Pharmacokinetics of Vancomycin in Healthy Korean Volunteers and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients with Normal Renal Function.

Background/Objectives: To date, population pharmacokinetic (PK) studies of vancomycin on healthy Korean adults have not been conducted. This study aimed to investigate the PK properties of vancomycin in healthy volunteers and to identify optimal dosing regimens based on the area under the concentration-time curve (AUC) in adult patients with normal renal function. Methods: We conducted a prospective clinical study, analysing PK samples from 12 healthy participants using noncompartmental analysis and non-linear mixed-effects modelling. The population PK parameters derived were employed in Monte Carlo simulations to evaluate the adequacy of the current dosing regimen and to formulate dosing recommendations. Results: The PK profiles were optimally described by a two-compartment model, with body weight and age as significant covariates affecting total clearance. The simulations indicated that to achieve a therapeutic target-defined as an AUC at steady-state over 24 h of 400-600 mg·h/L-daily doses ranging from 60 to 70 mg/kg are necessary in adults with normal renal function. Conclusions: This study underscores the need to actively adjust dosage and administration based on a vancomycin PK model that adequately reflects the demographic characteristics of patients to meet both safety and efficacy standards.

Predicting long-term mortality of patients with postoperative acute kidney injury following noncardiac general anesthesia surgery using machine learning.

Background: This study addresses the gap in knowledge regarding the long-term mortality implications of postoperative acute kidney injury (PO-AKI) utilizing advanced machine learning techniques to predict outcomes more accurately than traditional statistical models. Methods: A retrospective cohort study was conducted using data from seven institutions between March 2009 and December 2019. Machine learning models were developed to predict all-cause mortality of PO-AKI patients using 23 preoperative variables and one postoperative variable. Model performance was compared to a traditional statistical approach with Cox regression analysis. The concordance index was used as a predictive performance metric to compare prediction capabilities among different models. Results: Among 199,403 patients, 2,105 developed PO-AKI. During a median follow-up of 144 months (interquartile range, 99.61-170.71 months), 472 in-hospital deaths occurred. Subjects with PO-AKI had a significantly lower survival rate than those without PO-AKI (p < 0.001). For predicting mortality, the XGBoost with an accelerated failure time model had the highest concordance index (0.7521), followed by random survival forest (0.7371), multivariable Cox regression model (0.7318), survival support vector machine (0.7304), and gradient boosting (0.7277). Conclusion: XGBoost with an accelerated failure time model was developed in this study to predict long-term mortality associated with PO-AKI. Its performance was superior to conventional models. The application of machine learning techniques may offer a promising approach to predict mortality following PO-AKI more accurately, providing a basis for developing targeted interventions and clinical guidelines to improve patient outcomes.

Precision Dosing of Meropenem in Adults with Normal Renal Function: Insights from a Population Pharmacokinetic and Monte Carlo Simulation Study.

This study aimed to develop a population pharmacokinetic (PK) model for meropenem in healthy adults and explore optimal dosing regimens for patients with normal renal function. PK samples were obtained from 12 healthy participants, which were analyzed using noncompartmental analysis and nonlinear mixed-effect modeling. The PK profiles of meropenem were characterized using a two-compartment model, and serum creatinine level was identified as a significant covariate affecting total clearance. Monte Carlo simulations were conducted using this model to inform dosing recommendations. The target index for meropenem efficacy was defined as the cumulative percentage over 24 h during which free (f) drug concentration exceeded the minimum inhibitory concentration (MIC) under steady state conditions (fT>MIC). These simulations indicated that the current dosage regimen of 1 g for 30 min infusions every 8 h achieved a 90% probability of target attainment (PTA) for 40%fT>MIC when the MIC was <2 mg/L. However, to achieve more stringent therapeutic targets, such as a 90%PTA for 100%fT>MIC or a 90%PTA for 100%fT>4MIC, higher doses administered as 3 h extended infusions or as continuous infusions may be necessary. These results highlight the need for model-informed precision dosing to enhance the efficacy of meropenem therapy across various MIC levels and therapeutic targets.

