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Ultrasmall nanoparticles (usNPs) have emerged as promising theranostic tools in cancer nanomedicine. With sizes comparable to globular proteins, usNPs exhibit unique physicochemical properties and physiological behavior distinct from larger particles, including lack of protein corona formation, efficient renal clearance, and reduced recognition and sequestration by the reticuloendothelial system. In cancer treatment, usNPs demonstrate favorable tumor penetration and intratumoral diffusion. Active targeting strategies, incorporating ligands for specific tumor receptor binding, serve to further enhance usNP tumor selectivity and therapeutic performance. Numerous preclinical studies have already demonstrated the potential of actively targeted usNPs, revealing increased tumor accumulation and retention compared to non-targeted counterparts. In this review, we explore actively targeted inorganic usNPs, highlighting their biological properties and behavior, along with applications in both preclinical and clinical settings.

Aims Methods Results Conclusion The ideal dosing weight metric for enoxaparin remains elusive. Dosing remains focused on actual body weight, which may inadvertently increase the risk of bleeding in those with obesity, or ideal weight, which may underdose those with obesity. Our aim was to determine the optimal obesity‐adjusted enoxaparin dosing weight.Multisite retrospective data were collected over a 2.0‐year period for those with minimum 48 h of in‐hospital twice‐daily enoxaparin and factor anti‐Xa level 3–5 h postdose (n = 220). Multiple linear regression calculated the associated variance between a range of nominal dosing weights and factor anti‐Xa levels, adjusted for renal function. Dosing weights were calculated as ideal body weight (IBW) and then adjusted for increasing percentages of weight above IBW, i.e. IBW + 10% above IBW, IBW + 20% etc. up to actual body weight. A similar approach was used for lean body weight (LBW).For body mass index ≥30 kg/m2 optimal variance explained by dosing weight metrics was at IBW + 40% (23%) and similarly for LBW + 40% (23%). Using actual body weight (ABW) had lowest associated variance with factor anti‐Xa levels (18%) followed by unadjusted IBW (13%) or unadjusted LBW (19%). In those with body mass index <30 kg/m2 there was similar associated variance in the ranges of IBW + 20–50% and LBW 10–40% (21%).Compared to IBW + 40% or LBW + 40% use of ABW to calculate dose was poorly associated with factor anti‐Xa levels, as was IBW or LBW. IBW + 40% and LBW + 40% require further study as a dosing weight metric and may provide a more consistent factor anti‐Xa response in those with obesity. [ABSTRACT FROM AUTHOR]

Context Due to the essential role of carnitine as an intermediary in amino acid, carbohydrate, and lipid metabolism, a detailed characterization of circulating and urinary carnitine concentrations will aid in elucidating the molecular basis of impaired maternal metabolic flexibility and facilitating timely intervention for expectant mothers. Objective To investigate the association of maternal plasma and urinary free carnitine and acylcarnitines with cardiometabolic risk factors. Methods Liquid chromatography tandem mass spectrometry–based quantification of free carnitine and acylcarnitines (C2-C18) was performed on 765 plasma and 702 urine samples collected at preconception, 26 to 28 weeks' pregnancy, and 3 months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study. Results Plasma concentrations of free carnitine and acylcarnitines decreased coupled with increased renal clearance in pregnancy compared with preconception and postpartum. Renal clearance of carnitine increased with an increase in prepregnancy body mass index (ppBMI) and gestational weight gain. Plasma short-chain acylcarnitines were positively associated with ppBMI, irrespective of the physiological state, while medium- and long-chain acylcarnitines were negatively associated with ppBMI at preconception and postpartum but showed a positive association in pregnancy. Similarly, plasma short-chain acylcarnitines were positively associated with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) whereas medium- and long-chain acylcarnitines were negatively associated with HOMA-IR at preconception and in pregnancy. Mothers who developed gestational diabetes mellitus during pregnancy had ∼10% higher plasma propionylcarnitine concentration and ∼18% higher urine tiglylcarnitine concentration than mothers with normal glucose metabolism at preconception. Conclusion This study provides the metabolic and physiological basis of maternal carnitine homeostasis, which can be used in assessment of maternal cardiometabolic health at preconception to improve pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Renal‐clearable engineered nanoparticles are being explored for their potential to deliver therapeutic agents for kidney disease treatment. A fundamental understanding of how these nanoparticles accumulate in diseased kidneys at the cellular level is essential to enhance their effectiveness and minimize side effects on adjacent healthy tissues. Herein, we report that the accumulation of glutathione‐coated, near‐infrared emitting gold nanoparticles (GS‐AuNPs) correlates strongly with the necrotic stages of injured proximal tubular cells. Using a rhabdomyolysis‐induced acute kidney injury (AKI) mouse model, we observed that GS‐AuNPs were significantly accumulated in the extracellular lumen of proximal tubular epithelial cells (PTECs) at advanced necrotic stage, where cellular debris and released intracellular contents impeded their clearance. In contrast, during early necrosis, GS‐AuNPs were still cleared through the unobstructed lumen. Additionally, intracellular uptake of GS‐AuNPs was significantly reduced across all necrotic stages. These findings underscore the need for new strategies to design nanoparticles that can effectively target and be taken up by the diseased tubular cells before extensive necrosis occurs; so that nanoparticle‐mediated drug delivery for kidney disease treatment can be achieved with desired efficacy and precision. [ABSTRACT FROM AUTHOR]

Abstract Background The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. Results In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. Conclusions We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis. Graphical Abstract

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)

