure levels. • BADGE and BADGE·2H 2 O are the BDGEs with the highest renal clearance rate. • Most BDGEs have higher enrichment capacity in human serum than that in urine. [ABSTRACT FROM AUTHOR]

The article evaluates the pharmacokinetic interaction of the anti-inflammmatory drug diclofenac on the disposition and renal clearance of the antibiotic amoxicillin in ewes. A cross-over study was done in Saudi Arabia wherein the ewes were intravenously injected with the antibiotic, either alone or with the analgesic. Results showed that the concomitant administration of the two drugs presented no significant effects in the pharmacokinetic parameters or renal elimination for amoxicillin.

Most undergraduate physiology laboratories are very limited in how they treat renal physiology. It is common to find teaching laboratories equipped with the capability for high-resolution digital recordings of physiological functions (muscle twitches, ECG, action potentials, respiratory responses, etc.), but most urinary laboratories still rely on a "dipstick" approach of urinalysis. Although this technique can provide some basic insights into the functioning of the kidneys, it overlooks the dynamic processes of filtration, reabsorption, and secretion. In the present article, we provide a straightforward approach of using renal clearance measurements to estimate glomerular filtration rate, fractional water reabsorption, glucose clearance, and other physiologically relevant parameters. The estimated values from our measurements in laboratory are in close agreement with those anticipated based on textbook parameters. For example, we found glomerular filtration rate to average 124 ± 45 ml/min, serum creatinine to be 1.23 ± 0.4 mg/dl, and fractional water reabsorption to be ~96.8%. Furthermore, analyses for the class data revealed significant correlations between parameters like fractional water reabsorption and urine concentration, providing opportunities to discuss urine concentrating mechanisms and other physiological processes. The procedures outlined here are general enough that most undergraduate physiology laboratory courses should be able to implement them without difficulty. [ABSTRACT FROM AUTHOR]

Veliparib ( ABT-888) is largely eliminated as parent drug in human urine (70% of the dose). Renal unbound clearance exceeds glomerular filtration rate, suggesting the involvement of transporter-mediated active secretion. Clinically relevant pharmacokinetic interactions in the kidney have been associated with OAT1, OAT3, OCT2, MATE1, and MATE2 K. In the present study, interactions of veliparib with these transporters were investigated. Veliparib inhibited OAT1, OAT3, OCT2, MATE1, and MATE2 K with IC50 values of 1371, 505, 3913, 69.9, and 69.5 μM, respectively. The clinical unbound maximum plasma concentration of veliparib after single oral dose of 50 mg (0.45 μM) is manyfold lower than IC50 values for OAT1, OAT3, OCT2, MATE1, or MATE2 K. These results indicate a low potential for drug-drug interaction ( DDI) with OAT1/3, OCT2, or MATE1/2 K. Additional studies demonstrated that veliparib is a substrate of OCT2. In Oct1/ Oct2 double-knockout mice, the plasma exposure of veliparib was increased by 1.5-fold, and the renal clearance was decreased by 1.8-fold as compared with wild-type mice, demonstrating that organic cation transporters contribute to the renal elimination in vivo. In summary, the in vitro transporter data for veliparib predicts minimal potential for an OAT1/3-, OCT2-, and MATE1/2 K-mediated DDI given the clinical exposure after single oral dose of 50 mg. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4426-4432, 2013 [ABSTRACT FROM AUTHOR]

Got it PEGged: PEGylation and zwitterionization have distinct effects on the pharmacokinetic and tumor‐targeting properties of luminescent gold nanoparticles (AuNPs), although both strategies lead to effective renal clearance. High tumor‐targeting efficiency and specificity were obtained with PEGylated AuNPs, whereas rapid tumor detection was more readily achieved with zwitterionic AuNPs. HD=hydrodynamic diameter, GS=glutathione. [ABSTRACT FROM AUTHOR]

Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293-Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, Vmax, [159 ± 3 nmol*(mg protein)-1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)-1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values ( Km) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CLR; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CLsec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CLR and CLsec. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3451-3457, 2013 [ABSTRACT FROM AUTHOR]

The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2941-2952, 2013 [ABSTRACT FROM AUTHOR]

