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Ma Y, Mu J, Gou X, Wu X. Precision medication based on the evaluation of drug metabolizing enzyme and transporter functions. PRECISION CLINICAL MEDICINE 2025; 8:pbaf004. [PMID: 40110576 PMCID: PMC11920622 DOI: 10.1093/pcmedi/pbaf004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/25/2025] [Accepted: 02/17/2025] [Indexed: 03/22/2025] Open
Abstract
Pharmacogenomics, therapeutic drug monitoring, and the assessments of hepatic and renal function have made significant contributions to the advancement of individualized medicine. However, their lack of direct correlation with protein abundance/non-genetic factors, target drug concentration, and drug metabolism/excretion significantly limits their application in precision drug therapy. The primary task of precision medicine is to accurately determine drug dosage, which depends on a precise assessment of the ability to handle drugs in vivo, and drug metabolizing enzymes and transporters are critical determinants of drug disposition in the body. Therefore, accurately evaluating the functions of these enzymes and transporters is key to assessing the capacity to handle drugs and predicting drug concentrations in target organs. Recent advancements in the evaluation of enzyme and transporter functions using exogenous probes and endogenous biomarkers show promise in advancing personalized medicine. This article aims to provide a comprehensive overview of the latest research on markers used for the functional evaluation of drug-metabolizing enzymes and transporters. It also explores the application of marker omics in systematically assessing their functions, thereby laying a foundation for advancing precision pharmacotherapy.
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Affiliation(s)
- Yanrong Ma
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Jing Mu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Xueyan Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Xinan Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China
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Barreto EF, Scheetz MH, Chang J, Cole KC, Fogelson LA, Paul J, Jannetto PJ, Gajic O, Rule AD. Cystatin C-Guided Dosing Nomogram Improves Target Attainment for Cefepime in the Critically Ill. Crit Care Med 2025:00003246-990000000-00480. [PMID: 40013864 DOI: 10.1097/ccm.0000000000006622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
OBJECTIVES Estimated glomerular filtration rate is more accurate with combined creatinine and cystatin C equations (eGFRcr-cys) than creatinine alone. This study created and evaluated a cefepime dosing nomogram based on eGFRcr-cys for initial dosing in the critically ill. DESIGN Pharmacokinetic modeling and simulation study. SETTING Academic medical center. PATIENTS Critically ill adults treated with cefepime. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data from 120 patients with baseline cystatin C and follow-up cefepime levels were used to develop a nomogram based on eGFRcr-cys and weight for initial cefepime dosing. The predicted proportion of patients who achieved a free cefepime concentration above the minimum inhibitory concentration of the organism for 100% of the dosing interval in the first 24 hours (100% ƒT > MIC at 24 hr) was compared between administered doses and those predicted by the nomogram doses. Overall drug exposure was estimated with the free area under the concentration time curve from 0 to 24 hours (ƒAUC0-24) and compared between administered and nomogram doses. Achievement of 100% ƒT > MIC at 24 hours was predicted to be significantly better with the nomogram compared with the administered dose (76% vs. 38%; p < 0.001). The median ƒAUC0-24 as predicted by the nomogram (666 mg·hr/L) was slightly higher than the actual ƒAUC0-24 with administered doses (612 mg·hr/L; p = 0.01), but the nomogram led to fewer ƒAUC0-24 values which were either too high (> 900) or too low (< 300) (7% vs. 20%; p = 0.004). CONCLUSIONS Use of a cystatin C-inclusive dosing nomogram for cefepime could improve target attainment without increasing the risk of potentially toxic levels in the critically ill.
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Affiliation(s)
| | - Marc H Scheetz
- Department of Pharmacy Practice, Chicago College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, IL
- Department of Pharmacy, Northwestern Medicine, Chicago, IL
| | - Jack Chang
- Gilead Sciences, Inc., Clinical Pharmacology Sciences, Foster City, CA
| | - Kristin C Cole
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
| | | | - Johar Paul
- Anesthesia Clinical Research Unit, Rochester, MN
| | - Paul J Jannetto
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN
| | - Ognjen Gajic
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
- Division of Epidemiology, Mayo Clinic, Rochester, MN
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Pinsino A, Jennings DL, Ladanyi A, Duong P, Sweat AO, Mahoney I, Bohn B, Demmer RT, Takeda K, Sayer GT, Uriel N, Leb JS, Husain SA, Mohan S, Colombo PC, Yuzefpolskaya M. Kidney function assessment using cystatin C and serum creatinine in heart transplantation recipients: Implications for valganciclovir dosing. J Heart Lung Transplant 2024; 43:1963-1972. [PMID: 39069163 DOI: 10.1016/j.healun.2024.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 06/11/2024] [Accepted: 07/16/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Among heart transplantation (HT) recipients, the accuracy of serum creatinine (sCr)-based estimated glomerular filtration rate (eGFR) may be limited by fluctuations in muscle mass. Cystatin C (cysC) is less influenced by muscle mass, but its levels may increase with obesity and steroid use. Herein, we (1) longitudinally compared eGFRcysC and eGFRsCr among HT recipients; (2) investigated the association of body mass index (BMI), steroid use, and muscle mass with discrepancies between eGFRs; and (3) explored the implications of eGFRcysC use on valganciclovir (VGC) dosing. METHODS cysC and sCr were measured in 294 blood samples obtained from 80 subjects. Intraindividual differences between eGFRs (eGFRdiffcysC-sCr) were calculated with negative values corresponding to eGFRsCr > eGFRcysC and positive values to eGFRcysC > eGFRsCr. In a patient subset (n = 21), pectoralis muscle measures were obtained. RESULTS Marked differences between eGFRcysC and eGFRsCr were observed, particularly early post-HT (1-week post-HT, median eGFRdiffcysC-sCr -28 ml/min/1.73 m2). eGFRcysC demonstrated stability following a transient postoperative decline, while eGFRsCr decreased in the first year post-HT. Lower BMI and higher prednisone dose displayed a modest association with more negative eGFRdiffcysC-sCr values. Pectoralis muscle measures indicative of greater muscle mass and better tissue quality exhibited a stronger association with more positive eGFRdiffcysC-sCr values. The use of eGFRcysC would have led to VGC dose adjustment in 46% of samples, predominantly resulting in dose reduction. CONCLUSIONS Among HT recipients, eGFRcysC and eGFRsCr markedly differ with implications for VGC dosing. The observed discrepancies may reflect changes in body composition and steroid use.
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Affiliation(s)
- Alberto Pinsino
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Douglas L Jennings
- Department of Pharmacy Practice, Long Island University College of Pharmacy, New York, New York; Department of Pharmacy, Columbia University Irving Medical Center, New York, New York
| | - Annamaria Ladanyi
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Phuong Duong
- Department of Radiology, Columbia University Irving Medical Center, New York, New York
| | - Austin O Sweat
- Department of Medicine, New York University, New York, New York
| | - Ian Mahoney
- Division of Pulmonary, Department of Medicine, Critical Care and Sleep Medicine, New York University, New York, New York
| | - Bruno Bohn
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Ryan T Demmer
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota; Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, College of Medicine and Science, Rochester, Minnesota; Division of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, New York
| | - Koji Takeda
- Division of Cardiac Surgery, Department of Surgery, Columbia University Irving Medical Center, New York, New York
| | - Gabriel T Sayer
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Nir Uriel
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Jay S Leb
- Department of Radiology, Columbia University Irving Medical Center, New York, New York
| | - Syed A Husain
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Sumit Mohan
- Division of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, New York; Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Paolo C Colombo
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Melana Yuzefpolskaya
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York.
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Hernandez BN, Wieruszewski PM, Barreto JN, Cole KC, Damani S, Kane-Gill SL, Kashani KB, Kelly E, Rule AD, Teaford HR, Zand J, Barreto EF. Challenges in renally eliminated medication use: Evaluating cystatin C and serum creatinine eGFR discordance. Pharmacotherapy 2024; 44:898-906. [PMID: 39601345 DOI: 10.1002/phar.4627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Accurately estimating glomerular filtration rate (GFR) is crucial for dosing medications in hospitalized patients. Due to limitations of serum creatinine for GFR estimation, serum cystatin C (CysC) has been explored as an alternative functional kidney biomarker. This study assessed discordance between eGFRCr and eGFRCysC in a large sample of hospitalized patients and examined the frequency of renally eliminated medications affected by eGFR discordance. METHODS This multisite historical study included adults hospitalized between 2011 and 2023 with CysC and serum creatinine reported within 24 h of each other. The first concurrent biomarker pair for each patient was analyzed. eGFR discordance and use of renally eliminated medications were described. RESULTS 17,718 hospitalized patients with concurrent creatinine and CysC assessments were included. The median eGFRCr was 65 mL/min, and the eGFRCysC was 46 mL/min. The median absolute difference of eGFRCr-eGFRCysC was 15 mL/min, and 7972 patients (45%) had a > 30% absolute difference. There was a significantly greater percentage of patients with an eGFR <30 mL/min based on eGFRCysC (26%) compared to eGFRCr (15%) (p < 0.001). Patients were prescribed an average of 20 medications in the 24 h surrounding the concurrent biomarker assessment. Renally eliminated medications accounted for 39% ± 13% of medication orders, and 80% of patients with eGFR discordance were prescribed five or more renally eliminated medications. CONCLUSION Substantial eGFR discordance between eGFRCysC and eGFRCr was observed in hospitalized patients, which directly affects the dosing of renally eliminated medications. Further research is needed to optimize the pharmacotherapy of renally eliminated medications with discordant GFR assessments to improve medication safety and effectiveness.
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Affiliation(s)
| | - Patrick M Wieruszewski
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jason N Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Kristin C Cole
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Shivam Damani
- Department of Medicine AI and Innovation, Mayo Clinic, Rochester, Minnesota, USA
| | - Sandra L Kane-Gill
- Department of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ellen Kelly
- Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Jaleh Zand
- Department of Medicine AI and Innovation, Mayo Clinic, Rochester, Minnesota, USA
| | - Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
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Ma P, Ma H, Liu R, Wen H, Li H, Huang Y, Li Y, Xiong L, Xie L, Wang Q. Prediction of vancomycin plasma concentration in elderly patients based on multi-algorithm mining combined with population pharmacokinetics. Sci Rep 2024; 14:27165. [PMID: 39511378 PMCID: PMC11544216 DOI: 10.1038/s41598-024-78558-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024] Open
Abstract
The pharmacokinetics of vancomycin exhibit significant inter-individual variability, particularly among elderly patients. This study aims to develop a predictive model that integrates machine learning with population pharmacokinetics (popPK) to facilitate personalized medication management for this demographic. A retrospective analysis incorporating 33 features, including popPK parameters such as clearance and volume of distribution. A combination of multiple algorithms and Shapley Additive Explanations was utilized for feature selection to identify the most influential factors affecting drug concentrations. The performance of each algorithm with popPK parameters was superior to that without popPK parameters. Our final ensemble model, composed of support vector regression, light gradient boosting machine, and categorical boosting in a 6:3:1 ratio, included 16 optimized features. This model demonstrated superior predictive accuracy compared to models utilizing all features, with testing group metrics including an R2 of 0.656, mean absolute error of 3.458, mean square error of 28.103, absolute accuracy within ± 5 mg/L of 81.82%, and relative accuracy within ± 30% of 76.62%. This study presents a rapid and cost-effective predictive model for estimating vancomycin plasma concentrations in elderly patients. The model offers a valuable tool for clinicians to accurately determine effective plasma concentration ranges and tailor individualized dosing regimens, thereby enhancing therapeutic outcomes and safety.