Background: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. Results: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. Conclusions: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines, which are elevated during inflammation or infections, can affect drug pharmacokinetics (PK) due to the altered expression or activity of drug transporters and/or metabolizing enzymes. To date, such studies have focused on the effect of cytokines on the activity and/or mRNA expression of hepatic transporters and drug-metabolizing enzymes. However, many antibiotics and antivirals used to treat infections are cleared by renal transporters, including the basal organic cation transporter 2 (OCT2), organic anion transporters 1 and 3 (OAT1 and 3), the apical multidrug and toxin extrusion proteins 1 and 2-K (MATE1/2-K), and multidrug resistance-associated protein 2 and 4 (MRP2/4). Here, we determined the concentration-dependent effect of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)-α, and interferon-γ (IFN-γ) on the mRNA expression of human renal transporters in freshly isolated primary human renal proximal tubular epithelial cells (PTECs, n = 3–5). PTECs were exposed to either a cocktail of cytokines, each at 0.01, 0.1, 1, or 10 ng/mL or individually at the same concentrations. Exposure to the cytokine cocktail for 48 h was found to significantly downregulate the mRNA expression, in a concentration-dependent manner, of OCT2, the organic anion transporting polypeptides 4C1 (OATP4C1), OAT4, MATE2-K, P-glycoprotein (P-gp), and MRP2 and upregulate the mRNA expression of the organic cation/carnitine transporter 1 (OCTN1) and MRP3. OAT1 and OAT3 also appeared to be significantly downregulated but only at 0.1 and 10 ng/mL, respectively, without a clear concentration-dependent trend. Among the cytokines, IL-1β appeared to be the most potent at down- and upregulating the mRNA expression of the transporters. Taken together, our results demonstrate for the first time that proinflammatory cytokines transcriptionally dysregulate renal drug transporters in PTECs. Such dysregulation could potentially translate into changes in transporter protein abundance or activity and alter renal transporter-mediated drug PK during inflammation or infections. [ABSTRACT FROM AUTHOR]

PurposeA dataset of fraction excreted unchanged in the urine (fe) values was developed and used to evaluate the ability of preclinical animal species to predict high urinary excretion, and corresponding poor metabolism, in humans.MethodsA literature review of fe values in rats, dogs, and monkeys was conducted for all Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3 and 4 drugs (n=352) and a set of Class 1 and 2 drugs (n=80). The final dataset consisted of 202 total fe values for 135 unique drugs. Human and animal data were compared through correlations, two-fold analysis, and binary classifications of high (fe ≥30%) versus low (

Background: Dose modification of renally secreted drugs in patients with chronic kidney disease (CKD) has relied on serum creatinine concentration as a biomarker to estimate glomerular filtration (GFR) under the assumption that filtration and secretion decline in parallel. A discrepancy between actual renal clearance and predicted renal clearance based on GFR alone is observed in severe CKD patients with tenofovir, a compound secreted by renal OAT1/3. Uremic solutes that inhibit OAT1/3 may play a role in this divergence. Methods: To examine the impact of transporter inhibition by uremic solutes on tenofovir renal clearance, we determined the inhibitory potential of uremic solutes hippuric acid, indoxyl sulfate, and p-cresol sulfate. The inhibition parameters (IC50) were incorporated into a previously validated mechanistic kidney model; simulated renal clearance and plasma PK profile were compared to data from clinical studies. Results: Without the incorporation of uremic solute inhibition, the PBPK model failed to capture the observed data with an absolute average fold error (AAFE) > 2. However, when the inhibition of renal uptake transporters and uptake transporters in the slow distribution tissues were included, the AAFE value was within the pre-defined twofold model acceptance criterion, demonstrating successful model extrapolation to CKD patients. Conclusion: A PBPK model that incorporates inhibition by uremic solutes has potential to better predict renal clearance and systemic disposition of secreted drugs in patients with CKD. Ongoing research is warranted to determine if the model can be expanded to include other OAT1/3 substrate drugs and to evaluate how these findings can be translated to clinical guidance for drug selection and dose optimization in patients with CKD. [ABSTRACT FROM AUTHOR]

Accurate predictions of drug uptake transporter involvement in renal excretion of xenobiotics require determination of in vitro transport kinetic parameters under initial-rate conditions. The purpose of the present study was to determine how changing the incubation time from initial rate to steady state influences ligand interactions with the renal organic anion transporter 1 (OAT1), and the impact of the different experimental conditions on pharmacokinetic predictions. Transport studies were performed with Chinese hamster ovary cells expressing OAT1 (CHO-OAT1) and the Simcyp Simulator was used for physiological-based pharmacokinetic predictions. Maximal transport rate and intrinsic uptake clearance (CLint) for PAH decreased with increasing incubation time. The CLint values ranged 11-fold with incubation times spanning from 15 s (CLint,15s, initial rate) to 45 min (CLint,45min, steady state). The Michaelis constant (Km) was also influenced by the incubation time with an apparent increase in the Km value at longer incubation times. Inhibition potency of five drugs against PAH transport was tested using incubation times of either 15 s or 10 min. There was no effect of time on inhibition potency for omeprazole or furosemide, whereas indomethacin was less potent, and probenecid (~2-fold) and telmisartan (~7-fold) more potent with the longer incubation time. Notably, the inhibitory effect of telmisartan was reversible, albeit slowly. A pharmacokinetic model was developed for PAH using the CLint,15s value. The simulated plasma concentration-time profile, renal clearance, and cumulative urinary excretion-time profile of PAH agreed well with reported clinical data, and the PK parameters were sensitive to the time-associated CLint value used in the model.

Augmented renal clearance (ARC) increases vancomycin (VCM) clearance. Therefore, higher VCM doses are recommended in patients with ARC; however, impacts of ARC on the area under the concentration–time curve (AUC) discrepancies between initial dosing design and therapeutic drug monitoring (TDM) period remains unclear. We retrospectively collected data from critically ill patients treated with VCM. The primary endpoint was the association between ARC and AUC 24–48h deviations. ARC and AUC deviation were defined as a serum creatinine clearance (CCr) ≥130 mL/min/1.73 m2 and an AUC at TDM 30% or more higher than the AUC at the initial dosing design, respectively. The pharmacokinetic profiles of VCM were analyzed with the trough levels or peak/trough levels using the Bayesian estimation software Practical AUC-guided TDM (PAT). Among 141 patients (median [IQR]; 66 [58–74] years old; 30% women), 35 (25%) had ARC. AUC deviations were significantly more frequent in the ARC group than in the non-ARC group (20/35 [57.1%] and 17/106 [16.0%] patients, respectively, p < 0.001). Age- and sex-adjusted multivariate analyses revealed that the number of VCM doses before TDM ≥5 (odds ratio, 2.56; 95% confidence interval [CI]: 1.01–6.44, p = 0.047) and CCr ≥130 mL/min/1.73 m2 were significantly associated with AUC deviations (odds ratio, 7.86; 95%CI: 2.91–21.19, p < 0.001). Our study clarifies that the AUC of VCM in patients with ARC is higher at the time of TDM than at the time of dosage design. [ABSTRACT FROM AUTHOR]