The Impairment of Endothelial Autophagy Accelerates Renal Senescence by Ferroptosis and NLRP3 Inflammasome Signaling Pathways with the Disruption of Endothelial Barrier.

Autophagy is a cellular process that degrades damaged cytoplasmic components and regulates cell death. The homeostasis of endothelial cells (ECs) is crucial for the preservation of glomerular structure and function in aging. Here, we investigated the precise mechanisms of endothelial autophagy in renal aging. The genetic deletion of Atg7 in the ECs of Atg7flox/flox;Tie2-Cre mice accelerated aging-related glomerulopathy and tubulointerstitial fibrosis. The EC-specific Atg7 deletion in aging mice induced the detachment of EC with the disruption of glomerular basement membrane (GBM) assembly and increased podocyte loss resulting in microalbuminuria. A Transwell co-culture system of ECs and kidney organoids showed that the iron and oxidative stress induce the disruption of the endothelial barrier and increase vascular permeability, which was accelerated by the inhibition of autophagy. This resulted in the leakage of iron through the endothelial barrier into kidney organoids and increased oxidative stress, which led to ferroptotic cell death. The ferritin accumulation was increased in the kidneys of the EC-specific Atg7-deficient aging mice and upregulated the NLRP3 inflammasome signaling pathway. The pharmacologic inhibition of ferroptosis with liproxstatin-1 recovered the disrupted endothelial barrier and reversed the decreased expression of GPX4, as well as NLRP3 and IL-1ß, in endothelial autophagy-deficient aged mice, which attenuated aging-related renal injury including the apoptosis of renal cells, abnormal structures of GBM, and tubulointerstitial fibrosis. Our data showed that endothelial autophagy is essential for the maintenance of the endothelial barrier during renal aging and the impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways. These processes may be attractive therapeutic targets to reduce cellular injury from renal aging.

Mortality in patients receiving renal replacement therapy in South Korea.

Background: This study analyzed data from the end-stage renal disease patient registry collected by the Korean Society of Nephrology to explore trends in mortality among dialysis patients from 2001 to 2022. Methods: Mortality was analyzed in two ways: firstly, using the annual mortality rate; and secondly, by assessing survivability after a certain period of time since the initiation of dialysis. Additionally, we categorized the causes of death by disease group annually to observe how the proportions changed. Results: Since 2001, annual mortality for dialysis patients generally declined, except for a rise in 2020 and 2021 among hemodialysis patients. Overall mortality rates for all dialysis patients dropped from 74.2/1,000 person-years in 2001 to 42.3/1,000 person-years in 2022, with a more pronounced decrease in peritoneal dialysis. While survival probability over the 5 years following initiation of dialysis has shown a steady increase, short-term mortality from 2018 to 2020 affected by coronavirus disease 2019 (COVID-19) has shown a yearly increase by age group, with a greater effect in those aged 75 years and older. The leading causes of death for all dialysis patients have changed little, in the order of heart disease, infection, and vascular problems. Conclusion: While annual mortality and survival probability after dialysis initiation have generally improved in dialysis patients, there has been a temporary deterioration during the COVID-19 pandemic, most pronounced in the elderly.

A Rare Case of Stroke in a 76-Year-Old Woman: Left Atrial Papillary Fibroelastoma as the Culprit.