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Affiliation(s)
- Pan Ma
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Huan Ma
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Ruixiang Liu
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Haini Wen
- Department of Pharmacy, Uppsala University, Husargatan 3, 751 37, Uppsala, Sweden
| | - Haisheng Li
- Institute of Burn Research, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Yifan Huang
- Medical Big Data and Artificial Intelligence Center, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Ying Li
- Medical Big Data and Artificial Intelligence Center, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Lirong Xiong
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Linli Xie
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
| | - Qian Wang
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
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Tootooni MS, Barreto EF, Wutthisirisart P, Kashani KB, Pasupathy KS. Determining steady-state trough range in vancomycin drug dosing using machine learning. J Crit Care 2024; 82:154784. [PMID: 38503008 PMCID: PMC11139571 DOI: 10.1016/j.jcrc.2024.154784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/05/2024] [Accepted: 03/10/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND Vancomycin is a renally eliminated, nephrotoxic, glycopeptide antibiotic with a narrow therapeutic window, widely used in intensive care units (ICU). We aimed to predict the risk of inappropriate vancomycin trough levels and appropriate dosing for each ICU patient. METHODS Observed vancomycin trough levels were categorized into sub-therapeutic, therapeutic, and supra-therapeutic levels to train and compare different classification models. We included adult ICU patients (≥ 18 years) with at least one vancomycin concentration measurement during hospitalization at Mayo Clinic, Rochester, MN, from January 2007 to December 2017. RESULT The final cohort consisted of 5337 vancomycin courses. The XGBoost models outperformed other machine learning models with the AUC-ROC of 0.85 and 0.83, specificity of 53% and 47%, and sensitivity of 94% and 94% for sub- and supra-therapeutic categories, respectively. Kinetic estimated glomerular filtration rate and other creatinine-based measurements, vancomycin regimen (dose and interval), comorbidities, body mass index, age, sex, and blood pressure were among the most important variables in the models. CONCLUSION We developed models to assess the risk of sub- and supra-therapeutic vancomycin trough levels to improve the accuracy of drug dosing in critically ill patients.
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Affiliation(s)
- M Samie Tootooni
- Department of Health Informatics and Data Science, Loyola University Chicago, Maywood, IL, United States of America.
| | - Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN, United States of America
| | - Phichet Wutthisirisart
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, United States of America.
| | - Kalyan S Pasupathy
- Department of Biomedical and Health Information Sciences, University of Illinois Chicago, Chicago, IL, United States of America.
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Zhang L, Nizhamuding X, Zheng H, Zeng J, Yuan X, Ma Z, Zhou W, Zhang C, Zhang T, Zhang C. An LC-MS/MS method for serum cystatin C quantification and its comparison with two commercial immunoassays. Clin Chem Lab Med 2024; 62:1092-1100. [PMID: 38253403 DOI: 10.1515/cclm-2023-0821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024]
Abstract
OBJECTIVES The standardization of cystatin C (CysC) measurement has received increasing attention in recent years due to its importance in estimating glomerular filtration rate (GFR). Mass spectrometry-based assays have the potential to provide an accuracy base for CysC measurement. However, a precise, accurate and sustainable LC-MS/MS method for CysC is still lacking. METHODS The developed LC-MS/MS method quantified CysC by detecting signature peptide (T3) obtained from tryptic digestion. Stable isotope labeled T3 peptide (SIL-T3) was spiked to control matrix effects and errors caused by liquid handling. The protein denaturation, reduction and alkylation procedures were combined into a single step with incubation time of 1 h, and the digestion lasted for 3.5 h. In the method validation, digestion time-course, imprecision, accuracy, matrix effect, interference, limit of quantification (LOQ), carryover, linearity, and the comparability to two routine immunoassays were evaluated. RESULTS No significant matrix effect or interference was observed with the CysC measurement. The LOQ was 0.21 mg/L; the within-run and total imprecision were 1.33-2.05 % and 2.18-3.90 % for three serum pools (1.18-5.34 mg/L). The LC-MS/MS method was calibrated by ERM-DA471/IFCC and showed good correlation with two immunoassays traceable to ERM-DA471/IFCC. However, significant bias was observed for immunoassays against the LC-MS/MS method. CONCLUSIONS The developed LC-MS/MS method is robust and simpler and holds the promise to provide an accuracy base for routine immunoassays, which will promote the standardization of CysC measurement.
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Affiliation(s)
- Li Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Xiaerbanu Nizhamuding
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Hao Zheng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, P.R. China
| | - Jie Zeng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, P.R. China
| | - Xinyi Yuan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Zijia Ma
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Weiyan Zhou
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, P.R. China
| | - Chao Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, P.R. China
| | - Tianjiao Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, P.R. China
| | - Chuanbao Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing, P.R. China
- National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, P.R. China
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Zhang X, Wu Y, Wang D. Clinical application of vancomycin TDM in ventilated patients with gastrointestinal cancer: a propensity-matched analysis. BMC Infect Dis 2024; 24:10. [PMID: 38166695 PMCID: PMC10759445 DOI: 10.1186/s12879-023-08885-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 12/08/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Therapeutic drug monitoring (TDM) of vancomycin is widely recommended for clinical treatment. Due to the complexity of 24-h area under the curve (AUC) guided vancomycin monitoring in clinical practice, the vancomycin trough level remains the most common and practical method. The purpose of this study was designed to investigate the differences in the safety and efficacies of vancomycin TDM based on the two different monitoring methods, and further explore the clinical application of trough-guided vancomycin monitoring in patients with gastrointestinal cancer requiring mechanical ventilation. METHODS We included a total of 78 gastrointestinal cancer patients who required mechanical ventilation due to various diseases. All patients included in this study were aged 18 years or older and were treated with intravenous vancomycin therapy for more than 2 days due to documented or suspected Gram-positive bacterial infections, and have at least one available vancomycin plasma concentration. First, we compared the safety and efficacies of vancomycin TDM based on different monitoring methods as trough-guided monitoring or AUC-guided monitoring. Then, based on whether the initial vancomycin concentration achieving the target trough concentration (less than 48 h), patients were divided into early and delayed groups, and the clinical factors were compared between them. The primary endpoints include the incidence of new-onset acute kidney injury (AKI) or renal replacement therapy (RRT), clinical success rate and 28-day all-cause mortality. Finally, the overall relationship between trough concentration and potential covariates is screened by univariate and multivariate analysis to explore potential information covariates. RESULTS The research revealed that patients with gastrointestinal cancer exhibited significantly lower initial vancomycin trough concentrations (median [interquartile range (IQR)]: 6.90[5.28-11.20] mg/L). And there were no statistically significant differences in the safety and efficacies of vancomycin TDM based on the two different monitoring methods for the primary endpoint. Moreover, base on trough-guided vancomycin monitoring, the early group demonstrated a notably shorter duration of mechanical ventilation compared with the delayed group (χ2 = 4.532; p < 0.05; Fig. 2E). Propensity score weighting further confirmed that the duration of mechanical ventilation (χ2 = 6.607; p < 0.05; Fig. 2F) and duration of vasoactive agent (χ2 = 6.106; p < 0.05; Fig. 2D) were significantly shorter in the early group compared with delayed group. Multivariate regression analysis revealed that Cystatin C (Cys-C) was the most important variable for vancomycin target trough achievement (odds ratio, 5.274; 95% CI, 1.780 to 15.627; p = 0.003). CONCLUSIONS Trough-guided vancomycin monitoring is a simple and effective marker of TDM for ventilated patients with gastrointestinal cancer. Timely achievement of target trough concentrations for vancomycin can improve partial clinical outcomes in Gram-positive bacterial infections. Cys-C level is a potentially valuable parameter for predicting the vancomycin concentration.
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Affiliation(s)
- Xiaowu Zhang
- Department of Intensive Care Unit, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin, 300060, China.
| | - Yulin Wu
- Department of Intensive Care Unit, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin, 300060, China
| | - Donghao Wang
- Department of Intensive Care Unit, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin, 300060, China
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Barreto EF, Chang J, Rule AD, Mara KC, Meade LA, Paul J, Jannetto PJ, Athreya AP, Scheetz MH. Impact of Various Estimated Glomerular Filtration Rate Equations on the Pharmacokinetics of Meropenem in Critically Ill Adults. Crit Care Explor 2023; 5:e1011. [PMID: 38107538 PMCID: PMC10723891 DOI: 10.1097/cce.0000000000001011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023] Open
Abstract
IMPORTANCE Meropenem dosing is typically guided by creatinine-based estimated glomerular filtration rate (eGFR), but creatinine is a suboptimal GFR marker in the critically ill. OBJECTIVES This study aimed to develop and qualify a population pharmacokinetic model for meropenem in critically ill adults and to determine which eGFR equation based on creatinine, cystatin C, or both biomarkers best improves model performance. DESIGN SETTING AND PARTICIPANTS This single-center study evaluated adults hospitalized in an ICU who received IV meropenem from 2018 to 2022. Patients were excluded if they had acute kidney injury, were on kidney replacement therapy, or were treated with extracorporeal membrane oxygenation. Two cohorts were used for population pharmacokinetic modeling: a richly sampled development cohort (n = 19) and an opportunistically sampled qualification cohort (n = 32). MAIN OUTCOMES AND MEASURES A nonlinear mixed-effects model was developed using parametric methods to estimate meropenem serum concentrations. RESULTS The best-fit structural model in the richly sampled development cohort was a two-compartment model with first-order elimination. The final model included time-dependent weight normalized to a 70-kg adult as a covariate for volume of distribution (Vd) and time-dependent eGFR for clearance. Among the eGFR equations evaluated, eGFR based on creatinine and cystatin C expressed in mL/min best-predicted meropenem clearance. The mean (se) Vd in the final model was 18.2 (3.5) liters and clearance was 11.5 (1.3) L/hr. Using the development cohort as the Bayesian prior, the opportunistically sampled cohort demonstrated good accuracy and low bias. CONCLUSIONS AND RELEVANCE Contemporary eGFR equations that use both creatinine and cystatin C improved meropenem population pharmacokinetic model performance compared with creatinine-only or cystatin C-only eGFR equations in adult critically ill patients.