Accurate predictions of drug uptake transporter involvement in renal excretion of xenobiotics require determination of in vitro transport kinetic parameters under initial-rate conditions. The purpose of the present study was to determine how changing the incubation time from initial rate to steady state influences ligand interactions with the renal organic anion transporter 1 (OAT1), and the impact of the different experimental conditions on pharmacokinetic predictions. Transport studies were performed with Chinese hamster ovary cells expressing OAT1 (CHO-OAT1) and the Simcyp Simulator was used for physiological-based pharmacokinetic predictions. Maximal transport rate and intrinsic uptake clearance (CLint) for PAH decreased with increasing incubation time. The CLint values ranged 11-fold with incubation times spanning from 15 s (CLint,15s, initial rate) to 45 min (CLint,45min, steady state). The Michaelis constant (Km) was also influenced by the incubation time with an apparent increase in the Km value at longer incubation times. Inhibition potency of five drugs against PAH transport was tested using incubation times of either 15 s or 10 min. There was no effect of time on inhibition potency for omeprazole or furosemide, whereas indomethacin was less potent, and probenecid (~2-fold) and telmisartan (~7-fold) more potent with the longer incubation time. Notably, the inhibitory effect of telmisartan was reversible, albeit slowly. A pharmacokinetic model was developed for PAH using the CLint,15s value. The simulated plasma concentration-time profile, renal clearance, and cumulative urinary excretion-time profile of PAH agreed well with reported clinical data, and the PK parameters were sensitive to the time-associated CLint value used in the model. [ABSTRACT FROM AUTHOR]

Background: Perfluorooctanoic acid (PFOA) is one of the major per- and polyfluoroalkyl substances. The role of ATP-binding cassette (ABC) transporters in PFOA toxicokinetics is unknown. Methods: In this study, two ABC transporters, ABCB1 and ABCB4, were examined in mice with single intravenous PFOA administration (3.13 µmol/kg). To identify candidate renal PFOA transporters, we used a microarray approach to evaluate changes in gene expression of various kidney transporters in Abcb4 null mice. Results: Biliary PFOA concentrations were lower in Abcb4 null mice (mean ± standard deviation: 0.25 ± 0.12 µg/mL) than in wild-type mice (0.87 ± 0.02 µg/mL). Immunohistochemically, ABCB4 expression was confirmed at the apical region of hepatocytes. However, renal clearance of PFOA was higher in Abcb4 null mice than in wild-type mice. Among 642 solute carrier and ABC transporters, 5 transporters showed significant differences in expression between wild-type and Abcb4 null mice. These candidates included two major xenobiotic transporters, multidrug resistance 1 (Abcb1) and organic anion transporter 3 (Slc22a8). Abcb1 mRNA levels were higher in Abcb4 null mice than in wild-type mice in kidney. In Abcb4 null mice, Abcb1b expression was enhanced in proximal tubules immunohistochemically, while that of Slc22a8 was not. Finally, in Abcb1a/b null mice, there was a significant decrease in the renal clearance of PFOA (0.69 ± 0.21 vs 1.1 mL ± 0.37/72 h in wild-type mice). A homology search of ABCB1 showed that several amino acids are mutated in humans compared with those in rodents and monkeys. Conclusions: These findings suggest that, in the mouse, Abcb4 and Abcb1 are excretory transporters of PFOA into bile and urine, respectively.

Abstract 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 (82Rb) 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 82Rb 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 82Rb 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 K1 kinetic parameter representing renal 82Rb clearance. Day-to-day variation was calculated based on the difference between the unstimulated K1 values on Day A and Day B and paired t-testing was performed to compare K1 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). K1 values determined after amino acid-infusion were significantly higher than pre-infusion values (n = 17, p = 0.001). The mean percentage change in K1 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 K1 increase from baseline is detected after application of a known RBF stimulus, indicating that 82Rb 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.

Abstract 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.

Although radiotherapy has become indispensable for tumor treatment in recent years, the inevitable side effects of high-dose radiation on the normal tissue and deficiency of appropriate radiosensitizers without long-term body retention that do not cause potential toxicity limit further clinical applications to a certain extent. Herein, we rationally synthesized BiOI nanodots coated with M1 macrophage membrane (BiOI@M) by utilizing their coordination interaction. With two high-atomic-number elements and ultrasmall size, the prepared BiOI nanodots not only enhanced radiosensitivity by reactive oxygen species under X-ray irradiation in vitro, but also could be excreted quickly by kidneys. Meanwhile, the M1 macrophage membrane functioned as a highly desirable carrier with long-circulating and tumor-targeting capability. As a result, treatment with as-prepared BiOI@M could improve the therapeutic outcome of radiotherapy in a xenograft mouse model and reduce the potential toxicity of nanoparticles. Simultaneously, BiOI nanodots exhibited excellent CT imaging ability as contrast agents to visualize biodistribution in vivo and to monitor tumor growth. Therefore, our work demonstrated the preparation of a tumor targeting and renal clearable radiosensitizer and offered a potential approach to enhance the radiotherapy efficacy of hepatocellular carcinoma.