Organic anion transporters (OATs) and organic cation transporters (OCT) play pivotal roles in the uptake of drugs into epithelial cells at the basolateral membranes, and multidrug and toxin extrusion (MATE) mediates drug secretion into urine at the brush-border membranes. In this study, the expression and distribution of apical MATE1 and MATE2-K, and basolateral OAT1, OAT3, and OCT2 were compared using serial sections of human kidney cortex. First, mRNA expression in the proximal tubules was evaluated using laser microdissection. Levels of OAT, OCT2, and MATE mRNA in the proximal tubules were greatly higher compared with glomerulus. The results quantitatively indicated that these transporters were localized to proximal tubules in the renal cortex. Second, MATE1 and MATE2-K protein were detected in proximal epithelial cells in which OCT2 protein was expressed at the basolateral membranes. In addition, MATE1 was expressed at the brush-border membranes of tubular epithelial cells in which OAT1 and OAT3 were expressed. The results confirmed that OAT1, OAT3, OCT2, MATE1, and MATE2-K were coexpressed in tubular epithelial cells. The cooperation among OAT, OCT, and MATE in renal drug secretion was consistent with their distribution. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3302-3308, 2013 [ABSTRACT FROM AUTHOR]

The purpose of this study was to clarify the relationship between the physicochemical properties of drugs and their urinary excretion mechanisms. Three hundred twenty-five drugs were classified into the reabsorption, intermediate, and secretion types based on their ratio of renal clearance to protein-unbound fraction glomerular filtration rate. Fifty percent of ionized and neutral drugs were the secretion and reabsorption types, respectively. The mean molecular weight of the neutral drugs was slightly smaller than those of the ionized drugs (296 vs. 330-368 g/mol). The reabsorption-type anionic drugs were characterized by their low molecular weights (mean value 269 g/mol) and the logarithmic measure of the acid dissociation constants (p Ka s) greater than 4.5, whereas the secretion-type anionic drugs all had p Kas below 4.5. Cationic drugs with p Kas lower than 8.0 tended to be the reabsorption type. Some cationic drugs were classified as the secretion type, despite their high molecular weights (734-811 g/mol) and high log P values (3.1-5.3). The organic anion transporter (OAT)1 and OAT3 substrates were all secretion-type drugs. The same trend was observed for the substrates of organic cation transporter 2, multidrug and toxin extrusion, multidrug resistance-associated protein 4, and multidrug resistance 1/breast cancer resistance protein, but substantial fractions of the substrates were categorized as the intermediate or reabsorption types (9%-38%). This work provides a clue to the renal elimination mechanism of new chemical entities during drug development. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3294-3301, 2013 [ABSTRACT FROM AUTHOR]

Several single sample methods for determination of 99m Tc-mercaptoacetyltriglycine ( MAG3) clearance are being used clinically. Kabasakal et al. proposed a similar formula for 99m Tc-ethylenedicysteine ( EC). This study was performed to compare his method with Bubeck et al. formula for 99m Tc- MAG3 already in use. Twenty-eight subjects divided in two groups were registered which included 22 patients with various renal diseases (group-I) and six normal volunteers (group II). All subjects were studied twice using both the radiopharmaceuticals. The images and renogram parameters, that is TMAX and T1/2 of both the agents, were similar in all the subjects. The clearance of the 99mTc- EC was however considerably higher than 99mTc- MAG3 in both the groups (mean ± SEM =279 ± 14 ml min−1/1·73 m2 versus 177 ± 15 ml min−1/1·73 m2 in group-I and 377 ± 11·90 ml min−1/1·73 m2 versus 238 ± 8·23 ml min−1/1·73 m2 in group II). This difference was more pronounced in cases with reduced renal functions. Among the Effective Renal Plasma Flow ( ERPF) values determined from EC and MAG3 clearances in six normal volunteers, four cases only in MAG3 had ERPF below the lower limit. This study has demonstrated superiority of single sample method for 99 mTc- EC clearance over its analogous method for 99m Tc- MAG3. [ABSTRACT FROM AUTHOR]

