scholarly journals Of Rats and Men, a Translational Model to Understand Vancomycin Pharmacokinetic/Toxicodynamic relationships

2021 ◽  
Author(s):  
Marc H. Scheetz ◽  
Gwendolyn Pais ◽  
Thomas P. Lodise ◽  
Steven Y.C. Tong ◽  
Joshua S. Davis ◽  
...  
Keyword(s):  
Therapeutic Range ◽  
Rat Model ◽  
Clinical Studies ◽  
Linear Models ◽  
External Validation ◽  
Hospital Setting ◽  
Kidney Injury ◽  
The United States ◽  
Concentration Curve ◽  
Clinical Model

AbstractBackgroundVancomycin is a first line antibiotic for many common infectious diseases and is the most commonly prescribed antibiotic in the United States hospital setting. Vancomycin is also well known to cause kidney injury; two recent prospective studies have identified that increasing vancomycin area under the concentration curve predicts vancomycin induced kidney injury (VIKI). However, outside of clinical trials, it is unclear if pre-clinical data can quantitatively describe VIKI in patients.MethodsData were simultaneously analyzed from a pre-clinical rat model and two prospective clinical studies. Logged vancomycin area under the concentration curve (AUC) data for rats (n=48) and patients from PROVIDE (n=263) and CAMERA2 (n=291) were included. VIKI was defined as urinary KIM-1 concentrations ≥9.42 ng/mL in the rat and according to KDIGO stage 1 kidney injury for all human patients. Multiple generalized linear models were explored, and the order of magnitude was calculated between the probability of acute kidney injury (AKI) from the average obtained in the clinical studies (i.e. CAMERA2 and PROVIDE) and the rat for 0.1 increments in Log10AUC bounded common concentrations obtained in the therapeutic range (i.e. ~200 −800 mg*24h/L).ResultsA logit link model best fit the data. When calculating the multiplicative factors between the studies therapeutic range AUCs, the rat was an average 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 (i.e. log 10 AUC=2.3) and 794.3 mg*h/L (i.e. log 10 AUC=2.9), respectively.ConclusionsA pre-clinical rat model was quantitatively linked to toxicity data from two large human studies. The rat is an attractive pre-clinical model to explore exposure toxicity relationships with vancomycin. External validation is required.

scholarly journals Of Rats and Men, a Translational Model to Understand Vancomycin Pharmacokinetic/Toxicodynamic relationships.

2021 ◽  
Author(s):  
Marc H. Scheetz ◽  
Gwendolyn Pais ◽  
Thomas P. Lodise ◽  
Steven Y.C. Tong ◽  
Joshua S. Davis ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Rat Model ◽  
Clinical Studies ◽  
Kidney Injury ◽  
Concentration Curve ◽  
Translational Model ◽  
Link Model

Vancomycin area under the concentration curve (AUC) is known to predict vancomycin induced acute kidney injury (AKI). Data were analyzed from a rat model (n=48) and two prospective clinical studies [PROVIDE (n=263) and CAMERA2 (n=291)]. A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg*h/L, respectively.

scholarly journals Urinary biomarker and histopathological evaluation of vancomycin and piperacillin-tazobactam nephrotoxicity in comparison with vancomycin in a rat model and a confirmatory cellular model

2019 ◽  
Author(s):  
Gwendolyn M. Pais ◽  
Jiajun Liu ◽  
Sean N. Avedissian ◽  
Theodoros Xanthos ◽  
Athanasios Chalkias ◽  
...  
Keyword(s):  
Rat Model ◽  
Rat Kidney ◽  
Hospital Setting ◽  
Kidney Injury ◽  
Sprague Dawley ◽  
Drug Dosing ◽  
Viability Assay ◽  
Sprague Dawley Rats ◽  
Kidney Epithelial Cell ◽  
High Doses

AbstractIntroductionVancomycin and piperacillin tazobactam (VAN+TZP) are two of the most commonly utilized antibiotics in the hospital setting and are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated that synergistic toxicity occurs, only that serum creatinine (SCr) increases with VAN+TZP. The purpose of this study was to assess biologic plausibility by quantifying kidney injury between VAN, TZP, and VAN+TZP treatments using a translational rat model of AKI and rat kidney epithelial cell studies.Methods(i) Male Sprague-Dawley rats (n=32) received either saline, VAN 150 mg/kg/day intravenously, TZP 1400 mg/kg/day via intraperitoneal injection, or VAN+TZP. Animals were placed in metabolic cages pre-study and on drug dosing days 1-3. Urinary biomarkers and histopathology were analyzed. (ii) Cellular injury of VAN+TZP was assessed in serum-deprived rat kidney cells (NRK-52E) using an alamarBlue® viability assay. Cells were incubated with antibiotics VAN, TZP, cefepime, and gentamicin alone or combined with the same drugs plus VAN 1 mg/mL.ResultsIn the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 compared to controls (P<0.001). Elevations were seen only after 3 days of treatment with VAN+TZP (P<0.001 KIM-1, P<0.05 clusterin). Histopathology was only elevated in the VAN group when compared to TZP as a control (P=0.04). Results were consistent across biomarkers and histopathology suggesting that adding TZP did not worsen VAN induced AKI and may even be protective. In NRK-52E cells, VAN alone caused moderate cell death with high doses (IC5048.76 mg/mL). TZP alone did not cause cellular death under the same conditions. VAN+TZP was not different from VAN alone in NRK-52E cells (P>0.2).ConclusionsVAN+TZP does not cause more kidney injury than VAN alone in a rat model of VIKI or in rat kidney epithelial cells.