The pronephros (early-stage kidney) is an important osmoregulatory organ, and the onset of its function occurs relatively early in some teleost fishes. As such, any defects in kidney development and function are likely associated with a decreased ability to osmoregulate. Previous work has shown that early-life stage (ELS) zebrafish (Danio rerio) acutely exposed to Deepwater Horizon (DWH) crude oil exhibit transcriptional changes in key genes involved in pronephros development and function, as well as pronephric morphological defects and whole-animal osmoregulatory impairment. The objective of this study was to examine the acute effects of crude oil exposure during zebrafish ELS on pronephros function by assessing its fluid clearance capacity and glomerular filtration integrity. Following a 72-h exposure to control conditions, 20% or 40% dilutions of high-energy water-accommodated fractions (HEWAF) of DWH crude oil, zebrafish were injected into the common cardinal vein either with fluorescein-labeled (FITC) 70-kDa dextran to assess glomerular filtration integrity or with FITC-inulin to assess pronephric clearance capacity. Fluorescence was quantified after the injections at predetermined time intervals by fluorescence microscopy. The results demonstrated a diminished pronephric fluid clearance capacity and failed glomerular perfusion when larvae were exposed to 40% HEWAF dilutions, whereas only a reduced glomerular filtration selectivity was observed in zebrafish previously exposed to the 20% HEWAF dilution. [ABSTRACT FROM AUTHOR]

Real-time renal imaging is indispensable for monitoring kidney-related disease processes and evaluating the nephrotoxicity of nanoprobes. Owing to their small size, tunable photoluminescence properties, and low biotoxicity, carbon dots (CDs) are widely employed as nanoprobes for imaging-guided disease diagnosis. However, the preparation of near-infrared CDs is a stupendous challenging. Here, CDs with near-infrared fluorescence (NIR-CDs) were prepared by one-pot pyrolysis and were comprehensively evaluated for real-time renal imaging. The NIR-CDs possessed super-small size (1.8 ± 0.2 nm) and high quantum yield (14.3% in aqueous solution) at 696 nm. NIR-CDs exhibited high-efficiency renal clearance at 24 h post-treatment (97.47–99.27% ID) via glomerular filtration. The irreversible clearance of NIR-CDs enables effective real-time monitoring of kidney function in the normal and acute kidney injury (AKI) mouse models. Consequently, NIR-CDs can be utilized for imaging analyses of impaired kidney function, pioneering a serviceable guideline for neoapplications of NIR-CDs. [Display omitted] [ABSTRACT FROM AUTHOR]

Renal clearance is critical for nanodrug to avoid the long‐term body retention‐related side effects, while it is difficult to achieve efficient tumor accumulation and retention. The over‐developed lysosomes in cancer cells have become an emerging target for more precise and effective cancer therapy. Herein, a pH‐responsive reversible self‐assembled Cu2‐xSe‐BSA, which can be renal cleared under neutral or basic conditions, is developed for selectively targeted aggregation in cancer lysosomes with enhanced tumor accumulation and retention. Moreover, the aggregation of Cu2‐xSe‐BSA can enhance the photoacoustic imaging signal, photothermal therapy, and chemodynamic therapy capability. Cu2‐xSe‐BSA accumulated in lysosomes cannot only induce lysosomes swelling, but also generate reactive oxygen species in situ, causing lysosomal membrane permeabilization and finally lysosomal cell death. Notably, the assembled Cu2‐xSe‐BSA can dissociate to be renal clearable after the treatments are completed and left the acid tumor microenvironment, being of great significance both in scientific research and clinical trial. [ABSTRACT FROM AUTHOR]

Masked cryptic kidney injury (MCKI), an early stage of acute kidney injury (AKI), is challenging to detect and diagnose, especially in the modern context where toxic substances, such as surfactants, are increasingly misused. Consequently, there is an urgent need for methods for the visual diagnosis of MCKI. In this study, we synthesized environmentally friendly spirulina-derived carbon dots (SpiCDs) using spirulina as a biobased raw material through a simple hydrothermal process. These SpiCDs, with their ultrasmall size, enable efficient renal clearance. In cellular experiments, SpiCDs rapidly entered SDS-damaged cells, facilitating dynamic monitoring of the cell membrane damage process. In vivo animal experiments demonstrated that SpiCDs were efficiently excreted through the kidneys and began to accumulate in the bladder within 10 min after tail vein injection. The detection of red fluorescence in excreted urine confirmed the renal metabolic pathway of the SpiCDs. Furthermore, in an MCKI model induced by SDS, SpiCDs showed accelerated excretion and earlier accumulation in the bladder, indicating an increased sensitivity to kidney injury. These results suggest that SpiCDs provide a promising approach for the early diagnosis of MCKI, offering insights into its visual detection and monitoring.

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 (82Rb) 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 82Rb 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 82Rb 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 K1 kinetic parameter representing renal 82Rb clearance. Day-to-day variation was calculated based on the difference between the unstimulated K1 values on Day A and Day B and paired t-testing was performed to compare K1 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). K1 values determined after amino acid-infusion were significantly higher than pre-infusion values (n = 17, p = 0.001). The mean percentage change in K1 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 K1 increase from baseline is detected after application of a known RBF stimulus, indicating that 82Rb 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. [ABSTRACT FROM AUTHOR]

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. Iron is an essential metal nutrient, but excess iron produces toxic effects that damage multiple organs including the heart, liver and pancreas. Deferoxamine (DFO) is a US FDA-approved drug for treating iron overload, but its use is limited by serious adverse effects and an inconvenient daily dose scheme. The recent development of a DFO-based nanomedicine (DFO-NP) has shown promise in treating iron overload in animals and was safer in animals. Before this new drug can be given to humans, how it is absorbed into the body, processed in the body and removed from the body when given in different amounts and dose routes must be determined. In this study, we tested the absorption, distribution and removal of DFO-NPs after intravenous and subcutaneous injection in rats. This study showed that DFO-NPs behave differently when changing the dose and that subcutaneous injection makes the drug stay in the body longer without ill effect, which means it could be given to patients this way. [ABSTRACT FROM AUTHOR]