The contribution of renal and non-renal clearance toward targeted concentrations and/or effects of therapeutic proteins in nephrotic patients are unknown. This study dissected the contribution of clearance pathways to adalimumab elimination in patients with focal segmental glomerulosclerosis (FSGS). Urine was collected from seven patients treated with adalimumab. Renal clearance (ClR) was measured and non-renal clearance (ClNR) was calculated as the difference between total clearance and ClR. Differences in cumulative amount in urine, ClR, and ClNR between study weeks 1 and 16 and relationships between proteinuria (protein:creatinine ratio (Up/c)), and ClR and ClNR were evaluated. Up to 13% of the adalimumab dose was lost in urine. ClNR contributed more than ClR to enhanced total clearance. There was a nonlinear relationship between Up/c and ClR (R2 0.7059); an increase in ClR beginning at Up/c of 12 mg/mg [slope 1.755, (C.I. −7.825 to 11.34)]. There was a linear relationship between Up/c and ClNR (R2 0.5039); for every one unit increase in Up/c, ClNR would increase by 3.5 mL/hr ( P = 0.01). Both ClR and ClNR contribute to enhanced total clearance of adalimumab in glomerular disease secondary to FSGS. Additional research is needed to identify mechanisms for the increased ClNR pathways. [ABSTRACT FROM AUTHOR]

Purpose: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. Methods: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. Results: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and C by 1.4-fold ( p < 0.001), and reduced its oral and renal clearance ( p < 0.01). Ticlopidine reduced the AUC of M1 ( p < 0.001) and the ratio of the AUC of M1 to that of tramadol, but did not influence the AUC of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. Conclusions: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used. [ABSTRACT FROM AUTHOR]

Background: Changes in renal perfusion may play a pathophysiological role in hypertension and kidney disease, however to date, no method for renal blood flow (RBF) determination in humans has been implemented in clinical practice. In a previous study, we demonstrated that estimation of renal perfusion based on a single positron emission tomography/computed tomography (PET/CT) scan with Rubidium-82 ( 82 Rb) is feasible and found an approximate 5% intra-assay coefficient of variation for both kidneys, indicative of a precise method.This study's aim was to determine the day-to day variation of 82 Rb PET/CT and to test the method's ability to detect increased RBF induced by infusion of amino acids., Methods: Seventeen healthy subjects underwent three dynamic 82 Rb PET/CT scans over two examination days comprising: Day A, a single 8-minute dynamic scan and Day B, two scans performed before (baseline) and after RBF stimulation by a 2-hour amino acid-infusion. The order of examination days was determined by randomization. Time activity curves for arterial and renal activity with a 1-tissue compartment model were used for flow estimation; the K 1 kinetic parameter representing renal 82 Rb clearance. Day-to-day variation was calculated based on the difference between the unstimulated K 1 values on Day A and Day B and paired t-testing was performed to compare K 1 values at baseline and after RBF stimulation on Day B., Results: Day-to-day variation was observed to be 5.5% for the right kidney and 6.0% for the left kidney (n = 15 quality accepted scans). K 1 values determined after amino acid-infusion were significantly higher than pre-infusion values (n = 17, p = 0.001). The mean percentage change in K 1 from baseline was 13.2 ± 12.9% (range - 10.4 to 35.5) for the right kidney; 12.9 ± 13.2% (range - 15.7 to 35.3) for the left kidney., Conclusion: Day-to-day variation is acceptably low. A significant K 1 increase from baseline is detected after application of a known RBF stimulus, indicating that 82 Rb PET/CT scanning can provide a precise method for evaluation of RBF and it is able to determine changes herein., Clinical Trial Registration: EU Clinical Trials Register, 2017-005008-88. Registered 18/01/2018., (© 2022. The Author(s).)