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Affiliation(s)
| | - Jack Chang
- Department of Pharmacy Practice, Chicago College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, IL
- Department of Pharmacy, Northwestern Medicine, Chicago, IL
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
- Division of Epidemiology, Mayo Clinic, Rochester, MN
| | - Kristin C Mara
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
| | - Laurie A Meade
- Anesthesia Clinical Research Unit, Mayo Clinic, Rochester, MN
| | - Johar Paul
- Anesthesia Clinical Research Unit, Mayo Clinic, Rochester, MN
| | - Paul J Jannetto
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Arjun P Athreya
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN
| | - Marc H Scheetz
- Department of Pharmacy Practice, Chicago College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, IL
- Department of Pharmacy, Northwestern Medicine, Chicago, IL
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10
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Barreto EF, Chang J, Rule AD, Mara KC, Meade LA, Paul J, Jannetto PJ, Athreya AP, Scheetz MH. Population pharmacokinetic model of cefepime for critically ill adults: a comparative assessment of eGFR equations. Antimicrob Agents Chemother 2023; 67:e0081023. [PMID: 37882514 PMCID: PMC10648925 DOI: 10.1128/aac.00810-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/15/2023] [Indexed: 10/27/2023] Open
Abstract
Cefepime exhibits highly variable pharmacokinetics in critically ill patients. The purpose of this study was to develop and qualify a population pharmacokinetic model for use in the critically ill and investigate the impact of various estimated glomerular filtration rate (eGFR) equations using creatinine, cystatin C, or both on model parameters. This was a prospective study of critically ill adults hospitalized at an academic medical center treated with intravenous cefepime. Individuals with acute kidney injury or on kidney replacement therapy or extracorporeal membrane oxygenation were excluded. A nonlinear mixed-effects population pharmacokinetic model was developed using data collected from 2018 to 2022. The 120 included individuals contributed 379 serum samples for analysis. A two-compartment pharmacokinetic model with first-order elimination best described the data. The population mean parameters (standard error) in the final model were 7.84 (0.24) L/h for CL1 and 15.6 (1.45) L for V1. Q was fixed at 7.09 L/h and V2 was fixed at 10.6 L, due to low observed interindividual variation in these parameters. The final model included weight as a covariate for volume of distribution and the eGFRcr-cysC (mL/min) as a predictor of drug clearance. In summary, a population pharmacokinetic model for cefepime was created for critically ill adults. The study demonstrated the importance of cystatin C to prediction of cefepime clearance. Cefepime dosing models which use an eGFR equation inclusive of cystatin C are likely to exhibit improved accuracy and precision compared to dosing models which incorporate an eGFR equation with only creatinine.
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Affiliation(s)
- Erin F. Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Jack Chang
- Department of Pharmacy Practice, Chicago College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacy, Northwestern Medicine, Chicago, Illinois, USA
| | - Andrew D. Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kristin C. Mara
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
| | - Laurie A. Meade
- Anesthesia Clinical Research Unit, Mayo Clinic, Rochester, Minnesota, USA
| | - Johar Paul
- Anesthesia Clinical Research Unit, Mayo Clinic, Rochester, Minnesota, USA
| | - Paul J. Jannetto
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Arjun P. Athreya
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Marc H. Scheetz
- Department of Pharmacy Practice, Chicago College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacy, Northwestern Medicine, Chicago, Illinois, USA
| | - for the BLOOM Study Group
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
- Department of Pharmacy Practice, Chicago College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacy, Northwestern Medicine, Chicago, Illinois, USA
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
- Anesthesia Clinical Research Unit, Mayo Clinic, Rochester, Minnesota, USA
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
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11
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Campbell RE, Chen CH, Edelstein CL. Overview of Antibiotic-Induced Nephrotoxicity. Kidney Int Rep 2023; 8:2211-2225. [PMID: 38025228 PMCID: PMC10658282 DOI: 10.1016/j.ekir.2023.08.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 12/01/2023] Open
Abstract
Drug-induced nephrotoxicity accounts for up to 60% of cases of acute kidney injury (AKI) in hospitalized patients and is associated with increased morbidity and mortality in both adults and children. Antibiotics are one of the most common causes of drug-induced nephrotoxicity. Mechanisms of antibiotic-induced nephrotoxicity include glomerular injury, tubular injury or dysfunction, distal tubular obstruction from casts, and acute interstitial nephritis (AIN) mediated by a type IV (delayed-type) hypersensitivity response. Clinical manifestations of antibiotic-induced nephrotoxicity include acute tubular necrosis (ATN), AIN, and Fanconi syndrome. Given the potential nephrotoxic effects of antibiotics on critically ill patients, the use of novel biomarkers can provide information to optimize dosing and duration of treatment and can help prevent nephrotoxicity when traditional markers, such as creatinine, are unreliable. Use of novel kidney specific biomarkers, such as cystatin C and urinary kidney injury molecule-1 (KIM-1), may result in earlier detection of AKI, dose adjustment, or discontinuation of antibiotic and development of nonnephrotoxic antibiotics.
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Affiliation(s)
- Ruth E. Campbell
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Chang Huei Chen
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Charles L. Edelstein
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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12
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Ma Y, Ran F, Xin M, Gou X, Wang X, Wu X. Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel. J Pharm Anal 2023; 13:1205-1220. [PMID: 38024860 PMCID: PMC10657973 DOI: 10.1016/j.jpha.2023.05.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/08/2023] [Accepted: 05/12/2023] [Indexed: 12/01/2023] Open
Abstract
Renal tubular secretion mediated by organic anion transporters (OATs) and the multidrug resistance-associated protein 4 (MRP4) is an important means of drug and toxin excretion. Unfortunately, there are no biomarkers to evaluate their function. The aim of this study was to identify and characterize an endogenous biomarker of the renal tubular OATs-MRP4 channel. Twenty-six uremic toxins were selected as candidate compounds, of which kynurenic acid was identified as a potential biomarker by assessing the protein-binding ratio and the uptake in OAT1-, OAT3-, and MRP4-overexpressing cell lines. OAT1/3 and MRP4 mediated the transcellular vectorial transport of kynurenic acid in vitro. Serum kynurenic acid concentration was dramatically increased in rats treated with a rat OAT1/3 (rOAT1/3) inhibitor and in rOAT1/3 double knockout (rOAT1/3-/-) rats, and the renal concentrations were markedly elevated by the rat MRP4 (rMRP4) inhibitor. Kynurenic acid was not filtered at the glomerulus (99% of albumin binding), and was specifically secreted in renal tubules through the OAT1/3-MRP4 channel with an appropriate affinity (Km) (496.7 μM and 382.2 μM for OAT1 and OAT3, respectively) and renal clearance half-life (t1/2) in vivo (3.7 ± 0.7 h). There is a strong correlation in area under the plasma drug concentration-time curve (AUC0-t) between cefmetazole and kynurenic acid, but not with creatinine, after inhibition of rOATs. In addition, the phase of increased kynurenic acid level is earlier than that of creatinine in acute kidney injury process. These results suggest that albumin-bound kynurenic acid is an appropriate endogenous biomarker for adjusting the dosage of drugs secreted by this channel or predicting kidney injury.
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Affiliation(s)
- Yanrong Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Fenglin Ran
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Mingyan Xin
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Xueyan Gou
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Xinyi Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Xinan Wu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
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13
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Behal ML, Flannery AH, Barreto EF. Medication Management in the Critically Ill Patient with Acute Kidney Injury. Clin J Am Soc Nephrol 2023; 18:1080-1088. [PMID: 36723347 PMCID: PMC10564345 DOI: 10.2215/cjn.0000000000000101] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 01/20/2023] [Indexed: 02/02/2023]
Abstract
ABSTRACT AKI occurs frequently in critically ill patients. Patients with AKI, including those who require KRT, experience multiple pharmacokinetic and pharmacodynamic perturbations that dynamically influence medication effectiveness and safety. Patients with AKI may experience both subtherapeutic drug concentrations, which lead to ineffective therapy, and supratherapeutic drug concentrations, which increase the risk for toxicity. In critically ill patients with AKI not requiring KRT, conventional GFR estimation equations, especially those based on serum creatinine, have several limitations that can limit the accuracy when used for medication dosing. Alternative methods to estimate kidney function may be informative, including use of measured urinary creatinine clearance, kinetic eGFR, and equations that integrate novel kidney biomarkers. For critically ill patients with AKI requiring KRT, physicochemical properties of the drug, the KRT prescription and circuit configuration, and patient-specific factors each contribute to medication clearance. Evidence-based guidance for medication dosing during AKI requiring KRT is often limited. A working knowledge of the basic tenets of drug elimination during KRT can provide a framework for how to approach decision making when the literature is lacking. Iterative re-evaluation of a patient's progress toward therapeutic goals with a medication must occur over the arc of critical illness, including and especially in the setting of dynamic kidney function.
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Affiliation(s)
- Michael L. Behal
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, Kentucky
- Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, Kentucky
| | - Alexander H. Flannery
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, Kentucky
- Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, Kentucky
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14
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Hanna PE, Wang Q, Strohbehn IA, Moreno D, Harden D, Ouyang T, Katz-Agranov N, Seethapathy H, Reynolds KL, Gupta S, Leaf DE, Sise ME. Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer. JAMA Netw Open 2023; 6:e2321715. [PMID: 37405775 PMCID: PMC10323710 DOI: 10.1001/jamanetworkopen.2023.21715] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/19/2023] [Indexed: 07/06/2023] Open
Abstract
Importance Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR. Objective To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr. Design, Setting, and Participants This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date. Exposure The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr. Main Outcomes and Measures The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 μg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance. Results A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 μg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 μg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003). Conclusions and relevance Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.
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Affiliation(s)
- Paul E. Hanna
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Qiyu Wang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Ian A. Strohbehn
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Daiana Moreno
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Destiny Harden
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Tianqi Ouyang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Nurit Katz-Agranov
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Harish Seethapathy
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Kerry L. Reynolds
- Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Shruti Gupta
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - David E. Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Meghan E. Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
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15
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Hanna PE, Wang Q, Strohbehn I, Moreno D, Harden D, Ouyang T, Katz-Agranov N, Seethapathy H, Reynolds KL, Gupta S, Leaf DE, Sise ME. Medication-related adverse events in patients with cancer and discrepancies in cystatin C- versus creatinine-based eGFR. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.01.18.23284656. [PMID: 36711583 PMCID: PMC9882433 DOI: 10.1101/2023.01.18.23284656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with cancer. Cystatin C-based eGFR (eGFRCYS) is an alternative marker of kidney function. We investigated whether patients with an eGFR discrepancy, defined as eGFRCYS >30% lower than the concurrent eGFRCRE, had an increased risk of adverse events resulting from renally-cleared medications. Patients and Methods We conducted a cohort study of adult patients with cancer who had serum creatinine and cystatin C measured on the same day between May 2010 and January 2022 at two academic cancer centers in Boston, MA. The primary outcome was the incidence of each of the following medication-related adverse events: 1) supratherapeutic vancomycin levels (>30μg/mL); 2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5mEq/L); 3) baclofen-induced neurotoxicity; and 4) supratherapeutic digoxin levels (>2.0ng/mL). Results 1988 patients with cancer had simultaneous eGFRCYS and eGFRCRE. The mean age was 66 years (SD±14), 965 (49%) were female, and 1555 (78%) were non-Hispanic white. eGFR discrepancy occurred in 579 patients (29%). Patients with eGFR discrepancy were more likely to experience medication-related adverse events compared to those without eGFR discrepancy: vancomycin levels >30μg/mL (24% vs. 10%, p=0.004), trimethoprim- sulfamethoxazole-related hyperkalemia (24% vs. 12%, p=0.013), baclofen-induced neurotoxicity (25% vs. 0%, p=0.13), and supratherapeutic digoxin levels (38% vs. 0%, p=0.03). The adjusted OR for vancomycin levels >30μg/mL was 2.30 (95% CI 1.05 - 5.51, p = 0.047). Conclusion Among patients with cancer with simultaneous assessment of eGFRCYS and eGFRCRE, medication-related adverse events occur more commonly in those with eGFR discrepancy. These findings underscore the importance of accurate assessment of kidney function and appropriate dosing of renally-cleared medications in patients with cancer.