Abstract Background As we know, radiotherapy plays an irreplaceable role in the clinical management on solid tumors. However, due to the non-specific killing effects of ionizing radiation, normal tissues damages would be almost simultaneous inevitably. Therefore, ideal radioprotective agents with high efficiency and low toxicity are always desirable. In this work, atomically precise Ag14 clusterzymes were developed, and their applications in radioprotection were studied in vitro and in vivo for the first time. Methods The ultra-small glutathione supported Ag14 clusterzymes were synthesized by convenient sodium borohydride (NaBH4) reduction of thiolate-Ag (I) complexes and then they were purified by desalting columns. The enzyme-like activity and antioxidant capacity of Ag14 clusterzymes have been tested by various commercial kits, salicylic acid method and electron spin resonance (ESR). Next, they were incubated with L929 cells to evaluate whether they could increase cell viability after γ-ray irradiation. And then Ag14 clusterzymes were intravenously injected into C57 mice before 7 Gy whole-body γ-ray irradiation to evaluate the radioprotection effects in vivo. At last, the in vivo toxicities of Ag14 clusterzymes were evaluated through biodistribution test, hematological details, serum biochemical indexes and histological test in female Balb/c mice with intravenous injection of Ag14 clusterzymes. Results Our studies suggested atomically precise Ag14 clusterzymes were potential radioprotectants. Ag14 clusterzymes exhibited unique superoxide dismutase (SOD)-like activity, strong anti-oxidative abilities, especially on •OH scavenging. The Ag14 clusterzymes could effectively improve cell viability through eliminating ROS and prevent DNA damages in cells dealt with γ-ray irradiation. In vivo experiments showed that Ag14 clusterzymes could improve the irradiated mice survival rate by protecting hematological systems and repairing tissue oxidative stress damage generated by γ-ray irradiation. In addition, bio-distribution and toxicological experiments demonstrated that the ultrasmall Ag14 clusterzymes could be excreted quickly from the body by renal clearance and negligible toxicological responses were observed in mice up to 30 days. Conclusion In summary, atomically precise, ultrasmall and water soluble Ag14 clusterzymes with SOD-like activity were successfully developed and proved to be effective both in vitro and in vivo for radioprotection. Furthermore, with atomically precise molecular structure, Ag14 clusterzymes, on aspect of the catalytic and optical properties, may be improved by structure optimization on atom-scale level for other applications in disease diagnosis and treatment. Graphical Abstract

Nano calcium phosphate (nCaP), a bone mineral in mammals, shows a promising prospect in biomedicine. Herein, we report a biomimetic mineralization strategy, based on stoichiometric polyacrylic acid (PAA) complexation-precipitation process, to facilitate the development of nCaP as bioimaging agents. As a result, the monodisperse and sub-10 nm europium-doped calcium phosphate nanodots (PAA-Eu:CaP NDs) is controllably obtained with enhanced fluorescence properties, tumor passive targeting and bioimaging ability. Compared with europium-doped calcium phosphate nanoparticles (Eu:CaP NPs), the fluorescence emission, quantum yield and lifetime of PAA-Eu:CaP NDs are significantly improved up to 3.84, 4.48 and 5.59 times, respectively. Deriving from the synergy of surface effect and organic/inorganic hybrid crystal field effect, such CaP matrix brings to local asymmetry environment and distinguished anti-quenching for Eu3+ ion. The strongest radiance signal is improved to 117 % for in vivo imaging; moreover, the tumor accumulation is obviously increased to 5.15 times, and 7.09 times for tumor permeability. The accumulation is decreased 80.2 %, 79.4 % and 70.2 % in liver, spleen and lung suggesting lower clearance by mononuclear phagocyte system, while it’s increased up to 15.4 times in kidney indicating higher renal clearance. Eventually, it’s convinced that this study can provide help for promoting CaP application in nanomedicine.

Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s−1 cm−5, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s−1 cm−5, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.

ObjectivesTo determine the potential effect of substituting glomerular filtration rate (GFR) estimates for renal clearance estimated using the Cockcroft-Gault method (CrCL-CG) to calculate direct oral anticoagulant (DOAC) dosing.DesignSimulation and retrospective data analysis.SettingCommunity, academic institution, nursing home.ParticipantsNoninstitutionalized individuals aged 19 to 80 from the National Health and Nutrition Examination Survey (NHANES) (2011/12) (n = 4,687) and medically stable research participants aged 25 to 105 (n = 208).MeasurementsAge, height, weight, sex, race, serum creatinine, CrCL-CG, and GFR (according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations). Outcome measures were dosing errors if GFR were to be substituted for CrCL-CG.ResultsRenal clearance estimates according to all methods were highly correlated (P < .001), although at lower clearances, substitution of GFR estimates for CrCL-CG resulted in failure to recognize needs for dose reductions of rivaroxaban or edoxaban in 28% of NHANES subjects and 47% to 56% of research subjects. At a CrCL-CG of less than 30 mL/min, GFR estimates missed indicated dosage reductions for dabigatran in 18% to 21% of NHANES subjects and 57% to 86% of research subjects. Age and weight contributed to differences between renal clearance estimates (P < .001), but correction of GFR for body surface area (BSA) did not reduce dosing errors. At a CrCL-CG greater than 95 mL/min, edoxaban is not recommended, and GFR esimates misclassified 24% of NHANES and 39% of research subjects. Correction for BSA reduced misclassification to 7% for NHANES and 14% in research subjects.ConclusionSubstitution of GFR estimates for estimated CrCl can lead to failure to recognize indications for reducing DOAC dose and potentially higher bleeding rates than in randomized trials.

Renal clearance is one of the main pathways for a drug to be cleared from plasma. The aim of this study is to develop in-silico models to find out the relationship between the type of renal clearance, and structural parameters. Literature data were used to categorise the drugs into those that undergo tubular secretion and those that undergo reabsorption. Different structural descriptors (VolSurf descriptors, Abraham solvation parameters, data warrior descriptors, logarithm of distribution coefficient at pH = 7.4 (logD7.4)) were applied to develop a mechanistic model for estimating renal clearance class whether its secretion or reabsorption. The results of this study show that logD7.4 and the number of hydrogen bond donors, as well as available uncharged species (AUS7.4), are the most effective descriptors to establish mechanistic models for predicting renal clearance class. The classification models were established with a level of accuracy of more than 75%. Developed models of this study can be helpful to predict renal clearance class for new drug candidates with an acceptable error. Hydrophilicity and hydrogen bond formation ability of drugs are among the main descriptors. [ABSTRACT FROM AUTHOR]