Near-infrared-II (NIR-II) bioimaging gradually becomes a vital visualization modality in the real-time investigation for fundamental biological research and clinical applications. The favorable NIR-II contrast agents are vital in NIR-II imaging technology for clinical translation, which demands good optical properties and biocompatibility. Nevertheless, most NIR-II contrast agents cannot be applied to clinical translation due to the acute or chronic toxicity caused by organ retention in vivo imaging. Therefore, it is critical to understand the pharmacokinetic properties and optimize the clearance pathways of NIR-II contrast agents in vivo to minimize toxicity by decreasing organ retention. In this review, the clearance mechanisms of biomaterials, including renal clearance, hepatobiliary clearance, and mononuclear phagocytic system (MPS) clearance, are synthetically discussed. The clearance pathways of NIR-II contrast agents (classified as inorganic, organic, and other complex materials) are highlighted. Successively analyzing each contrast agent barrier, this review guides further development of the clearable and biocompatible NIR-II contrast agents., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Due to the deep tissue penetration and reduced scattering, NIR-II fluorescence imaging is advantageous over conventional visible and NIR-I fluorescence imaging for the detection of bone growth, metabolism, metastasis, and other bone-related diseases., Methods: Bone-targeted heptamethine cyanine fluorophores were synthesized by substituting the meso-carbon with a sulfur atom, resulting in a bathochromic shift and increased fluorescence intensity. The physicochemical, optical, and thermal stability of newly synthesized bone-targeted NIR fluorophores was performed in aqueous solvents. Calcium binding, bone-specific targeting, biodistribution, pharmacokinetics, and 2D and 3D NIR imaging were performed in animal models., Results: The newly synthesized S-substituted heptamethine fluorophores demonstrated a high affinity for hydroxyapatite and calcium phosphate, which improved bone-specific targeting with signal-background ratios > 3.5. Particularly, P800SO3-PEG showed minimum nonspecific uptake, and most unbound molecules were excreted into the urinary bladder. Histological analyses demonstrated that P800SO3-PEG remained stable in the bone for over two weeks and was incorporated into bone matrices. Interestingly, the flexible thiol ethylene glycol linker on P800SO3-PEG induced a promising photothermal effect upon NIR laser irradiation, demonstrating potential theranostic imaging., Conclusions: P800SO3-PEG shows a high affinity for bone tissues, deeper tissue imaging capabilities, minimum nonspecific uptake in the major organs, and photothermal effect upon laser irradiation, making it optimal for bone-targeted theranostic imaging., (© 2022. The Author(s).)

Rationale & Objective: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease., Study Design: Observational cohort., Settings & Participants: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at study entry., Exposure: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine., Outcome: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes)., Analytical Approach: Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons., Results: The mean baseline eGFR was 44 mL/min/1.73 m 2 . Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses., Limitations: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m 2 , potential residual confounding by GFR, no dietary information., Conclusions: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Second near-infrared window fluorescence imaging (NIR-II FI) has attracted tremendous attention in bioimaging. Until now, most probes for NIR-II FI are nanomaterials that are metabolized via hepatobiliary metabolism. Such a metabolic pathway may take several months, causing long-term toxicity. Herein, we design and synthesize a renal-clearable PEGylated semiconducting oligomer (PSO) for the NIR-II FI of tumor. PSO is composed of a semiconducting oligomer (SO) backbone as an NIR-II fluorescence reporter and four poly(ethylene glycol) (PEG) side chains as water-soluble enhancers. PSO can emit an NIR-II fluorescence signal with the maximum emission at 1000 nm under the excitation of 808 nm light. PSO shows good biocompatibility and can be partially cleared out of body via renal clearance. PSO can be utilized for the NIR-II FI of tumor as it can effectively accumulate into tumor.

Aim: To characterize the pharmacokinetics of deferoxamine-conjugated nanoparticles (DFO-NPs), a novel nanochelator for removing excess iron. Materials & methods: The pharmacokinetics of DFO-NPs were evaluated in Sprague-Dawley rats at three doses (3.3, 10 and 30 μmol/kg) after intravenous and subcutaneous administration. Results: DFO-NPs exhibited a biphasic concentration-time profile after intravenous administration with a short terminal half-life (2.0-3.2 h), dose-dependent clearance (0.111-0.179 l/h/kg), minimal tissue distribution and exclusive renal excretion with a possible saturable reabsorption mechanism. DFO-NPs after subcutaneous administration exhibited absorption-rate-limited kinetics with a prolonged half-life (5.7-10.1 h) and favorable bioavailability (47-107%). Conclusion: DFO-NPs exhibit nonlinear pharmacokinetics with increasing dose, and subcutaneous administration substantially improves drug exposure, thereby making it a clinically viable administration route for iron chelation.