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Affiliation(s)
- Paul E Hanna
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Qiyu Wang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Ian Strohbehn
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Daiana Moreno
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Destiny Harden
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Tianqi Ouyang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Nurit Katz-Agranov
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Harish Seethapathy
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Kerry L Reynolds
- Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Shruti Gupta
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
- Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, MA
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - Meghan E Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
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16
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Ebert N, Bevc S, Bökenkamp A, Gaillard F, Hornum M, Jager KJ, Mariat C, Eriksen BO, Palsson R, Rule AD, van Londen M, White C, Schaeffner E. Assessment of kidney function: clinical indications for measured GFR. Clin Kidney J 2021; 14:1861-1870. [PMID: 34345408 PMCID: PMC8323140 DOI: 10.1093/ckj/sfab042] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Indexed: 12/18/2022] Open
Abstract
In the vast majority of cases, glomerular filtration rate (GFR) is estimated using serum creatinine, which is highly influenced by age, sex, muscle mass, body composition, severe chronic illness and many other factors. This often leads to misclassification of patients or potentially puts patients at risk for inappropriate clinical decisions. Possible solutions are the use of cystatin C as an alternative endogenous marker or performing direct measurement of GFR using an exogenous marker such as iohexol. The purpose of this review is to highlight clinical scenarios and conditions such as extreme body composition, Black race, disagreement between creatinine- and cystatin C-based estimated GFR (eGFR), drug dosing, liver cirrhosis, advanced chronic kidney disease and the transition to kidney replacement therapy, non-kidney solid organ transplant recipients and living kidney donors where creatinine-based GFR estimation may be invalid. In contrast to the majority of literature on measured GFR (mGFR), this review does not include aspects of mGFR for research or public health settings but aims to reach practicing clinicians and raise their understanding of the substantial limitations of creatinine. While including cystatin C as a renal biomarker in GFR estimating equations has been shown to increase the accuracy of the GFR estimate, there are also limitations to eGFR based on cystatin C alone or the combination of creatinine and cystatin C in the clinical scenarios described above that can be overcome by measuring GFR with an exogenous marker. We acknowledge that mGFR is not readily available in many centres but hope that this review will highlight and promote the expansion of kidney function diagnostics using standardized mGFR procedures as an important milestone towards more accurate and personalized medicine.
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Affiliation(s)
- Natalie Ebert
- Institute of Public Health, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastjan Bevc
- Department of Nephrology, Faculty of Medicine, Clinic for Internal Medicine, University Medical Center Maribor, University of Maribor, Maribor, Slovenia
| | - Arend Bökenkamp
- Department of Pediatric Nephrology, Amsterdam University Medical Center, Emma Kinderziekenhuis, Amsterdam, The Netherlands
| | - Francois Gaillard
- AP-HP, Hôpital Bichat, Service de Néphrologie, Université de Paris, INSERM U1149, Paris, France
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kitty J Jager
- Department of Medical Informatics, ERA-EDTA Registry, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Bjørn Odvar Eriksen
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
| | - Runolfur Palsson
- Internal Medicine Services, Division of Nephrology, Landspitali–The National University Hospital of Iceland and Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Marco van Londen
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Christine White
- Department of Medicine, Division of Nephrology, Queen’s University, Kingston, Canada
| | - Elke Schaeffner
- Institute of Public Health, Charité Universitätsmedizin Berlin, Berlin, Germany
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Abstract
Drugs are the third leading cause of acute kidney injury (AKI) in critically ill patients. Nephrotoxin stewardship ensures a structured and consistent approach to safe medication use and prevention of patient harm. Comprehensive nephrotoxin stewardship requires coordinated patient care management strategies for safe medication use, ensuring kidney health, and avoiding unnecessary costs to improve the use of nephrotoxins, renally eliminated drugs, and kidney disease treatments. Implementing nephrotoxin stewardship reduces medication errors and adverse drug events, prevents or reduces severity of drug-associated AKI, prevents progression to or worsening of chronic kidney disease, and alleviates financial burden on the health care system.
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Affiliation(s)
- Sandra L Kane-Gill
- Department of Pharmacy and Therapeutics, School of Pharmacy, Center for Critical Care Nephrology, School of Medicine, University of Pittsburgh, PRESBY/SHY Pharmacy Administration Building, 3507 Victoria Street, Mailcode PFG-01-01-01, Pittsburgh, PA 15213, USA.
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18
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Oh Y, Park S, Park E, Lee J, Lee H, Kim J, Cho J. Correlation between vancomycin clearance and cystatin C-based glomerular filtration rate in paediatric patients. Br J Clin Pharmacol 2021; 87:3190-3196. [PMID: 33496976 DOI: 10.1111/bcp.14733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/12/2020] [Accepted: 12/28/2020] [Indexed: 11/29/2022] Open
Abstract
AIMS Because of limitations with the serum creatinine-based glomerular filtration rate (GFRcr), estimates of the serum cystatin C-based glomerular filtration rate (GFRcys) are getting attention to predict vancomycin clearance (CLvan). We evaluated the correlations between (i) CLvan and GFRcr, and (ii) CLvan and GFRcys in paediatric patients. METHODS We evaluated a retrospective cohort of patients between 1 and 19 years old admitted to a tertiary hospital between 2017 and 2019. CLvan was estimated using measured vancomycin trough concentrations. We conducted Spearman's correlation analyses between CLvan and 1/creatinine, GFRcr, 1/cystatin C and GFRcys. Subgroup analyses were conducted for the young child, child, adolescent subgroups, intensive care unit patients and low body weight (<10th percentile) patients. RESULTS We analysed 40 patients. GFRcys correlated with CLvan better than GFRcr did (ρ = 0.731, P < 0.001 vs ρ = 0.504, P = 0.001). In the subgroup analyses, the correlation between GFRcys and CLvan was stronger than that between GFRcr and CLvan (child subgroup ρ = 0.712, P = 0.002 vs ρ = 0.282, P = 0.289; intensive care unit patients ρ = 0.772, P < 0.001 vs ρ = 0.540, P = 0.004; low body weight patients ρ = 0.671, P < 0.001 vs ρ = 0.464, P = 0.022). CONCLUSIONS Serum cystatin C-based GFR strongly correlates with vancomycin clearance, suggesting the possibility of better prediction models than creatinine-based GFR. Further prospective studies are required for the validation of the prediction model in a large paediatric population.
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Affiliation(s)
- Yunmi Oh
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sojin Park
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Esther Park
- Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jaehyun Lee
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hukyoung Lee
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeongmee Kim
- Department of Pharmaceutical Services, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joongbum Cho
- Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Teaford HR, Stevens RW, Rule AD, Mara KC, Kashani KB, Lieske JC, O'Horo J, Barreto EF. Prediction of Vancomycin Levels Using Cystatin C in Overweight and Obese Patients: a Retrospective Cohort Study of Hospitalized Patients. Antimicrob Agents Chemother 2020; 65:e01487-20. [PMID: 33106257 PMCID: PMC7927827 DOI: 10.1128/aac.01487-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/16/2020] [Indexed: 01/16/2023] Open
Abstract
The use of the kidney function biomarker cystatin C (cysC) can improve the accuracy of vancomycin dosing for target trough attainment in nonobese patients. It is unknown whether cysC can also improve vancomycin target trough attainment in overweight and obese patients. We conducted a retrospective observational study of overweight or obese hospitalized adults with stable renal function administered intravenous vancomycin between January 2011 and July 2019. Linear regression models were used to predict initial steady-state vancomycin troughs using several factors, including various cysC- and serum creatinine (SCr)-based estimates of kidney function. We compared the predicted proportion of patients within the target trough range (10 to 20 mg/liter) using the derived models to that observed from usual care. Of the 200 included patients, the mean trough level was 15 ± 6.3 mg/liter. The optimal model to predict the initial trough included both cysC and SCr (R2 = 0.48) rather than either biomarker alone. This model predicted that 79% (95% confidence interval [CI], 73% to 85%) of troughs could be between 10 and 20 mg/liter compared to the 62% observed in clinical practice (P < 0.001), a 1.3-fold increase. This study is the first to examine the role of cysC in predicting vancomycin levels in an exclusively overweight or obese population. While dosing models based on cysC appear promising in this setting, prospective validation is needed.
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Affiliation(s)
| | - Ryan W Stevens
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - John C Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - John O'Horo
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota, USA
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Markos JR, Schaepe KS, Teaford HR, Rule AD, Kashani KB, Lieske JC, Barreto EF. Clinician perspectives on inpatient cystatin C utilization: A qualitative case study at Mayo Clinic. PLoS One 2020; 15:e0243618. [PMID: 33306741 PMCID: PMC7732069 DOI: 10.1371/journal.pone.0243618] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/24/2020] [Indexed: 11/24/2022] Open
Abstract
Introduction Serum creatinine (SCr) testing has been the mainstay of kidney function assessment for decades despite known limitations. Cystatin C (CysC) is an alternative biomarker that is generally less affected than SCr by pertinent non-renal factors in hospitalized patients, such as muscle mass. Despite its potential advantages, the adoption of CysC for inpatient care is not widespread. At one hospital with CysC testing, we demonstrated a significant rise in non-protocolized use over the last decade. This study uses qualitative methods to provide the first report of how clinicians understand, approach, and apply CysC testing in inpatient care. Methods Fifteen clinicians from various disciplines were interviewed about their experience with inpatient CysC testing. The semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed thematically using a phenomenological approach. Results Knowledge and confidence with CysC varied greatly. Clinicians reported first learning about the test from colleagues on consulting services or multidisciplinary teams. The majority believed CysC to provide a more accurate measure of kidney function than SCr. Common scenarios for CysC ordering included medication dosing, evaluation of acute kidney injury, and a thorough evaluation of kidney function in patients with risk factors for an altered SCr. Facilitators for ordering CysC included the availability of rapid results turnaround and the automated calculation of glomerular filtration rate based on the biomarker. Barriers to use included a lack of education about CysC, and the absence of an institutional protocol for use. Discussion Clinicians at our site decided independent of institutional guidance whether and when CysC added value to patient care. While the majority of study participants indicated advantages to rapid turnaround CysC testing, its use depended not just on the features of the specific case but on clinician familiarity and personal preference. Findings from this research can guide the implementation and expansion of CysC testing.
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Affiliation(s)
- James Roland Markos
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Karen S. Schaepe
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, United States of America
| | - Hilary R. Teaford
- Department of Pharmacy, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Andrew D. Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States of America
- Division of Epidemiology, Mayo Clinic, Rochester, MN, United States of America
| | - Kianoush B. Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States of America
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - John C. Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States of America
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Erin F. Barreto
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, United States of America
- Department of Pharmacy, Mayo Clinic, Rochester, MN, United States of America
- * E-mail:
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Effect of Cystatin C on Vancomycin Clearance Estimation in Critically Ill Children Using a Population Pharmacokinetic Modeling Approach. Ther Drug Monit 2020; 42:848-855. [PMID: 32947559 DOI: 10.1097/ftd.0000000000000796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Vancomycin is eliminated by glomerular filtration, but current approaches to estimate kidney function in children are unreliable. The authors sought to compare the suitability of cystatin C (CysC)-based glomerular filtration rate equations with the most commonly used creatinine-based equation, bedside Schwartz, to estimate vancomycin clearance (CL). METHODS This prospective observational study enrolled critically ill patients (2-18 years) receiving intravenous vancomycin at the Children's Hospital of Philadelphia during December 2015-November 2017. Vancomycin levels were collected during clinical care and at 3 times during a single dosing interval. Plasma CysC was measured within 24 hours before intravenous vancomycin (baseline) initiation or immediately after enrollment and along with the third pharmacokinetic sample. Nonlinear mixed effects modeling was performed using NONMEM software. Covariate selection was used to test model fit with inclusion of the estimated glomerular filtration rate (eGFR) on CL using bedside Schwartz versus various published CysC-based equations. RESULTS In total, 83 vancomycin levels were obtained from 20 children. The median age was 12.7 years; 6 patients were women. A 1-compartment model best described the data; CL was allometrically scaled to 0.75. During covariate selection, inclusion of the eGFR calculated using a CysC-based equation significantly improved model fit [reduction in objective function value (OFV) range: -17.191 to -18.704] than bedside Schwartz ([INCREMENT]OFV -12.820). Including the full age spectrum equation, an eGFR equation based on both creatinine and CysC, led to the largest OFV reduction (-22.913); female sex was also a significant covariate of CL in the model. Final model pharmacokinetic indices were CL = 0.29 L/h/kg and volume of distribution = 0.48 L/kg. CONCLUSIONS CysC-based equations help better estimate vancomycin CL than bedside Schwartz in critically ill children.