Stimuli‐responsive nanoagents, which simultaneously satisfy normal tissue clearance and tumor‐specific responsive treatment, are highly attractive for precise cancer theranostics. Herein, we develop a unique template‐induced self‐assembly strategy for the exquisitely controlled synthesis of self‐assembled lanthanide (Ln3+) nucleotide nanoparticles (LNNPs) with amorphous structure and tunable size from sub‐5 nm to 105 nm. By virtue of the low‐temperature (10 K) and high‐resolution spectroscopy, the local site symmetry of Ln3+ in LNNPs is unraveled for the first time. The proposed LNNPs are further demonstrated to possess the ability for highly efficient loading and tumor‐microenvironment‐responsive release of doxorubicin. Particularly, sub‐5 nm LNNPs not only exhibit excellent biocompatibility and predominant renal‐clearance performance, but also enable efficient tumor retention. These findings reveal the great potential of LNNPs as a new generation of therapeutic platform to overcome the dilemma between efficient therapy and long‐term toxicity of nanoagents for future clinical applications. [ABSTRACT FROM AUTHOR]

Abstract Purpose Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA0,TYR3-octreotate ([177Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in female Lewis rats. Methods Animals received 200 MBq of [177Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [177Lu]Lu-DOTA-TATE; group 4, everolimus + [177Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS). Results Rats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [177Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [99mTc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups. Conclusion Renal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [177Lu]Lu-DOTA-TATE.

The mononuclear phagocytic system clears the circulating inorganic nanomaterials from the bloodstream, which raises concerns about the chronic toxicity of the accumulated metal species. A better understanding of the behavior of each metal after systemic injection is thus required for clinical translations. This study investigates the significance of the metal-ligand interaction on the accumulation of cerium and demonstrates that only the form in which cerium is coordinated to a multidentate chelator with a strong binding affinity does not accumulate in major organs. Specifically, cerium complexed with diethylenetriamine pentaacetic acid (DTPA) forms renally excretable nanoparticles in vivo to circumvent the leaching of cerium ions, whereas weakly coordinated cerium-based nanomaterials produce insoluble precipitates upon encountering physiological phosphate anions. Ceria-based renally clearable nanoparticles (CRNs) derived from cerium-DTPA are utilized as the antioxidant pair with iron-DTPA, in which their combination leverages the Fenton reaction to synergistically scavenge hydrogen peroxide. This reduces the gene expression of pro-inflammatory factors in the macrophages activated with lipopolysaccharide as well as improves the survival rate of septic mice by alleviating the systemic inflammatory response and its downstream tissue injury in the liver, spleen, and kidneys. This study demonstrates that CRNs combined with iron-DTPA can be utilized as nonaccumulative nanomedicines for treating systemic inflammation, thereby overcoming the limitations of conventional ceria nanoparticle-based treatments.

Objective: This study aimed to investigate the relationship between procalcitonin (PCT) kinetic and estimated glomerular filtration rates (eGFR) in critically ill patients who had Gram-negative primary bloodstream infection (GN-BSI) and responded to the antimicrobial therapy., Materials and Methods: This single-centered study was retrospective and observational. Critically ill GN-BSI patients over 18 years old who had clinical and microbiological responses to antibiotic treatment were included in the study. Patients were divided into two groups according to eGFR (eGFR <30 mL/min/1.73m 2 and ≥30 mL/min/1.73m 2 ) and compared for PCT kinetic at seven different measurement points as initial, first, third, fifth, seventh, tenth, and fourteenth days., Results: The study included 138 patients. Initial PCT levels were higher in patients with eGFR <30 mL/min/1.73m 2 (4.58 [1.36-39.4] ng/mL) than in eGFR ≥30 mL/min/1.73m 2 (0.91 [0.32-10.2]) ( p <0.001). This elevation was present at all measurement points ( p <0.05). The decrease in PCT values by ≥30% (26.0% vs 47.9%; p =0.024) on the third day and ≥50% (69.2% vs 76.6%; p =0.411) on the fifth day was less in the low eGFR (<30 mL/min/1.73m 2 ) group. The effect of low GFR on serum PCT kinetic was present in both fermenter and non-fermenter GN-BSIs but was more prominent in the fermenter group., Conclusion: Serum PCT levels during therapy were higher in patients with low eGFR. Early PCT (<5 days) response was not obtained in non-fermenter GN-BSI patients with low eGFR. Antibiotic revision decisions should be made more carefully in patients with low eGFR due to high initial PCT levels and slow PCT kinetic., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Infectious Diseases and Clinical Microbiology.)

Modulation of the transport-mediated active uptake by human serum albumin (HSA) for highly protein-bound substrates has been reported and improved the in vitro -to- in vivo extrapolation (IVIVE) of hepatic clearance. However, evidence for the relevance of such a phenomenon in the case of renal transporters is sparse. In this study, transport of renal organic anion transporter 1 or 3 (OAT1/3) substrates into conditionally immortalized proximal tubular epithelial cells transduced with OAT1/3 was measured in the presence and absence of 1 and 4% HSA while keeping the unbound substrate concentration constant (based on measured fraction unbound, f u,inc ). In the presence of 4% HSA, the unbound intrinsic active uptake clearance (CL int,u,active ) of six highly protein-bound substrates increased substantially relative to the HSA-free control (3.5- to 122-fold for the OAT1 CL int,u,active , and up to 28-fold for the OAT3 CL int,u,active ). The albumin-mediated uptake effect (fold increase in CL int,u,active ) was more pronounced with highly bound substrates compared to no effect seen for weakly protein-bound substrates adefovir (OAT1-specific) and oseltamivir carboxylate (OAT3-specific). The relationship between OAT1/3 CL int,u,active and f u,inc agreed with the facilitated-dissociation model; a relationship was established between the albumin-mediated fold change in CL int , u,active OAT1/3 expression were applied for IVIVE of renal clearance. The inclusion of HSA improved the bottom-up prediction of the level of OAT1/3-mediated secretion and renal clearance (CL f u,inc for both the OAT1 and OAT3, with implications for IVIVE modeling. The relative activity factor and the relative expression factor based on global proteomic quantification of in vitro OAT1/3 expression were applied for IVIVE of renal clearance. The inclusion of HSA improved the bottom-up prediction of the level of OAT1/3-mediated secretion and renal clearance (CL sec and CL r ), in contrast to the underprediction observed with the control (HSA-free) scenario. For the first time, this study confirmed the presence of the albumin-mediated uptake effect with renal OAT1/3 transporters; the extent of the effect was more pronounced for highly protein-bound substrates. We recommend the inclusion of HSA in routine in vitro OAT1/3 assays due to considerable improvements in the IVIVE of CL sec and CL r .