BACKGROUND Papillary fibroelastoma is the most common type of benign primary cardiac tumor and is usually asymptomatic. However, tumor fragments or surface thrombus can embolize and cause transient ischemic attacks, strokes, or myocardial infarction. This report describes a 76-year-old woman who presented with dysarthria and right-sided weakness due to a stroke associated with a left atrial papillary fibroelastoma. CASE REPORT A 76-year-old woman visited the Emergency Department because she had right-sided weakness and dysarthria from 12 h ago. Brain magnetic resonance image was done at the Emergency Department, showing multiple small embolic, acute infarction in left basal ganglia and fronto-temporo-parietal lobes. Transthoracic and transesophageal echocardiogram showed a hypermobile echogenic mass (0.8×1.5 cm) with villous surface on the orifice of left atrial appendage. Twenty-four-hour Holter monitoring was performed to evaluate the cause of cerebral infarction, and there was no paroxysmal atrial fibrillation. Thoracic computed tomography angiography also showed a sea anemone-shaped mass around the left atrial appendage. Cardiac tumor excision was done via a lower partial sternotomy. Histopathologic analysis showed multiple delicate fronds, and the avascular fibroelastic cores were lined by a single layer of CD31-positive endothelial cells. Histopathologic findings were consistent with papillary fibroelastoma. The patient was discharged without any other complications on day 30 of hospitalization. CONCLUSIONS This case highlights the importance of cardiac imaging in patients with acute stroke, including transthoracic and transesophageal echocardiography, which can show the typical imaging features of papillary fibroelastoma and other intracardiac sources of embolus.

Trends in clinical outcomes of older hemodialysis patients: data from the 2023 Korean Renal Data System (KORDS).

With an increasing aging population, the mean age of patients with end-stage kidney disease (ESKD) is globally increasing. However, the current clinical status of elderly patients undergoing hemodialysis (HD) is rarely reported in Korea. The current study analyzed the clinical features and trends of older patients undergoing HD from the Korean Renal Data System (KORDS) database. The patients were divided into three groups according to age: <65 years (the young group), n = 50,591 (35.9%); 65-74 years (the younger-old group), n = 37,525 (26.6%); and ≥75 years (the older-old group), n = 52,856 (37.5%). The proportion of older-old group undergoing HD significantly increased in incidence and decreased in prevalence from 2013 to 2022. The median levels of hemoglobin, serum creatinine, albumin, calcium, phosphorus, and intact parathyroid hormone significantly decreased in the older-old group. The proportions of arteriovenous fistula creation and left forearm placement showed decreased trends with age. Although the utilization of low surface area dialyzers increased with age, the dialysis adequacy, including urea reduction ratio and Kt/V was within acceptable range in the older-old group on HD. Over the past 20 years, the mortality rate in the older-old group has increased, with cardiovascular diseases decreasing and infectious diseases increasing. The incidence of elderly patients undergoing HD has increased over time, but the high mortality of the older-old group needs to be solved. Therefore, it is imperative to develop holistic strategies based on age and individual needs for patients with ESKD.

Guidelines for Manufacturing and Application of Organoids: Kidney.

Recent advancements in organoid technology have led to a vigorous movement towards utilizing it as a substitute for animal experiments. Organoid technology offers versatile applications, particularly in toxicity testing of pharmaceuticals or chemical substances. However, for the practical use in toxicity testing, minimal guidance is required to ensure reliability and relevance. This paper aims to provide minimal guidelines for practical uses of kidney organoids derived from human pluripotent stem cells as a toxicity evaluation model in vitro.

Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations.

Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.

Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration-time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP.

Shock indices are associated with in-hospital mortality among patients with septic shock and normal left ventricular ejection fraction.