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Šálek T, Vodička M, Gřiva M. Cystatin C may be better than creatinine for digoxin dosing in older adults with atrial fibrillation. J Clin Lab Anal 2020; 34:e23427. [PMID: 32716587 PMCID: PMC7595907 DOI: 10.1002/jcla.23427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/24/2020] [Accepted: 05/25/2020] [Indexed: 11/12/2022] Open
Abstract
Background Patients taking digoxin are older with high probability of having low muscle mass, and current clinical practice in digoxin dosing relies only on estimated glomerular filtration rate from serum creatinine (eGFRcrea). The aim of the study is to compare eGFRcrea and estimated glomerular filtration rate from serum cystatin C (eGFRcys) in older adult patients with atrial fibrillation (AF) overdosed with digoxin. Methods A total of 80 consecutive patients overdosed with digoxin and 33 controls with AF from Department of Internal Medicine were included in the prospective observational study. The median of age of participants was 81 years in both the overdosed and the control group. The eGFRs were calculated using The Chronic Kidney Disease Epidemiology (CKD‐ EPI) equations using standardized methods for serum creatinine and cystatin C measurement. Results The median (IQR) of eGFRcrea was higher than that of eGFRcys (45 mL/min/1.73 m2 (35‐59) vs 30 (21‐38), respectively; P < .0001) in overdosed patients. The median (IQR) of eGFRcrea was higher than that of eGFRcys (61 mL/min/1.73 m2 (49‐72) vs 40 (30‐56), respectively; P < .0001) in control group of patients. Serum predose digoxin concentration in overdosed patients was inversely associated with eGFRcys (ρ = −0.26, P < .05). Conclusion Physicians should consider GFR when changing digoxin dosing. eGFRcys was lower in both the overdosed and the control group. eGFRcys would lead to lower digoxin doses and thus prevent overdose.
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Affiliation(s)
- Tomáš Šálek
- Department of Clinical Biochemistry and Pharmacology The Tomas Bata Hospital in Zlín Zlín Czech Republic
- Department of Biomedical sciences Medical Faculty University of Ostrava Ostrava Czech Republic
| | - Martin Vodička
- Pharmacy The Tomas Bata Hospital in Zlín Zlín Czech Republic
| | - Martin Gřiva
- Department of Internal Medicine The Tomas Bata Hospital in Zlín Zlín Czech Republic
- Faculty of Medicine Palacký University Olomouc Olomouc Czech Republic
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Ostermann M, Zarbock A, Goldstein S, Kashani K, Macedo E, Murugan R, Bell M, Forni L, Guzzi L, Joannidis M, Kane-Gill SL, Legrand M, Mehta R, Murray PT, Pickkers P, Plebani M, Prowle J, Ricci Z, Rimmelé T, Rosner M, Shaw AD, Kellum JA, Ronco C. Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement. JAMA Netw Open 2020; 3:e2019209. [PMID: 33021646 DOI: 10.1001/jamanetworkopen.2020.19209] [Citation(s) in RCA: 388] [Impact Index Per Article: 77.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
IMPORTANCE In the last decade, new biomarkers for acute kidney injury (AKI) have been identified and studied in clinical trials. Guidance is needed regarding how best to incorporate them into clinical practice. OBJECTIVE To develop recommendations on AKI biomarkers based on existing data and expert consensus for practicing clinicians and researchers. EVIDENCE REVIEW At the 23rd Acute Disease Quality Initiative meeting, a meeting of 23 international experts in critical care, nephrology, and related specialties, the panel focused on 4 broad areas, as follows: (1) AKI risk assessment; (2) AKI prediction and prevention; (3) AKI diagnosis, etiology, and management; and (4) AKI progression and kidney recovery. A literature search revealed more than 65 000 articles published between 1965 and May 2019. In a modified Delphi process, recommendations and consensus statements were developed based on existing data, with 90% agreement among panel members required for final adoption. Recommendations were graded using the Grading of Recommendations, Assessment, Development and Evaluations system. FINDINGS The panel developed 11 consensus statements for biomarker use and 14 research recommendations. The key suggestions were that a combination of damage and functional biomarkers, along with clinical information, be used to identify high-risk patient groups, improve the diagnostic accuracy of AKI, improve processes of care, and assist the management of AKI. CONCLUSIONS AND RELEVANCE Current evidence from clinical studies supports the use of new biomarkers in prevention and management of AKI. Substantial gaps in knowledge remain, and more research is necessary.
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Affiliation(s)
- Marlies Ostermann
- Department of Critical Care and Nephrology, King's College London, Guy's and St Thomas' Hospital, London, United Kingdom
| | - Alexander Zarbock
- Department of Anaesthesiology, Intensive Care Medicine, and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Stuart Goldstein
- Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kianoush Kashani
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Division of Nephrology Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Etienne Macedo
- Division of Nephrology, Department of Medicine, University of California, San Diego
| | - Raghavan Murugan
- Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Max Bell
- Department of Perioperative Medicine and Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Lui Forni
- Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Surrey, United Kingdom
- Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University of Surrey, Surrey, United Kingdom
| | - Louis Guzzi
- Department of Critical Care Medicine, AdventHealth Waterman, Orlando, Florida
| | - Michael Joannidis
- Division of Intensive Care and Emergency Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Sandra L Kane-Gill
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
| | - Mathieu Legrand
- Department of Anesthesia and Perioperative Care, University of California, San Francisco
| | - Ravindra Mehta
- Department of Medicine, UCSD Medical Center, University of California, San Diego
| | | | - Peter Pickkers
- Department of Intensive Care Medicine, Nijmegen Medical Center, Radboud University, Nijmegen, the Netherlands
| | - Mario Plebani
- Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy
- Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - John Prowle
- William Harvey Research Institute, Royal London Hospital, Queen Mary University of London, London, United Kingdom
| | - Zaccaria Ricci
- Pediatric Cardiac Intensive Care Unit, Bambino Gesu Children's Hospital, Istituto Di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Thomas Rimmelé
- Anesthesiology and Intensive Care Medicine, Edouard Herriot Hospital, Lyon, France
| | - Mitchell Rosner
- Division of Nephrology, University of Virginia Health System, Charlottesville
| | - Andrew D Shaw
- Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - John A Kellum
- Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Claudio Ronco
- Department of Medicine, University of Padova, Padova, Italy
- Department of Nephrology, Dialysis, and Transplantation, International Renal Research Institute, San Bortolo Hospital, Vicenza, Italy
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Comparison of the Predictive Performance Between Cystatin C and Serum Creatinine by Vancomycin via a Population Pharmacokinetic Models: A Prospective Study in a Chinese Population. Eur J Drug Metab Pharmacokinet 2020; 45:135-149. [PMID: 31541402 DOI: 10.1007/s13318-019-00578-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Most of the current published population pharmacokinetic (PopPK) models are based on serum creatinine, but we often encounter an underestimation of its concentration in our clinical work. Therefore, we established a cystatin C-based model of vancomycin. OBJECTIVES The purpose of this study was to externally verify the PopPK model of vancomycin based on the glomerular filtration rate (GFR) estimated by serum cystatin C in our previous study and to compare the prediction performance of cystatin C (Cys C) and serum creatinine (SCR)-based models. METHODS The external data set consists of adults receiving vancomycin treatment at The First Affiliated Hospital of Guangxi Medical University. We summarized and restored published models based on serum creatinine values from the literature and used our external data set for initial screening. Visual and external verifications were used to further select candidate models for comparison. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were the primary outcomes for the overall comparison. Group comparisons of patients with different glomerular filtration rates (GFRs), ages and body mass index (BMI) levels were obtained by the Bayesian method. RESULTS A total of 156 patients with 233 samples were collected as an external data set. Sixteen published models were summarized and restored. After screening, four candidate models suitable for the external data set were finally obtained for comparison. The cystatin C-based model has a smaller ME value in the overall comparison. In the group comparison, serum creatinine-based models were underestimated in the prediction for patient groups with age ≥ 60 years, abnormal BMI values and GFR < 90 ml/min/1.73 m2, for which the cystatin C-based model could solve this problem. CONCLUSION After comparison, we suggest that cystatin C is a superior renal function marker to serum creatinine for vancomycin PopPK models.
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Population Pharmacokinetic Study of Ceftriaxone in Elderly Patients, Using Cystatin C-Based Estimates of Renal Function To Account for Frailty. Antimicrob Agents Chemother 2020; 64:AAC.00874-20. [PMID: 32778543 DOI: 10.1128/aac.00874-20] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/21/2020] [Indexed: 01/20/2023] Open
Abstract
Ceftriaxone is widely used for respiratory and urinary infections in elderly and frail patients, but there are few pharmacokinetic studies. A prospective population pharmacokinetic study of ceftriaxone in adults over 65 years old was undertaken. Dried blood spots collected at baseline (predose) and 0.5, 1, 4, 8, and 24 h after administration of 1 g of ceftriaxone were assayed using a validated liquid chromatography-mass spectroscopy analytical method. Frailty was classified using the Edmonton frailty scale and grip strength via a hand dynamometer. Estimates of glomerular filtration rate were determined using creatinine-based and cystatin C-based equations. Of 26 patients recruited, 23 (88%) were vulnerable or very frail. Estimates of drug clearance improved significantly with a cystatin C-based estimate of renal function that accounted for frailty. Simulations indicate that the combined effects of ranges of size and renal function resulted in a 6-fold range in peak ceftriaxone concentrations and 9-fold range in total exposure (area under the concentration-time curve [AUC]). For elderly patients with moderate or severe renal impairment, 48-h dosing results in greater trough concentrations and total exposure than the trough concentrations and total exposure in patients with normal renal function receiving 24-h dosing. Cystatin C-based measures of renal function improved predictions of ceftriaxone clearance in elderly patients.