Per the well‐known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment‐naïve and lamivudine‐resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open‐label, single‐dose parallel‐group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration‐time curves of LB80331 increased by 1.5‐, 2.5‐, and 4.5‐fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8‐, 3.2‐, and 6.2‐fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment. [ABSTRACT FROM AUTHOR]

We report that inverted iron oxide nanoparticles (i-IONPs) have great potential for musculoskeletal imaging, which is one of the fastest-growing fields in MRI. Upon intra-articular injection, i-IONPs provide positive T1 values and decent soft tissue contrast effects, allowing a clear visualization of complex anatomical details of the joint. i-IONPs show substantially stronger and longer-lasting T1 contrast effects than clinical gadolinium-based contrast agents. In addition, i-IONPs are completely eliminated from the joint cavity without accumulation or harmful effects and are excreted from body through a renal clearance route. [ABSTRACT FROM AUTHOR]

[Display omitted] Nanomedicine has grown structurally complex in order to perform multiple tasks at a time. However, their unsatisfied reliability, uniformity and reproducibility account for the high rates of attrition in translational research. So far, most studies have been one-sidedly focused on the treatment efficacy of inorganic nanoparticles as cancer therapeutics, but overlook their elimination from the body – a key factor in getting regulatory approval. Instead of developing a new drug nanocarrier with uncertain future in medical practice, we therefore choose to leverage the utility of promising and translatable gold nanoclusters (AuNCs) for designing a simple but robust "all-in-one" nanocluster drug delivery system, where the AuNCs not only strengthen the renal clearance of neutral red (NR) as a model drug, but also aid its passive tumor targeting via the enhanced permeability and retention (EPR) effect. More interestingly, NR can stimulate the production of reactive oxygen species (ROS) to suppress tumor growth under ultralow-level radiation with a smartphone's torch (fluence rate: 8 mW/cm2). This finding is especially valuable to low- and middle-income countries lacking resources in healthcare settings. By means of first-principles simulations, we also study in-depth the energies, structural and electronic properties of the AuNCs emitting in the second near-infrared window (NIR-II, 1000–1700 nm). In brief, our model fulfills safety, effectiveness and cost-effectiveness requirements for translational development. [ABSTRACT FROM AUTHOR]

Background: As we know, radiotherapy plays an irreplaceable role in the clinical management on solid tumors. However, due to the non-specific killing effects of ionizing radiation, normal tissues damages would be almost simultaneous inevitably. Therefore, ideal radioprotective agents with high efficiency and low toxicity are always desirable. In this work, atomically precise Ag14 clusterzymes were developed, and their applications in radioprotection were studied in vitro and in vivo for the first time. Methods: The ultra-small glutathione supported Ag14 clusterzymes were synthesized by convenient sodium borohydride (NaBH4) reduction of thiolate-Ag (I) complexes and then they were purified by desalting columns. The enzyme-like activity and antioxidant capacity of Ag14 clusterzymes have been tested by various commercial kits, salicylic acid method and electron spin resonance (ESR). Next, they were incubated with L929 cells to evaluate whether they could increase cell viability after γ-ray irradiation. And then Ag14 clusterzymes were intravenously injected into C57 mice before 7 Gy whole-body γ-ray irradiation to evaluate the radioprotection effects in vivo. At last, the in vivo toxicities of Ag14 clusterzymes were evaluated through biodistribution test, hematological details, serum biochemical indexes and histological test in female Balb/c mice with intravenous injection of Ag14 clusterzymes. Results: Our studies suggested atomically precise Ag14 clusterzymes were potential radioprotectants. Ag14 clusterzymes exhibited unique superoxide dismutase (SOD)-like activity, strong anti-oxidative abilities, especially on •OH scavenging. The Ag14 clusterzymes could effectively improve cell viability through eliminating ROS and prevent DNA damages in cells dealt with γ-ray irradiation. In vivo experiments showed that Ag14 clusterzymes could improve the irradiated mice survival rate by protecting hematological systems and repairing tissue oxidative stress damage generated by γ-ray irradiation. In addition, bio-distribution and toxicological experiments demonstrated that the ultrasmall Ag14 clusterzymes could be excreted quickly from the body by renal clearance and negligible toxicological responses were observed in mice up to 30 days. Conclusion: In summary, atomically precise, ultrasmall and water soluble Ag14 clusterzymes with SOD-like activity were successfully developed and proved to be effective both in vitro and in vivo for radioprotection. Furthermore, with atomically precise molecular structure, Ag14 clusterzymes, on aspect of the catalytic and optical properties, may be improved by structure optimization on atom-scale level for other applications in disease diagnosis and treatment. [ABSTRACT FROM AUTHOR]

We compared the regulation of the NaCl cotransporter (NCC) in adaptation to a low-K (LK) diet in male and female mice. We measured hydrochlorothiazide (HCTZ)-induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK), and fractional (FENa, FEK) excretion in male and female mice on control-K (CK, 1% KCl) and LK (0.1% KCl) diets for 7 days. With CK, NCC-dependent ENa and FENa were larger in females than males as observed previously. However, with LK, HCTZ-induced ENa and FENa increased in males but not in females, abolishing the sex differences in NCC function as observed in CK group. Despite large diuretic and natriuretic responses to HCTZ, EK was only slightly increased in response to the drug when animals were on LK. This suggests that the K-secretory apparatus in the distal nephron is strongly suppressed under these conditions. We also examined LK-induced changes in Na transport protein expression by Western blotting. Under CK conditions females expressed more NCC protein, as previously reported. LK doubled both total (tNCC) and phosphorylated NCC (pNCC) abundance in males but had more modest effects in females. The larger effect in males abolished the sex-dependence of NCC expression, consistent with the measurements of function by renal clearance. LK intake did not change NHE3, NHE2, or NKCC2 expression, but reduced the amount of the cleaved (presumably active) form of γENaC. LK reduced plasma K to lower levels in females than males. These results indicated that males had a stronger NCC-mediated adaptation to LK intake than females. [ABSTRACT FROM AUTHOR]