Achieving complete nanoparticle (NP) clearance is a key consideration in the design of safe and translatable nanomedicines. Renal-clearable nano formulations must encompass the beneficial nanoscale functionalities whilst exhibiting clearance profiles like those of small-molecule therapeutics. Recent developments in the field have enabled the growth of novel renal-clearable NPs with transformable sizes that take advantage of alternative clearance mechanisms to achieve controlled and efficient renal excretion to improve potential clinical translation., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The objective of the present study was to evaluate mechanistic pharmacokinetic models describing active renal secretion and reabsorption over a range of Michaelis-Menten parameter estimates and doses. Plasma concentration and urinary excretion profiles were simulated and renal clearance (CLr) was calculated for two pharmacokinetic models describing active renal reabsorption (R1/R2), two models describing active secretion (S1/S2), and a model containing both processes. A range of doses (1-1,000 mg/kg) was evaluated, and Vmax and Km parameter estimates were varied over a 100-fold range. Similar CLr values were predicted for reabsorption models (R1/R2) with variations in Vmax and Km. Tubular secretion models (S1/S2) yielded similar relationships between Michaelis-Menten parameter perturbations and CLr, but the predicted CLr values were threefold higher for model S1. For both reabsorption and secretion models, the greatest changes in CLr were observed with perturbations in Vmax, suggesting the need for an accurate estimate of this parameter. When intrinsic clearance was substituted for Michaelis-Menten parameters, it failed to predict similar CLr values even within the linear range. For models S1 and S2, renal secretion was predominant at low doses, whereas renal clearance was driven by fraction unbound in plasma at high doses. Simulations demonstrated the importance of Michaelis-Menten parameter estimates (especially Vmax) for determining CLr. Km estimates can easily be obtained directly from in vitro studies. However, additional scaling of in vitro Vmax estimates using in vitro/in vivo extrapolation methods are required to incorporate these parameters into pharmacokinetic models. [ABSTRACT FROM AUTHOR]

In clinical settings, decrease of renal function is frequently observed in patients treated with vancomycin (VCM). In this study, mutable covariates models (MCMs) were constructed to analyze the pharmacokinetics (PK) of VCM with Bayesian estimation, considering time-dependent decreases in creatinine clearance in 23 patients with decreasing renal function. The predicted mean percentage error (MPE) of VCM concentrations analyzed with a conventional fixed covariates model (FCM) was −19.1%, whereas the MPE was improved to 2.5% by applying MCM. Furthermore, a probable lag time between fluctuations in VCM clearance (CLVCM) and serum creatinine ( Scr) was analyzed by MCM, MCMLag1d, and MCMLag2d, which considered lag times of 0, 1, and 2 days, respectively. Compared with FCM, all MCMs improved fitness with the significantly decreased root mean square percentage error (RMSPE) and MPE. However, RMSPE and MPE analyzed with MCM were not significantly different from those with MCMLag1d and MCMLag2d, indicating that lag times between alterations in CLVCM and Scr were obscure in these patients. Collectively, these results suggest that PK parameters of VCM were more accurately calculated by MCMs than by conventional FCM, and that VCM dosages calculated by FCM would be overestimated by approximately 20% in patients with decreasing renal function. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2968-2975, 2012 [ABSTRACT FROM AUTHOR]

Background/Aims: Calcium overload in vascular smooth muscle is a highly pathogenic event, which progresses with advancing age. Old patients are polymedicated, and several pharmacotherapeutic agents circulate in the plasma as organic anions. The organic anion transporters 1 and 3 (Oat1 and Oat3) are present in renal basolateral membranes, which transport organic anions of pharmacological and physiological interest. This study was designed to evaluate the renal expression and function of Oat1 and Oat3 in rats with vascular calcification. Methods: Vascular calcification was induced by administration of a single dose of vitamin D3 (300,000 UI/ kg b.w., i.m.) to male Wistar rats 10 days before the experiments. Oat1 and Oat3 expression was assessed by immunoblotting, immunohistochemistry and reverse-transcriptase polymerase chain reaction. The renal clearance of p-aminohippurate (PAH, a prototypical organic anion, substrate of Oat1 and Oat3) was measured by conventional clearance techniques. Results: Oat1 and Oat3 protein levels showed an increase in plasma membranes of renal proximal tubules of treated animals, where both transporters are functional. This could explain the increase observed in the renal clearance of PAH in treated rats. Conclusions: These results suggest the relevance of considering the existence of vascular calcification, which is common in ageing, when organic anion drugs are prescribed. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Study goal: The aim of the study was to assess the role of the kidney in systemic elimination of IL-6 and growth factors (PDGF, TGF-β) by comparison of their concentrations in renal arteries and veins, peripheral veins and urine. Material and methods: 30 brain-dead kidney donors were included in the study. Samples were obtained during the harvesting procedure. 10 healthy volunteers served as controls. A mathematical model of elimination of investigated proteins from systemic circulation was developed. The elimination ratio (ER) formula indicates the predominance of renal synthesis or degradation and also quantifies the renal uptake (UR) and renal pass (PR) of investigated proteins. Serum levels of investigated proteins were estimated using an immunoenzymatic method (ELISA). Results: Renal IL-6 uptake ratio (UR) amounted to 6.6%, elimination ratio (ER) amounted to 6.4% and pass ratio (PR) amounted to 0.2%. PDGF ratios amounted to 5.1%, 5.0% and 0.1% and TGF-β ratios amounted to −9%, −9% and 0%, respectively. Conclusions: The kidney takes part in the elimination of IL-6 and PDGF from systemic circulation. The kidney does not take part in the elimination of TGF-β. [Copyright &y& Elsevier]