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Kim MC, Kim SO, Kim SH, Shin JH, Choi SH, Chung JW, Hwang JH. Efficacy and Safety of Cystatin C-Guided Renal Dose Adjustment of Cefepime Treatment in Hospitalized Patients with Pneumonia. J Clin Med 2020; 9:E2803. [PMID: 32872649 PMCID: PMC7564664 DOI: 10.3390/jcm9092803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/20/2020] [Accepted: 08/28/2020] [Indexed: 11/22/2022] Open
Abstract
Cystatin C (CysC) may estimate renal function more accurately than serum creatinine (SCr). The clinical impact of renal dose adjustment of cefepime according to CysC rather than SCr has remained uncertain. We investigated the efficacy and safety of CysC-guided cefepime dosing compared with SCr-guided dosing in hospitalized patients with pneumonia. All adults hospitalized with pneumonia between July 2016 and December 2018 who used cefepime for at least 3 days were enrolled. Mortality, acute kidney injury (AKI), cefepime-induced encephalopathy (CIE), and Clostridium difficile infection were compared between the CysC-guided and SCr-guided groups. One hundred and ninety patients were divided into two groups: 129 and 61 received cefepime based on CysC and SCr, respectively. In-hospital mortality did not significantly differ between the groups (12% versus 31%; hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.31-1.77; p = 0.50). CysC-guided cefepime dosing decreased the risk of AKI (13% versus 61%; HR 0.18; 95% CI, 0.07-0.44; p < 0.001) and CIE (2% versus 11%; HR 0.11; 95% CI, 0.03-0.47; p = 0.003) compared with SCr-guided dosing. There was no significant difference in the risk of Clostridium difficile infection. CysC-guided dosing of cefepime was associated with decreased risk of the cefepime-associated morbidities including AKI and CIE without increasing mortality among the hospitalized patients with pneumonia.
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Affiliation(s)
- Min-Chul Kim
- Division of Infectious diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Korea; (M.-C.K.); (S.-H.C.); (J.-W.C.)
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Seon Ok Kim
- Departments of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Su-Hyun Kim
- Division of Nephrology, Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Korea; (S.-H.K.); (J.-h.S.)
| | - Jung-ho Shin
- Division of Nephrology, Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Korea; (S.-H.K.); (J.-h.S.)
| | - Seong-Ho Choi
- Division of Infectious diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Korea; (M.-C.K.); (S.-H.C.); (J.-W.C.)
| | - Jin-Won Chung
- Division of Infectious diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Korea; (M.-C.K.); (S.-H.C.); (J.-W.C.)
| | - Jin Ho Hwang
- Division of Nephrology, Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Korea; (S.-H.K.); (J.-h.S.)
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Teaford HR, Rule AD, Mara KC, Kashani KB, Lieske JC, Schreier DJ, Wieruszewski PM, Barreto EF. Patterns of Cystatin C Uptake and Use Across and Within Hospitals. Mayo Clin Proc 2020; 95:1649-1659. [PMID: 32753139 PMCID: PMC7412578 DOI: 10.1016/j.mayocp.2020.03.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 02/23/2020] [Accepted: 03/04/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To characterize the use of cystatin C (cysC) across and within hospitals. PATIENTS AND METHODS This 2-part study first evaluated access to cysC testing across 129 hospitals in the state of Minnesota, using a telephone-based survey. Second, granular data from a single center (Mayo Clinic) with on-site, rapid-turnaround testing (<1 day) and automated estimated glomerular filtration rate (eGFR) reporting was used to describe temporal patterns. The characteristics of hospitals that offered cysC testing and of patients who underwent rapid cysC testing at Mayo Clinic between January 1, 2011, and March 31, 2018, were described. Poisson regression analyzed temporal trends in cysC testing. RESULTS Of the 114 hospitals (88%) that responded to the statewide survey, cysC was available in 91 (80%), but only 3 of 91 (3%) reported a turnaround time of <1 day. At Mayo Clinic, cysC use increased from 0.74 tests per 1000 patient-days in 2011 to 14 tests per 1000 patient-days in 2018 (P=.004). Of the 3774 patients with cysC tests, the mean first available eGFR was 46 mL/min per 1.73 m2 using cysC and 59 mL/min per 1.73 m2 using serum creatinine (P<.001). CysC testing was used across all intensities of care and was ordered by a variety of specialties. Nephrology was consulted in only 42% of cases. CONCLUSION In the hospital, rapid-turnaround cysC testing is necessary for practical use but was not widely available in Minnesota. When available, a marked increase in cysC testing was observed over the study timeframe. Additional research is needed to determine optimal strategies for implementation of cysC within hospitals.
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Affiliation(s)
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Division of Epidemiology, Mayo Clinic, Rochester, MN
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | - John C Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | - Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN; Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.
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Bioelectrical Impedance Measurements for Assessment of Kidney Function in Critically Ill Patients. Crit Care Med 2020; 47:e984-e992. [PMID: 31609770 DOI: 10.1097/ccm.0000000000004033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To evaluate the use of multifrequency bioelectrical impedance analysis to predict creatinine/urea clearance based on 24 hours urine collection. A practical formula was developed, and its performance was compared with that of established formulas such as Cockcroft-Gault, Modification of Diet in Renal Disease, and Jelliffe's. DESIGN An open-label prospective observational cohort study. SETTING A 12-bed ICU at a nonuniversity major teaching hospital (Gelre ziekenhuizen Apeldoorn/Zutphen, The Netherlands). PATIENTS Adult critical care patients with an expected ICU length of stay at admission of at least 48 hours. INTERVENTIONS Each patient's body composition was assessed using a validated Quadscan 4000 analyzer (Bodystat, Isle of Man, British Isles). Twenty-four hours urine was collected, and laboratory variables in serum including creatinine, urea, and albumin were obtained at the beginning and end of the collection period. MEASUREMENTS AND MAIN RESULTS A total of 151 patients, stratified to an acute and nonacute ICU-group, were enrolled in the study over a 2-year period. A formula to predict creatinine/urea clearance based on 24 hours urine collection was developed using stepwise linear regression using a training data set of 75 patients. This formula was subsequently tested and compared with other relevant predictive equations using a validation data set of 76 patients. Serum creatinine values ranged from 40 to 446 µmol/L. With the predictive model based on estimated body cell mass and a "prediction marker" more than 71% of the observed variance in creatinine/urea clearance based on 24 hours urine collection could be explained. Predictive performance was superior to the other eight evaluated models (R = 0.39-0.55) and demonstrated to be constant over the whole range of creatinine/urea clearance based on 24 hours urine collection values. CONCLUSIONS Multifrequency bioelectrical impedance analysis measurements can be used to predict creatinine/urea clearance based on 24 hours urine collection with superior performance than currently established prediction models. This rapid, noninvasive method enables correction for influences of a patient's actual body composition and may prove valuable in daily clinical practice.
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Nei AM, Kashani KB, Dierkhising R, Barreto EF. Predictors of Augmented Renal Clearance in a Heterogeneous ICU Population as Defined by Creatinine and Cystatin C. Nephron Clin Pract 2020; 144:313-320. [PMID: 32428906 DOI: 10.1159/000507255] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 03/14/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION The incidence of augmented renal clearance (ARC) in the intensive care unit (ICU) is highly variable, and identification of these patients remains challenging. OBJECTIVE The objective of this study was to define the incidence of ARC in a cohort of critically ill adults, using serum Cr and cystatin C, and to identify factors associated with its development. METHODS This is a retrospective cohort study of critically ill patients without stage 2 or 3 acute kidney injury with both serum Cr and cystatin C available. The incidence of ARC was defined as a Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)Cr-cystatin C-estimated glomerular filtration rate >130 mL/min. A multivariable logistic regression model using a penalized Lasso method was fit to identify independent predictors of ARC. RESULTS Among the 368 patients included in the study, indication for ICU admission was nonoperative in 55% of patients, and 9% of patients were admitted for major trauma. The overall incidence of ARC was low at 4.1%. In a multivariable logistic regression model, Charlson comorbidity index, major trauma, intracerebral hemorrhage, age, and Sequential Organ Failure Assessment score were found to predict ARC. CONCLUSION The incidence of ARC in this study was low, but prediction models identified several factors for early identification of patients with risk factors for or who develop ARC, particularly in a cohort with a low baseline risk of ARC. These factors could be used to help identify patients who may develop ARC.
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Affiliation(s)
- Andrea M Nei
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA,
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.,Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ross Dierkhising
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA.,Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota, USA
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A Population Pharmacokinetics Model for Vancomycin Dosage Optimization Based on Serum Cystatin C. Eur J Drug Metab Pharmacokinet 2020; 45:535-546. [DOI: 10.1007/s13318-020-00621-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Teaford HR, Barreto JN, Vollmer KJ, Rule AD, Barreto EF. Cystatin C: A Primer for Pharmacists. PHARMACY 2020; 8:E35. [PMID: 32182861 PMCID: PMC7151673 DOI: 10.3390/pharmacy8010035] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/22/2020] [Accepted: 03/05/2020] [Indexed: 12/20/2022] Open
Abstract
Pharmacists are at the forefront of dosing and monitoring medications eliminated by or toxic to the kidney. To evaluate the effectiveness and safety of these medications, accurate measurement of kidney function is paramount. The mainstay of kidney assessment for drug dosing and monitoring is serum creatinine (SCr)-based estimation equations. Yet, SCr has known limitations including its insensitivity to underlying changes in kidney function and the numerous non-kidney factors that are incompletely accounted for in equations to estimate glomerular filtration rate (eGFR). Serum cystatin C (cysC) is a biomarker that can serve as an adjunct or alternative to SCr to evaluate kidney function for drug dosing. Pharmacists must be educated about the strengths and limitations of cysC prior to applying it to medication management. Not all patient populations have been studied and some evaluations demonstrated large variations in the relationship between cysC and GFR. Use of eGFR equations incorporating cysC should be reserved for drug management in scenarios with demonstrated outcomes, including to improve pharmacodynamic target attainment for antibiotics or reduce drug toxicity. This article provides an overview of cysC, discusses evidence around its use in medication dosing and in special populations, and describes practical considerations for application and implementation.
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Affiliation(s)
- Hilary R. Teaford
- Department of Pharmacy, Mayo Clinic, Rochester, MN 55905, USA; (H.R.T.); (J.N.B.)
| | - Jason N. Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN 55905, USA; (H.R.T.); (J.N.B.)
| | - Kathryn J. Vollmer
- College of Pharmacy and Health Sciences, Drake University, Des Moines, IA 50311, USA;
| | - Andrew D. Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA;
- Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA
| | - Erin F. Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN 55905, USA; (H.R.T.); (J.N.B.)
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN 55905, USA
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Yu G, Li GF. Is Cystatin C Good Enough as a Biomarker for Vancomycin Dosing: A Pharmacokinetic Perspective. Eur J Drug Metab Pharmacokinet 2019; 45:151-156. [PMID: 31691904 DOI: 10.1007/s13318-019-00587-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Guo Yu
- Institution of Drug Clinical Trial, Subei People's Hospital, #98 West Nantong Rd, Yangzhou, Jiangsu, 225001, China.,College of Pharmacy, Dalian Medical University, Dalian, Liaoning, China
| | - Guo-Fu Li
- Institution of Drug Clinical Trial, Subei People's Hospital, #98 West Nantong Rd, Yangzhou, Jiangsu, 225001, China.