Background: Accurate, precise and straightforward methods for measuring glomerular filtration rate (GFR) and/or renal plasma flow (RPF) are still in demand today. The time‐consuming constant infusion technique (CIT) is the gold standard and preferred for research, whereas the simple, but less precise, single injection technique (SIT) is used in clinical settings. This study investigated the use of 99mTc‐DTPA and 99mTc‐MAG3 by CIT as a measure of renal function. We developed and evaluated a model to balance the primer dose and infusion rate in an attempt to obtain plasma steady state as quickly as possible. Methods: 14 healthy subjects received 99mTc‐DTPA and 6 hypertensive patients received 99mTc‐MAG3 in a standardized protocol. All participants had an eGFR above 60 ml/min and none had fluid retention. An intravenous primer injection of the relevant tracer was followed by a sustained infusion over 4.5 h with the same radiopharmaceutical. Blood and urine samples were collected at fixed intervals. Results: 99mTc‐DTPA clearance reached steady state after 210 min (plasma clearance 78 ± 18 ml/min, urine clearance 110 ± 28 ml/min), whereas 99mTc‐MAG3 clearance achieved steady state after 150 min (plasma clearance 212 ± 56 ml/min, urine clearance 233 ± 59 ml/min). Conclusion: Constant infusion technique with fixed primer and infusion rate using 99mTc‐MAG3 is feasible for research purposes. The longer time for reaching plasma steady state using 99mTc‐DTPA makes CIT with this tracer less optimal. If the primer/sustained balance can be optimized, for example using a priori SIT information, 99mTc‐DTPA as tracer for CIT may also be feasible. [ABSTRACT FROM AUTHOR]

Glomerular filtration rate (GFR) is a key index of renal function. The classic method for assessing GFR is the clearance of inulin. Several current methods using isotopic (125I-iothalamate, 51Cr-EDTA, or 99Tc-DTPA) or nonisotopic (iohexol or iothalamate) markers are available. Clinically, GFR is estimated (eGFR) from serum creatinine or cystatin C levels. Estimated GFR based on creatinine and/or cystatin are less accurate than measured GFR. The creatinine-based equations calculate higher eGFR values (suggesting better kidney function) for black individuals. This upward adjustment for all black individuals is embedded in eGFR calculations on the belief of higher serum creatinine concentrations among black individuals than among white individuals. Thus "race-corrected" eGFR has become a widely accepted and scientifically valid procedure. However, race is not a genetic or biological category. Rather, race is a social construction defined by region-specific cultural and historical ideas. Furthermore, there is no accepted scientific method for classifying people as black or white individuals. Studies typically rely on self-identification of race. However, any person in the United States with any known black ancestry is considered to be a black individual. This is known as the "one-drop rule," meaning that a single drop of "black blood" makes anyone a black individual. It does not matter if an individual has 50%, 25%, 5%, or 0.5% African ancestry. The limited accuracy and reliability of this approach would not be allowed for any other scientific variable. Admixture and migration have produced such broad variations that race categories should not be used as experimental variables. [ABSTRACT FROM AUTHOR]

Per - and poly-fluoroalkyl substances (PFAS) have a wide range of elimination half-lives (days to years) in humans, thought to be in part due to variation in proximal tubule reabsorption. While human biomonitoring studies provide important data for some PFAS, renal clearance (CL renal) predictions for hundreds of PFAS in commerce requires experimental studies with in vitro models and physiologically-based in vitro -to- in vivo extrapolation (IVIVE). Options for studying renal proximal tubule pharmacokinetics include cultures of renal proximal tubule epithelial cells (RPTECs) and/or microphysiological systems. This study aimed to compare CL renal predictions for PFAS using in vitro models of varying complexity (96-well plates, static 24-well Transwells and a fluidic microphysiological model, all using human telomerase reverse transcriptase-immortalized and OAT1-overexpressing RPTECs combined with in silico physiologically-based IVIVE. Three PFAS were tested: one with a long half-life (PFOS) and two with shorter half-lives (PFHxA and PFBS). PFAS were added either individually (5 μM) or as a mixture (2 μM of each substance) for 48 h. Bayesian methods were used to fit concentrations measured in media and cells to a three-compartmental model to obtain the in vitro permeability rates, which were then used as inputs for a physiologically-based IVIVE model to estimate in vivo CL renal. Our predictions for human CL renal of PFAS were highly concordant with available values from in vivo human studies. The relative values of CL renal between slow- and faster-clearance PFAS were most highly concordant between predictions from 2D culture and corresponding in vivo values. However, the predictions from the more complex model (with or without flow) exhibited greater concordance with absolute CL renal. Overall, we conclude that a combined in vitro-in silico workflow can predict absolute CL renal values, and effectively distinguish between PFAS with slow and faster clearance, thereby allowing prioritization of PFAS with a greater potential for bioaccumulation in humans. • Some PFAS can bioaccumulate in humans, in part due to slow renal clearance CL renal. • We test use of 2D culture and MPS models to measure CL renal for three PFAS. • Combined with physiologically-based IVIVE, we can accurately predict CL renal. • Our in vitro-in silico workflow can prioritize PFAS that bioaccumulate in humans. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Lead (Pb) remains an apparently indispensable material in several industrial processes. It is a potent environmental toxin with associated deleterious biological effects. The study investigated the effects of aqueous garlic extract (AGE) on renal clearance and proteinuria in Wistar rats with Pb-induced kidney injury. Methods Thirty male Wistar rats were divided into six groups of five rats each such that exposure to Pb (35 mg/kg i.p) for 10 consecutive days was either followed by 30 days recovery period (without treatment) or 30 days post-treatment with oral graded doses of AGE at 100, 200 and 400 mg/kg while comparisons where made against a control (2 ml/kg NORMAL SALINE) at p