scholarly journals A radiomics-based model for predicting prognosis of locally advanced gastric cancer in the preoperative setting

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaeseung Shin ◽  
Joon Seok Lim ◽  
Yong-Min Huh ◽  
Jie-Hyun Kim ◽  
Woo Jin Hyung ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Cox Regression ◽  
Characteristic Curve ◽  
External Validation ◽  
Locally Advanced ◽  
Clinical Model ◽  
Locally Advanced Gastric Cancer ◽  
Contrast Enhanced Ct ◽  
Preoperative Ct

AbstractThis study aims to evaluate the performance of a radiomic signature-based model for predicting recurrence-free survival (RFS) of locally advanced gastric cancer (LAGC) using preoperative contrast-enhanced CT. This retrospective study included a training cohort (349 patients) and an external validation cohort (61 patients) who underwent curative resection for LAGC in 2010 without neoadjuvant therapies. Available preoperative clinical factors, including conventional CT staging and endoscopic data, and 438 radiomic features from the preoperative CT were obtained. To predict RFS, a radiomic model was developed using penalized Cox regression with the least absolute shrinkage and selection operator with ten-fold cross-validation. Internal and external validations were performed using a bootstrapping method. With the final 410 patients (58.2 ± 13.0 years-old; 268 female), the radiomic model consisted of seven selected features. In both of the internal and the external validation, the integrated area under the receiver operating characteristic curve values of both the radiomic model (0.714, P < 0.001 [internal validation]; 0.652, P = 0.010 [external validation]) and the merged model (0.719, P < 0.001; 0.651, P = 0.014) were significantly higher than those of the clinical model (0.616; 0.594). The radiomics-based model on preoperative CT images may improve RFS prediction and high-risk stratification in the preoperative setting of LAGC.

scholarly journals An Exploratory Qualitative Study of Patient and Caregiver Perspectives of Ambulatory Kidney Palliative Care

2021 ◽  
pp. 104990912098612
Author(s):  
Alycia A. Bristol ◽  
Sobaata Chaudhry ◽  
Dana Assis ◽  
Rebecca Wright ◽  
Derek Moriyama ◽  
...  
Keyword(s):  
Palliative Care ◽  
Kidney Disease ◽  
Chronic Kidney Disease Stage ◽  
Stage Iv ◽  
The United States ◽  
Qualitative Description ◽  
Disease Stage ◽  
Structured Interviews ◽  
Care Clinic ◽  
Clinical Model

Objectives: The ideal clinical model to deliver palliative care to patients with advanced kidney disease is currently unknown. Internationally, ambulatory kidney palliative care clinics have emerged with positive outcomes, yet there is limited data from the United States (US). In this exploratory study we report perceptions of a US-based ambulatory kidney palliative care clinic from the perspective of patient and caregiver attendees. The objective of this study was to inform further improvement of our clinical program. Methods: Semi-structured interviews were conducted to elicit the patient and caregiver experience. Eleven interviews (8 patients with chronic kidney disease stage IV or V and 3 caregivers) were analyzed using qualitative description design. Results: We identified 2 themes: “Communication addressing the emotional and physical aspects of disease” and “Filling gaps in care”; Subthemes include perceived value in symptom management, assistance with coping with disease, engagement in advance care planning, program satisfaction and patient activation. Significance of Results: Qualitative analysis showed that attendees of an ambulatory kidney palliative care clinic found the clinic enhanced the management of their kidney disease and provided services that filled current gaps in their care. Shared experiences highlight the significant challenges of life with kidney disease and the possible benefits of palliative care for this population. Further study to determine the optimal model of care for kidney palliative care is needed. Inclusion of the patient and caregiver perspective will be essential in this development.