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34
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Barreto EF, Poyant JO, Coville HH, Dierkhising RA, Kennedy CC, Gajic O, Nystrom EM, Takahashi N, Moynagh MR, Kashani KB. Validation of the sarcopenia index to assess muscle mass in the critically ill: A novel application of kidney function markers. Clin Nutr 2019; 38:1362-1367. [DOI: 10.1016/j.clnu.2018.05.031] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 03/28/2018] [Accepted: 05/30/2018] [Indexed: 12/13/2022]
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Abstract
Blood urea nitrogen and serum creatinine are imperfect markers of kidney function because they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released directly into the blood or urine by the kidney in response to injury may be a better early marker of drug-induced kidney toxicity than blood urea nitrogen and serum creatinine. Urine albumin and urine protein, as well as urinary markers kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), cystatin C, clusterin, and trefoil factor-3 (TFF-3) have been accepted by the Food and Drug Administration and European Medicines Agency as highly sensitive and specific urinary biomarkers to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. Other biomarkers of drug-induced kidney toxicity that have been detected in the urine of rodents or patients include IL-18, neutrophil gelatinase-associated lipocalin, netrin-1, liver-type fatty acid-binding protein (L-FABP), urinary exosomes, and TIMP2 (insulin-like growth factor-binding protein 7)/IGFBP7 (insulin-like growth factor-binding protein 7), also known as NephroCheck, the first Food and Drug Administration-approved biomarker testing platform to detect acute kidney injury in patients. In the future, a combined use of functional and damage markers may advance the field of biomarkers of drug-induced kidney toxicity. Earlier detection of drug-induced kidney toxicity with a kidney-specific biomarker may result in the avoidance of nephrotoxic agents in clinical studies and may allow for earlier intervention to repair damaged kidneys.
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Affiliation(s)
- Benjamin R Griffin
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado
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36
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Liu TT, Pang HM, Jing L, Wei WX, Qin XL, Guo Q, Lu H, Cheng DH, Jiang WZ. A population pharmacokinetic model of vancomycin for dose individualization based on serum cystatin C as a marker of renal function. ACTA ACUST UNITED AC 2019; 71:945-955. [PMID: 30873627 DOI: 10.1111/jphp.13071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 01/19/2019] [Indexed: 01/06/2023]
Abstract
OBJECTIVES This study aimed to establish a vancomycin population pharmacokinetics (PPK) model based on serum cystatin C and to optimize dosing for achieving targeted steady-state trough concentrations (Css ) of 10-15 and 15-20 mg/l. METHODS Patients aged ≥18 years were prospectively enrolled. A vancomycin PPK model was built with glomerular filtration rate (GFR) as a renal covariate estimated by cystatin C. A new group of patients were used for external evaluation. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed effect modelling programme. KEY FINDINGS Two hundreds of patients with 514 samples were included. The final model was CL (L/h) = (5.07 × (GFR/105.5)0.524 × (AGE/48.5)-0.309 × (WT/60)0.491 ); V (l) = 46.3. Internal and external evaluations demonstrated good stability and predictability. The average probability of target attainment (PTA) of optimal dosing regimens for targeted Css achieving 10-15 and 15-20 mg/l were 51.2% and 40.6%, respectively. An average PTA ≥71% for targeted concentration of 10-20 mg/l was obtained. CONCLUSIONS A vancomycin PPK model with cystatin C as the renal marker has good stability and predictability. The new proposed dosing regimens were predicted to achieve a good PTA.
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Affiliation(s)
- Tao-Tao Liu
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hui-Mei Pang
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Li Jing
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wen-Xing Wei
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiao-Ling Qin
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qing Guo
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hua Lu
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Dao-Hai Cheng
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wei-Zhe Jiang
- Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi, China
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Barreto EF, Rule AD, Murad MH, Kashani KB, Lieske JC, Erwin PJ, Steckelberg JM, Gajic O, Reid JM, Kane-Gill SL. Prediction of the Renal Elimination of Drugs With Cystatin C vs Creatinine: A Systematic Review. Mayo Clin Proc 2019; 94:500-514. [PMID: 30713050 DOI: 10.1016/j.mayocp.2018.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 07/05/2018] [Accepted: 08/07/2018] [Indexed: 01/08/2023]
Abstract
Serum cystatin C has been proposed as a kidney biomarker to inform drug dosing. We conducted a systematic review to synthesize available data for the association between serum cystatin C and drug pharmacokinetics, dosing, and clinical outcomes in adults (≥18 years). PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, and Scopus were systematically searched from 1946 to September 2017 to identify candidate studies. Studies of cystatin C as a predictor for acute kidney injury or for management of contrast-associated acute kidney injury were excluded. Also, studies were excluded if drug concentrations were unavailable and if a reference standard for drug dosing (eg, serum creatinine) was not concurrently reported. The outcomes of interest included drug clearance (L/h), concentrations (mg/L), target level achievement (%), therapeutic failure (%), and drug toxicity (%). We included 28 articles that evaluated 16 different medications in 3455 participants. Vancomycin was the most well-studied drug. Overall, cystatin C-based estimated glomerular filtration rate (eGFRCystatin C) was more predictive of drug levels and drug clearance than eGFRCreatinine. In only one study were target attainment and outcomes compared between 2 drug-dosing regimens, one based on eGFRCreatinine-Cystatin C and one dosed with the Cockcroft-Gault creatinine clearance equation. Compared with eGFRCreatinine, use of eGFRCystatin C to predict elimination of medications via the kidney was as accurate, if not superior, in most studies, but infrequently were data on target attainment or clinical outcomes reported. Drug-specific dosing protocols that use cystatin C to estimate kidney function should be tested for clinical application.
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Affiliation(s)
- Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN; Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Division of Epidemiology, Mayo Clinic, Rochester, MN
| | - M Hassan Murad
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | - John C Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | - Ognjen Gajic
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | - Joel M Reid
- Division of Medical Oncology, Mayo Clinic, Rochester, MN; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN
| | - Sandra L Kane-Gill
- Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA
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Barreto EF, Kanderi T, DiCecco SR, Lopez-Ruiz A, Poyant JO, Mara KC, Heimgartner J, Gajic O, Rule AD, Nystrom EM, Kashani KB. Sarcopenia Index Is a Simple Objective Screening Tool for Malnutrition in the Critically Ill. JPEN J Parenter Enteral Nutr 2018; 43:780-788. [PMID: 30561031 DOI: 10.1002/jpen.1492] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/19/2018] [Accepted: 11/14/2018] [Indexed: 01/04/2023]
Abstract
BACKGROUND Reliable and valid tools to screen for malnutrition in the intensive care unit (ICU) remain elusive. The sarcopenia index (SI) [(serum creatinine/serum cystatin C) × 100], could be an inexpensive, objective tool to predict malnutrition. We evaluated the SI as a screening tool for malnutrition in the ICU and compared it with the modified-NUTRIC score. MATERIALS AND METHODS This was a historical cohort study of ICU patients with stable kidney function admitted to Mayo Clinic ICUs between 2008 and 2015. Malnutrition was defined by the Subjective Global Assessment. Diagnostic performance was evaluated with the area under the receiver operating characteristic curve (AUC) and multivariable logistic regression. RESULTS Of the 398 included patients, 181 (45%) had malnutrition, with 34 (9%) scored as severely malnourished. The SI was significantly lower in malnourished patients than in well-nourished patients (64 ± 27 vs 72 ± 25; P = 0.002), and reductions in SI corresponded to increased malnutrition severity (P = 0.001). As a screening tool, the SI was an indicator of malnutrition risk (AUC 0.61) and performed slightly better than the more complex modified-NUTRIC score (AUC = 0.57). SI cutoffs of 101 and 43 had >90% sensitivity and >90% specificity, respectively, for the prediction of malnutrition. Patients with a low SI (≤43) had a significantly higher risk of mortality (HR = 2.61, 95% CI 1.06-6.48, P = 0.038). CONCLUSION The frequency of malnutrition was high in this critically ill population, and it was associated with a poor prognosis. The SI could be used to assess nutrition risk in ICU patients.
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Affiliation(s)
- Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA.,Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota, USA
| | - Tejaswi Kanderi
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, Pennsylvania, USA
| | - Sara R DiCecco
- Clinical Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Arnaldo Lopez-Ruiz
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Janelle O Poyant
- Department of Pharmacy, Tufts Medical Center, Boston, Massachusetts, USA
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Ognjen Gajic
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.,Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Erin M Nystrom
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Kianoush B Kashani
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
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Peters BJ, Rule AD, Kashani KB, Lieske JC, Mara KC, Dierkhising RA, Barreto EF. Impact of Serum Cystatin C-Based Glomerular Filtration Rate Estimates on Drug Dose Selection in Hospitalized Patients. Pharmacotherapy 2018; 38:1068-1073. [PMID: 30120844 DOI: 10.1002/phar.2175] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
STUDY OBJECTIVE Serum creatinine (Sc r ) concentration is used to calculate estimated glomerular filtration rate (eGFR) for medication dosing. Serum cystatin C (CysC) concentration has been proposed as an adjunct or alternative to Scr . This study sought to evaluate the possible impact of using CysC in eGFR equations on drug dose recommendations in hospitalized patients with infections. DESIGN Retrospective analysis of prospectively collected data. SETTING Large academic tertiary care medical center. PATIENTS A total of 308 adults with suspected or documented infections and stable kidney function who were hospitalized between 2012 and 2015. MEASUREMENTS AND MAIN RESULTS Standardized Sc r and CysC measured at the time of antibiotic dosing were used to estimate GFR from the three Chronic Kidney Disease Epidemiology Collaborative (CKD-EPI) equations using Sc r (eGFRCr ), CysC(eGFRCysC ), or a combination of Sc r and CysC (eGFRCr-CysC ), and these values were compared with estimated creatinine clearance (eClcr ) from the Cockcroft-Gault equation (standard of care for drug dosage adjustments). The eGFRs were categorized into five common dosage adjustment strata (lower than 20, 20-49, 50-79, 80-130, and higher than 130 ml/min), and agreement between equations was tested with the weighted κ statistic. Recommended drug doses varied considerably between the eClcr and the CKD-EPI equations (weighted κ [95% confidence interval]: eGFRCr 0.73 [0.68-0.79], eGFRCysC 0.42 [0.35-0.5], eGFRCr-CysC 0.65 [0.6-0.71]). If eGFRCr, eGFRCysC , or eGFRCr-CysC were used instead of eClcr to dose drugs, 11%, 12%, and 8% of doses, respectively, would be higher, and 12%, 38%, and 24% of doses, respectively, would be lower. CONCLUSION Significant discordance in drug doses was observed when the CKD-EPI equations were used in place of eClcr . When CysC was included in eGFR equations, recommended doses were often lower. Further study is needed to develop and test drug-specific dosing guidelines that incorporate alternate renal biomarkers and/or more contemporary eGFR equations.