BACKGROUND: The understanding of shock indices in patients with septic shock is limited, and their values may vary depending on cardiac function. METHODS: This prospective cohort study was conducted across 20 university-affiliated hospitals (21 intensive care units [ICUs]). Adult patients (≥19 years) with septic shock admitted to the ICUs during a 29-month period were included. The shock index (SI), diastolic shock index (DSI), modified shock index (MSI), and age shock index (Age-SI) were calculated at sepsis recognition (time zero) and ICU admission. Left ventricular (LV) function was categorized as either normal LV ejection fraction (LVEF ≥ 50%) or decreased LVEF (<50%). RESULTS: Among the 1,194 patients with septic shock, 392 (32.8%) who underwent echocardiography within 24 h of time zero were included in the final analysis (normal LVEF: n = 246; decreased LVEF: n = 146). In patients with normal LVEF, only survivors demonstrated significant improvement in SI, DSI, MSI, and Age-SI values from time zero to ICU admission; however, no notable improvements were found in all patients with decreased LVEF. The completion of vasopressor or fluid bundle components was significantly associated with improved indices in patients with normal LVEF, but not in those with decreased LVEF. In multivariable analysis, each of the four indices at ICU admission was significantly associated with in-hospital mortality (P < 0.05) among patients with normal LVEF; however, discrimination power was better in the indices for patients with lower lactate levels (≤ 4.0 mmol/L), compared to those with higher lactate levels. CONCLUSIONS: The SI, DSI, MSI, and Age-SI at ICU admission were significantly associated with in-hospital mortality in patients with septic shock and normal LVEF, which was not found in those with decreased LVEF. Our study emphasizes the importance of interpreting shock indices in the context of LV function in septic shock.

Revolutionizing biomedical research: The imperative need for heart-kidney-connected organoids.

Organoids significantly advanced our comprehension of organ development, function, and disease modeling. This Perspective underscores the potential of heart-kidney-connected organoids in understanding the intricate relationship between these vital organs, notably the cardiorenal syndrome, where dysfunction in one organ can negatively impact the other. Conventional models fall short in replicating this complexity, necessitating an integrated approach. By co-culturing heart and kidney organoids, combined with microfluidic and 3D bioprinting technologies, a more accurate representation of in vivo conditions can be achieved. Such interconnected systems could revolutionize our grasp of multi-organ diseases, drive drug discovery by evaluating therapeutic agents on both organs simultaneously, and reduce the need for animal models. In essence, heart-kidney-connected organoids present a promising avenue to delve deeper into the pathophysiology underlying cardiorenal disorders, bridging existing knowledge gaps, and advancing biomedical research.

Status and trends in epidemiologic characteristics of diabetic end-stage renal disease: an analysis of the 2021 Korean Renal Data System.

Korean Renal Data System (KORDS) is a nationwide end-stage renal disease (ESRD) registry database operated by the Korean Society of Nephrology (KSN). Diabetes mellitus is currently the leading cause of ESRD in Korea; this article provides an update on the trends and characteristics of diabetic ESRD patients. The KORDS Committee of KSN collects data on dialysis centers and patients through an online registry program. Here, we analyzed the status and trends in characteristics of diabetic chronic kidney disease stage 5D (CKD 5D) patients using data from 2001 to 2021. In 2021, the dialysis adequacy of hemodialysis (HD) was lower in diabetic CKD 5D patients than in nondiabetic CKD 5D patients, while that of peritoneal dialysis (PD) was similar. Diabetic CKD 5D patients had a higher proportion of cardiac and vascular diseases and were more frequently admitted to hospitals than nondiabetic CKD 5D patients, and the leading cause of death was cardiac disease. From 2001 to 2020, diabetic CKD 5D patients had a higher mortality rate than nondiabetic CKD 5D patients, but in 2021 this trend was reversed. Diabetic PD patients had the highest mortality rate over 20 years. The mortality rate of diabetic HD patients was higher than that of nondiabetic HD patients until 2019 but became lower starting in 2020. There was a decreasing trend in mortality rate in diabetic CKD 5D patients, but cardiac and vascular diseases were still prevalent in diabetic CKD 5D patients with frequent admissions to hospitals. More specialized care is needed to improve the clinical outcomes of diabetic CKD 5D patients.

The origin of sequence type 72 community-associated methicillin-resistant Staphylococcus aureus (MRSA) and fusidic acid (FA) resistant sequence type 5 MRSA: Analysis of FA resistance and spa type in a single center in South Korea.