scholarly journals External validation of an opioid misuse machine learning classifier in hospitalized adult patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Majid Afshar ◽  
Brihat Sharma ◽  
Sameer Bhalla ◽  
Hale M. Thompson ◽  
Dmitriy Dligach ◽  
...  
Keyword(s):  
Machine Learning ◽  
Screening Program ◽  
External Validation ◽  
Hospital Setting ◽  
Opioid Misuse ◽  
Original Cohort ◽  
Learning Classifier ◽  
Observational Cohort ◽  
Drug Abuse Screening Test ◽  
Screening Barriers

Abstract Background Opioid misuse screening in hospitals is resource-intensive and rarely done. Many hospitalized patients are never offered opioid treatment. An automated approach leveraging routinely captured electronic health record (EHR) data may be easier for hospitals to institute. We previously derived and internally validated an opioid classifier in a separate hospital setting. The aim is to externally validate our previously published and open-source machine-learning classifier at a different hospital for identifying cases of opioid misuse. Methods An observational cohort of 56,227 adult hospitalizations was examined between October 2017 and December 2019 during a hospital-wide substance use screening program with manual screening. Manually completed Drug Abuse Screening Test served as the reference standard to validate a convolutional neural network (CNN) classifier with coded word embedding features from the clinical notes of the EHR. The opioid classifier utilized all notes in the EHR and sensitivity analysis was also performed on the first 24 h of notes. Calibration was performed to account for the lower prevalence than in the original cohort. Results Manual screening for substance misuse was completed in 67.8% (n = 56,227) with 1.1% (n = 628) identified with opioid misuse. The data for external validation included 2,482,900 notes with 67,969 unique clinical concept features. The opioid classifier had an AUC of 0.99 (95% CI 0.99–0.99) across the encounter and 0.98 (95% CI 0.98–0.99) using only the first 24 h of notes. In the calibrated classifier, the sensitivity and positive predictive value were 0.81 (95% CI 0.77–0.84) and 0.72 (95% CI 0.68–0.75). For the first 24 h, they were 0.75 (95% CI 0.71–0.78) and 0.61 (95% CI 0.57–0.64). Conclusions Our opioid misuse classifier had good discrimination during external validation. Our model may provide a comprehensive and automated approach to opioid misuse identification that augments current workflows and overcomes manual screening barriers.

scholarly journals Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model

2021 ◽  
Vol 22 (7) ◽  
pp. 3762
Author(s):  
Sarah M. Kedziora ◽  
Kristin Kräker ◽  
Lajos Markó ◽  
Julia Binder ◽  
Meryam Sugulle ◽  
...  
Keyword(s):  
Rat Model ◽  
Renal Damage ◽  
Kidney Injury ◽  
Tissue Growth ◽  
Female Rats ◽  
Male Rats ◽  
Renal Diseases ◽  
Transgenic Rat ◽  
Increased Risk ◽  
Before And After

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum.

scholarly journals The Current Management of Hepatorenal Syndrome‐Acute Kidney Injury in the United States and the Potential of Terlipressin

2021 ◽  
Author(s):  
Steven L. Flamm ◽  
Kimberly Brown ◽  
Hani M. Wadei ◽  
Robert S. Brown ◽  
Marcelo Kugelmas ◽  
...  
Keyword(s):  
United States ◽  
Acute Kidney Injury ◽  
Hepatorenal Syndrome ◽  
Kidney Injury ◽  
The United States ◽  
Current Management

Risk Factors for CKD Progression

2020 ◽  
pp. CJN.07830520
Author(s):  
Mary Hannan ◽  
Sajid Ansari ◽  
Natalie Meza ◽  
Amanda H. Anderson ◽  
Anand Srivastava ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genome Wide Association Study ◽  
Healthy Lifestyle ◽  
Interdisciplinary Collaboration ◽  
Fibroblast Growth Factor 23 ◽  
Kidney Injury ◽  
The United States ◽  
Future Research ◽  
Ckd Progression ◽  
Factors Associated

The Chronic Renal Insufficiency Cohort (CRIC) Study is an ongoing, multicenter, longitudinal study of nearly 5500 adults with CKD in the United States. Over the past 10 years, the CRIC Study has made significant contributions to the understanding of factors associated with CKD progression. This review summarizes findings from longitudinal studies evaluating risk factors associated with CKD progression in the CRIC Study, grouped into the following six thematic categories: (1) sociodemographic and economic (sex, race/ethnicity, and nephrology care); (2) behavioral (healthy lifestyle, diet, and sleep); (3) genetic (apoL1, genome-wide association study, and renin-angiotensin-aldosterone system pathway genes); (4) cardiovascular (atrial fibrillation, hypertension, and vascular stiffness); (5) metabolic (fibroblast growth factor 23 and urinary oxalate); and (6) novel factors (AKI and biomarkers of kidney injury). Additionally, we highlight areas where future research is needed, and opportunities for interdisciplinary collaboration.

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