Abstract: Gold nanoparticles have shown great prospective in cancer diagnosis and therapy, but they can not be metabolized and prefer to accumulate in liver and spleen due to their large size. The gold nanoclusters with small size can penetrate kidney tissue and have promise to decrease in vivo toxicity by renal clearance. In this work, we explore the in vivo renal clearance, biodistribution, and toxicity responses of the BSA- and GSH-protected gold nanoclusters for 24 h and 28 days. The BSA-protected gold nanoclusters have low-efficient renal clearance and only 1% of gold can be cleared, but the GSH-protected gold nanoclusters have high-efficient renal clearance and 36% of gold can be cleared after 24 h. The biodistribution further reveals that 94% of gold can be metabolized for the GSH-protected nanoclusters, but only less than 5% of gold can be metabolized for the BSA-protected nanoclusters after 28 days. Both of the GSH- and BSA-protected gold nanoclusters cause acute infection, inflammation, and kidney function damage after 24 h, but these toxicity responses for the GSH-protected gold nanoclusters can be eliminated after 28 days. Immune system can also be affected by the two kinds of gold nanoclusters, but the immune response for the GSH-protected gold nanoclusters can also be recovered after 28 days. These findings show that the GSH-protected gold nanoclusters have small size and can be metabolized by renal clearance and thus the toxicity can be significantly decreased. The BSA-protected gold nanoclusters, however, can form large compounds and further accumulate in liver and spleen which can cause irreparable toxicity response. Therefore, the GSH-protected gold nanoclusters have great potential for in vivo imaging and therapy, and the BSA-protected gold nanoclusters can be used as the agent of liver cancer therapy. [Copyright &y& Elsevier]

Abstract: Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable physicochemical and renal clearance properties. In vitro studies show that these two compounds have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that 4d and 5c have a higher urine recovery of the injected dose than iothalamate (a commonly considered gold standard GFR agent). Pharmacokinetic studies show that these two compounds exhibit a plasma clearance equivalent to iothalamate, but with a faster (i.e. lower) terminal half-life than iothalamate (possibly from restricted distribution into the extracellular space due to large molecular size and hydrodynamic volume). Furthermore, the plasma clearance of 4d and 5c remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration exclusively. Finally, noninvasive real-time monitoring of this class of compounds was demonstrated by pharmacokinetic clearance of 5c by optical measurements in rat model, which correlates strongly with plasma concentration of the tracer. Hence, 4d and 5c are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR. [Copyright &y& Elsevier]

To document trends and covariates of creatinemia (Scr) in extremely low birth weight (ELBW, < 1,000 g) neonates, maternal characteristics [betamethasone, premature preterm rupture of membranes (PPROM), pre-eclampsia, maternal Scr], characteristics at delivery [gestational age (GA), birth weight (BW), small for GA (SGA), Apgar, intubation] and during neonatal stay [ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, intraventricular hemorrhage, retinopathy of prematurity (ROP), phototherapy] were linked with Scr observations. Data were reported by median and range or incidence. Characteristics in ELBW neonates with raised peak Scr (>P75) were compared to controls (P75 (112.3 μmol/l), Scr remained elevated until day 28. Mothers of cases received less betamethasone, neonates had a lower GA, lower BW, lower Apgar, and needed more often intubation. Postnatal ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, ROP, and intraventricular hemorrhage were different. GA and ventilation or Apgar were independent factors for raised peak Scr. ELBW neonates display trends similar to heavier neonates, but peak Scr is higher, and the subsequent decrease slower. Raised creatinemia in ELBW neonates reflects immaturity (GA) and morbidity (ventilation, Apgar). [ABSTRACT FROM AUTHOR]