INTRODUCTION: We investigated the prevalence of fusidic acid (FA) resistance in MSSA and MRSA stratified by sequence (ST) and spa types, and determined the prevalence of FA resistance mechanisms. METHODS: From August 2014 to April 2020, S. aureus blood isolates were collected in Asan Medical Center, Seoul, South Korea. Antimicrobial susceptibility tests were performed using broth microdilution and interpreted according to EUCAST's FA criteria. We performed spa typing for fusA mutation presence and acquired FA resistance determinants (fusB, fusC, and fusD) by PCR. RESULTS: Of the 590 MRSA isolates, 372 were FA resistant, and among 425 MSSA isolates, 136 were resistant. Of the 380 ST5-MRSA isolates, 350 were FA resistant, whereas only 1 of 14 ST5-MSSA isolates was FA resistant. Conversely, of the 163 ST72-MRSA isolates, only 8 were resistant, whereas 37 of 42 ST72-MSSA were resistant. The fusA mutation (80%) was the most common determinant. The one FA resistant ST5-MSSA isolate belonged to the t2460 spa type, the most common spa type (24 of 35 isolates) of FA resistant ST5-MRSA. In addition, t324 and t148, which are minor spa types of ST72-MSSA, were susceptible to FA, in contrast to other ST72-MSSA spa types, and the major spa type of ST72-MRSA (110 of 163 isolates). CONCLUSIONS: FA resistance was common in ST5-MRSA and ST72-MSSA, and rare in ST5-MSSA and ST72-MRSA. Our findings suggest that minor clones of ST5-MSSA isolates, with the fusA mutation and minor clones of ST72-MSSA susceptible to FA, may have evolved to harbor the mecA gene.

Topographic Consideration on the Occurrence of Ipsilesional Facial Paresis in Lateral Medullary Infarction.

INTRODUCTION: The purpose of this study was to identify course of the corticobulbar tract and factors associated with the occurrence of facial paresis (FP) in lateral medullary infarction (LMI). METHODS: Patients diagnosed with LMI who were admitted to tertiary hospital were retrospectively investigated and divided into two groups based on the presence of FP. FP was defined as grade 2 or more by the House-Brackmann scale. Differences between the two groups were analyzed with respect to anatomical location of the lesions, demographic data (age, sex), risk factors (diabetes, hypertension, smoking, prior stroke, atrial fibrillation, and other cardiac risk factors for stroke), large vessel involvement on magnetic resonance angiography, other symptoms and signs (sensory symptoms, gait ataxia, limb ataxia, dizziness, Horner syndrome, hoarseness, dysphagia, dysarthria, nystagmus, nausea/vomiting, headache, neck pain, diplopia, and hiccup). RESULTS: Among 44 LMI patients, 15 patients (34%) had FP, and all of them had ipsilesional central-type FP. The FP group tended to involve upper (p < 0.0001) and relative ventral (p = 0.019) part of the lateral medulla. Horizontally large lesion was also related to the presence of FP (p = 0.044). Dysphagia (p = 0.001), dysarthria (p = 0.003), and hiccups (p = 0.034) were more likely to be accompanied by FP. Otherwise, there were no significant differences. CONCLUSION: The results of present study indicate that the corticobulbar fibers innervating the lower face decussate at the upper level of the medulla and ascend through the dorsolateral medulla, where the concentration of the fibers is densest near the nucleus ambiguus.

Molecular Characteristics and Prevalence of Rifampin Resistance in Staphylococcus aureus Isolates from Patients with Bacteremia in South Korea.

Rifampin resistance (RIF-R) in Staphylococcus aureus (S. aureus) with rpoB mutations as one of its resistance mechanisms has raised concern about clinical treatment and infection prevention strategies. Data on the prevalence and molecular epidemiology of RIF-R S. aureus blood isolates in South Korea are scarce. We used broth microdilution to investigate RIF-R prevalence and analyzed the rpoB gene mutation in 1615 S. aureus blood isolates (772 methicillin-susceptible and 843 methicillin-resistant S. aureus (MRSA)) from patients with bacteremia, between 2008 and 2017. RIF-R prevalence and antimicrobial susceptibility were determined. Multilocus sequence typing was used to characterize the isolate's molecular epidemiology; Staphylococcus protein A (spa), staphylococcal cassette chromosome mec (SCCmec), and rpoB gene mutations were detected by PCR. Among 52 RIF-R MRSA isolates out of 57 RIF-R S. aureus blood isolates (57/1615, 0.4%; 5 methicillin-susceptible and 52 MRSA), ST5 (44/52, 84.6%), SCCmec IIb (40/52, 76.9%), and spa t2460 (27/52, 51.9%) were predominant. rpoB gene mutations with amino acid substitutions showed that A477D (17/48, 35.4%) frequently conferred high-level RIF resistance (MIC > 128 mg/L), followed by H481Y (4/48, 8.3%). RIF-R S. aureus blood isolates in South Korea have unique molecular characteristics and are closely associated with rpoB gene mutations. RIF-R surveillance through S. aureus-blood isolate epidemiology could enable effective therapeutic management.

Effectiveness and Adverse Events of Nirmatrelvir/Ritonavir Versus Molnupiravir for COVID-19 in Outpatient Setting: Multicenter Prospective Observational Study.

BACKGROUND: In this study, we aimed to compare the effectiveness and adverse reactions of nirmatrelvir/ritonavir and molnupiravir in high-risk outpatients with coronavirus disease 2019 (COVID-19). METHODS: This multicenter prospective observational study evaluated the rate of hospitalization, death, and adverse events within 28 days of oral antiviral agent prescription (molnupiravir, n = 240; nirmatrelvir/ritonavir, n = 240) to 480 nonhospitalized adult patients with COVID-19 from August 2, 2022 to March 31, 2023. RESULTS: Patients receiving molnupiravir had a higher prevalence of comorbidities (85.8% vs. 70.4%; P < 0.001) and a higher Charlson comorbidity index (2.8 ± 1.4 vs. 2.5 ± 1.5; P = 0.009) than those receiving nirmatrelvir/ritonavir. Three patients required hospitalization (nirmatrelvir/ritonavir group, n = 1 [0.4%]; molnupiravir group, n = 2 [0.8%]; P = 1.000). Nirmatrelvir/ritonavir was associated with a higher risk of adverse events than molnupiravir (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.27-3.03), especially for patients aged 65 years and older (OR, 3.04; 95% CI, 1.71-5.39). The severity of adverse events in both groups was mild to moderate and improved after discontinuation of medication. In the molnupiravir group, age ≥ 65 years (OR, 0.43 95% CI, 0.22-0.86) and appropriate vaccination (OR, 0.37; 95% CI, 0.15-0.91) reduced the occurrence of adverse events. CONCLUSION: The rates of hospitalization and death were low and not significantly different between high-risk patients who received either nirmatrelvir/ritonavir or molnupiravir. Although adverse events were more frequent with nirmatrelvir/ritonavir than with molnupiravir, none were severe. Nirmatrelvir/ritonavir can be safely used to treat COVID-19, while molnupiravir could be considered as an alternative treatment option for high-risk groups.

3D Cell Printing of Advanced Vascularized Proximal Tubule-on-a-Chip for Drug Induced Nephrotoxicity Advancement.

Renal dysfunction due to drug-induced nephrotoxicity (DIN) affects >20% of the adult population worldwide. The vascularized proximal tubule is a complex structure that is often the primary site of drug-induced kidney injury. Herein, a vascularized proximal tubule-on-a-chip (Vas-POAC) was fabricated, demonstrating improved physiological emulation over earlier single-cell proximal tubule models. A perfusable model of vascularized proximal tubules permits the growth and proliferation of renal proximal tubule cells and adjacent endothelial cells under various conditions. An in vitro Vas-POAC showed mature expressions of the tubule and endothelial cell markers in the mature epithelium and endothelium lumens after 7 days of culture. Expression in the mature proximal tubule epithelium resembled the polarized expression of sodium-glucose cotransporter-2 and the de novo synthesis of ECM proteins. These perfusable Vas-POACs display significantly improved functional properties relative to the proximal tubules-on-a-chip (POAC), which lacks vascular components. Furthermore, the developed Vas-POAC model evaluated the cisplatin-induced nephrotoxicity and revealed enhanced drug receptivity compared to POAC. We further evaluated the capability of the developed proximal tubule model to act as a functional platform that targets screening drug doses that can cause renal proximal tubule injury in adults. Thus, our cell-printed models may prove valuable for screening, thoughtful mechanistic investigations of DIN, and discovery of drugs that interfere with tubule formation.

Electrochemical Detection of Dopamine Release from Living Neurons Using Graphene Oxide-Incorporated Polypyrrole/Gold Nanocluster Hybrid Nanopattern Arrays.

Stem-cell-based therapeutics have shown immense potential in treating various diseases that are currently incurable. In particular, partial recovery of Parkinson's disease, which occurs due to massive loss or abnormal functionality of dopaminergic (DAnergic) neurons, through the engraftment of stem-cell-derived neurons ex vivo is reported. However, precise assessment of the functionality and maturity of DAnergic neurons is still challenging for their enhanced clinical efficacy. Here, a novel conductive cell cultivation platform, a graphene oxide (GO)-incorporated metallic polymer nanopillar array (GOMPON), that can electrochemically detect dopamine (DA) exocytosis from living DAnergic neurons, is reported. In the cell-free configuration, the linear range is 0.5-100 µm, with a limit of detection of 33.4 nm. Owing to its excellent biocompatibility, a model DAnergic neuron (SH-SY5Y cell) can be cultivated and differentiated on the platform while their DA release can be quantitatively measured in a real-time and nondestructive manner. Finally, it is showed that the functionality of the DAnergic neurons derived from stem cells can be precisely assessed via electrochemical detection of their DA exocytosis. The developed GOMPON is highly promising for a wide range of applications, including real-time monitoring of stem cell differentiation into neuronal lineages, evaluating differentiation protocols, and finding practical stem cell therapies.

Role of increased neutrophil extracellular trap formation on acute kidney injury in COVID-19 patients.

Background: A strong association between elevated neutrophil extracellular trap (NET) levels and poor clinical outcomes in patients with coronavirus infection 2019 (COVID-19) has been reported. However, while acute kidney injury (AKI) is a common complication of COVID-19, the role of NETs in COVID-19-associated AKI is unclear. We investigated the association between elevated NETs and AKI and the prognostic role of NETs in COVID-19 patients. Methods: Two representative markers of NETs, circulating nucleosomes and myeloperoxidase-DNA, were measured in 115 hospitalized patients. Serum levels of interleukin [IL]-6, monocyte chemotactic protein-1 [MCP-1], plasma von Willebrand factor (vWF) and urinary biomarkers of renal tubular damage (ß2-microglobulin [ß2M] and kidney injury molecule 1 [KIM-1]) were measured. Results: AKI was found in 43 patients (37.4%), and pre-existing chronic kidney disease (CKD) was a strong risk factor for AKI. Higher circulating NET levels were a significant predictor of increased risk of initial ICU admission, in-hospital mortality (adjusted HR 3.21, 95% CI 1.08-9.19) and AKI (OR 3.67, 95% CI 1.30-10.41), independent of age, diabetes, pre-existing CKD and IL-6 levels. There were strong correlations between circulating nucleosome levels and urinary KIM-1/creatinine (r=0.368, p=0.001) and ß2M (r=0.218, p=0.049) levels. NETs were also strongly closely associated with serum vWF (r = 0.356, p<0.001), but not with IL-6 or MCP-1 levels. Conclusions: Elevated NETs were closely associated with AKI, which was a strong predictor of mortality. The close association between NETs and vWF may suggest a role for NETs in COVID-19-associated vasculopathy leading to AKI.