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Affiliation(s)
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.,Division of Epidemiology, Mayo Clinic, Rochester, Minnesota
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.,Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
| | - John C Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.,Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Ross A Dierkhising
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota.,Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
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Wang CH, Rubinsky AD, Minichiello T, Shlipak MG, Price EL. Creatinine Versus Cystatin C: Differing Estimates of Renal Function in Hospitalized Veterans Receiving Anticoagulants. J Gen Intern Med 2018; 33:1299-1306. [PMID: 29855865 PMCID: PMC6082212 DOI: 10.1007/s11606-018-4461-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 10/13/2017] [Accepted: 04/13/2018] [Indexed: 11/26/2022]
Abstract
BACKGROUND Current practice in anticoagulation dosing relies on kidney function estimated by serum creatinine using the Cockcroft-Gault equation. However, creatinine can be unreliable in patients with low or high muscle mass. Cystatin C provides an alternative estimation of glomerular filtration rate (eGFR) that is independent of muscle. OBJECTIVE We compared cystatin C-based eGFR (eGFRcys) with multiple creatinine-based estimates of kidney function in hospitalized patients receiving anticoagulants, to assess for discordant results that could impact medication dosing. DESIGN Retrospective chart review of hospitalized patients over 1 year who received non-vitamin K antagonist anticoagulation, and who had same-day measurements of cystatin C and creatinine. PARTICIPANTS Seventy-five inpatient veterans (median age 68) at the San Francisco VA Medical Center (SFVAMC). MAIN MEASURES We compared the median difference between eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) study equation using cystatin C (eGFRcys) and eGFRs using three creatinine-based equations: CKD-EPI (eGFREPI), Modified Diet in Renal Disease (eGFRMDRD), and Cockcroft-Gault (eGFRCG). We categorized patients into standard KDIGO kidney stages and into drug-dosing categories based on each creatinine equation and calculated proportions of patients reclassified across these categories based on cystatin C. KEY RESULTS Cystatin C predicted overall lower eGFR compared to creatinine-based equations, with a median difference of - 7.1 (IQR - 17.2, 2.6) mL/min/1.73 m2 versus eGFREPI, - 21.2 (IQR - 43.7, - 8.1) mL/min/1.73 m2 versus eGFRMDRD, and - 25.9 (IQR - 46.8, - 8.7) mL/min/1.73 m2 versus eGFRCG. Thirty-one to 52% of patients were reclassified into lower drug-dosing categories using cystatin C compared to creatinine-based estimates. CONCLUSIONS We found substantial discordance in eGFR comparing cystatin C with creatinine in this group of anticoagulated inpatients. Our sample size was limited and included few women. Further investigation is needed to confirm these findings and evaluate implications for bleeding and other clinical outcomes. NIH TRIAL REGISTRY NUMBER Not applicable.
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Affiliation(s)
- Christina Hao Wang
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Anna D Rubinsky
- Kidney Health Research Collaborative, UCSF and SFVAMC, San Francisco, CA, USA
| | - Tracy Minichiello
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Michael G Shlipak
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA
- Kidney Health Research Collaborative, UCSF and SFVAMC, San Francisco, CA, USA
- Department of Epidemiology & Biostatistics, UCSF, San Francisco, CA, USA
| | - Erika Leemann Price
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
- Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA.
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Barreto EF, Rule AD, Voils SA, Kane-Gill SL. Innovative Use of Novel Biomarkers to Improve the Safety of Renally Eliminated and Nephrotoxic Medications. Pharmacotherapy 2018; 38:794-803. [PMID: 29883532 DOI: 10.1002/phar.2149] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Over the last decade, the discovery of novel renal biomarkers and research on their use to improve medication effectiveness and safety has expanded considerably. Pharmacists are uniquely positioned to leverage this new technology for renal assessment to improve medication dosing and monitoring. Serum cystatin C is a relatively new, inexpensive, functional renal biomarker that responds more quickly to changing renal function than creatinine and is not meaningfully affected by age, sex, skeletal muscle mass, dietary intake, or deconditioning. Cystatin C has been proposed as an adjunct or alternative to creatinine for glomerular filtration rate assessment and estimation of drug clearance. Tissue inhibitor of metalloproteinase-2·insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]) is a composite of two damage biomarkers released into the urine at a checkpoint in mitosis when renal cells undergo stress or sense a future risk of damage. Concentrations of [TIMP-2]·[IGFBP7] increase before a rise in serum creatinine is evident, thus providing insightful information for evaluation in the context of other patient data to predict the risk for impending kidney injury. This article provides a brief overview of novel renal biomarkers being used as a mechanism to improve medication safety including a discussion of cystatin C, as part of drug-dosing algorithms and specifically for vancomycin dosing, and the use of [TIMP-2]·[IGFBP7] for risk prediction in acute kidney injury and drug-induced kidney disease. Select cases of clinical experience with novel renal biomarkers are outlined, and lessons learned and future applications are described.
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Affiliation(s)
- Erin F Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota.,Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.,Division of Epidemiology, Mayo Clinic, Rochester, Minnesota
| | - Stacy A Voils
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Sandra L Kane-Gill
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
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Donato LJ, Meeusen JW, Lieske JC, Bergmann D, Sparwaßer A, Jaffe AS. Analytical performance of an immunoassay to measure proenkephalin. Clin Biochem 2018; 58:72-77. [PMID: 29782819 DOI: 10.1016/j.clinbiochem.2018.05.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 04/13/2018] [Accepted: 05/17/2018] [Indexed: 10/16/2022]
Abstract
BACKGROUND Endogenous opioids, enkephalins, are known to increase with acute kidney injury. Since the mature pentapeptides are unstable, we evaluated the performance of an assay that measures proenkephalin 119-159 (PENK), a stable peptide formed concomitantly with mature enkephalins. METHODS PENK assay performance was evaluated on two microtiterplate/chemiluminescence sandwich immunoassay formats that required 18 or 1 h incubation times. PENK concentration was measured in plasma from healthy individuals to establish a reference interval and in patients with varied levels of kidney function and comorbidities to assess the association with measured glomerular filtration rate (mGFR) using iothalamate clearance. RESULTS Assay performance characteristics in plasma were similar between the assay formats. Limit of quantitation was 26.0 pmol/L (CV = 20%) for the 1 h assay and 17.3 pmol/L (CV = 3%) for the 18 h assay. Measurable ranges were 26-1540 pmol/L (1 h assay) and 18-2300 pmol/L (18 h assay). PENK concentrations are stable in plasma stored ambient to 10 days, refrigerated to at least 15 days, and frozen to at least 90 days. Results were comparable in paired SST serum and EDTA plasma. Age and sex were not associated with PENK concentrations in healthy individuals (reference interval: 36-97.5 pmol/L). Plasma PENK concentration correlated with mGFR. In a multivariate model PENK concentration, age, sex and transplant status were significant predictors of mGFR, and 49% of predicted GFR values fell within 30% of the mGFR. CONCLUSIONS Both assay formats are accurate and precise for measuring clinically relevant PENK concentrations. The association of PENK concentration with mGFR is influenced by gender, age, and history of kidney transplantation. Future studies will determine if blood PENK can be used clinically to estimate GFR and/or detect AKI.
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Affiliation(s)
- Leslie J Donato
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States.
| | - Jeffrey W Meeusen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States
| | - John C Lieske
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States
| | | | | | - Allan S Jaffe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States; Division of Cardiology, Mayo Clinic, Rochester, MN 55905, United States
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Yasui T, Suzuki T, Hara F, Watanabe S, Uga N, Naoe A, Kondo Y. Tailored Predictive Formulas for Glomerular Filtration Rate for Early Detection of Deteriorating Renal Function After Pediatric Living-Donor Liver Transplant. EXP CLIN TRANSPLANT 2018. [PMID: 29534656 DOI: 10.6002/ect.2017.0159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES In pediatric patients, renal dysfunction after living-donor liver transplant is a major issue that is difficult to evaluate. Recently, predictive equations for Japanese children have been introduced. MATERIALS AND METHODS We conducted a retrospective study by prospectively collecting data on 26 patients under 16 years old who underwent living-donor liver transplant between June 2004 and March 2015. Serum creatinine and cystatin C levels were measured. Paired t tests and Bland-Altman plots were used to compare the following formulas for estimated glomerular filtration rate: the Schwartz formula and 3 formulas that were matched with Japanese children (polynomial, simple, and cystatin C formulas). RESULTS Average estimated glomerular filtrations rates (in mL/min/1.73 m2) were 143.46, 122.90, 121.58, and 123.31 using the Schwartz, polynomial, simple, and cystatin C formulas, respectively. The estimated glomerular filtrations rate for biliary atresia was 141.53 ± 31.37 versus 109.95 ± 19.52 for other diseases, with significant differences only noted with the cystatin C formula. The formulas tailored for Japanese children showed significantly lower estimated glomerular filtrations rates than those obtained using the Schwartz formula (P < .01). CONCLUSIONS The use of formulas for measuring estimated glomerular filtrations rates that are based on race may allow early detection of deteriorating renal function.
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Affiliation(s)
- Toshihiro Yasui
- From the Department of Pediatric Surgery, Fujita Health University, Toyoake, Aichi,Japan
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Methods of Estimating Kidney Function for Drug Dosing in Special Populations. Clin Pharmacokinet 2018; 57:943-976. [DOI: 10.1007/s40262-018-0628-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Delanaye P, Guerber F, Scheen A, Ellam T, Bouquegneau A, Guergour D, Mariat C, Pottel H. Discrepancies between the Cockcroft-Gault and Chronic Kidney Disease Epidemiology (CKD-EPI) Equations: Implications for Refining Drug Dosage Adjustment Strategies. Clin Pharmacokinet 2017; 56:193-205. [PMID: 27417226 DOI: 10.1007/s40262-016-0434-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
INTRODUCTION The dosages of many medications require adjustment for renal function. There is debate regarding which equation, the Chronic Kidney Disease Epidemiology (CKD-EPI) equation vs. the Cockcroft-Gault (CG) equation, should be recommended to estimate glomerular filtration rate. METHODS We used a mathematical simulation to determine how patient characteristics influence discrepancies between equations and analyzed clinical data to demonstrate the frequency of such discrepancies in clinical practice. In the simulation, the modifiable variables were sex, age, serum creatinine, and weight. We considered estimated glomerular filtration rate results in mL/min, deindexed for body surface area, because absolute excretory function (rather than per 1.73 m2 body surface area) determines the rate of filtration of a drug at a given plasma concentration. An absolute and relative difference of maximum (±) 10 mL/min and 10 %, respectively, were considered concordant. Clinical data for patients aged over 60 years (n = 9091) were available from one hospital and 25 private laboratories. RESULTS In the simulation, differences between the two equations were found to be influenced by each variable but age and weight had the biggest effect. Clinical sample data demonstrated concordance between CKD-EPI and CG results in 4080 patients (45 %). The majority of discordant results reflected a CG result lower than the CKD-EPI equation. With aging, the CG result became progressively lower than the CKD-EPI result. When weight increased, the opposite occurred. DISCUSSION The choice of equation for excretory function adjustment of drug dosage will have different implications for patients of different ages and body habitus. CONCLUSIONS The optimum equation for drug dosage adjustment should be defined with consideration of individual patient characteristics.
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Affiliation(s)
- Pierre Delanaye
- Division of Nephrology, Dialysis and Transplantation, CHU Sart Tilman, University of Liège (ULg-CHU), 4000, Liège, Belgium.
| | | | - André Scheen
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines, University of Liège, Liège, Belgium
| | - Timothy Ellam
- Sheffield Kidney Institute, Northern General Hospital and Department of Infection, Immunity and Cardiovascular Science, University of Sheffield, Sheffield, UK
| | - Antoine Bouquegneau
- Division of Nephrology, Dialysis and Transplantation, CHU Sart Tilman, University of Liège (ULg-CHU), 4000, Liège, Belgium
| | - Dorra Guergour
- Biochemistry Laboratory, Grenoble University Hospital, Grenoble, France
| | - Christophe Mariat
- Division of Nephrology, Dialysis, Transplantation and Hypertension, CHU Hôpital Nord, University Jean Monnet, PRES Université de LYON, Saint-Etienne, France
| | - Hans Pottel
- Department of Public Health and Primary Care, KU, Leuven Kulak, Kortrijk, Belgium
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Higdon EA, Kimmons LA, Duhart BT, Hudson JQ. Disagreement in Estimates of Kidney Function for Drug Dosing in Obese Inpatients. J Pharm Pract 2017; 32:41-47. [PMID: 29105574 DOI: 10.1177/0897190017737895] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND: The Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are used to estimate kidney function. However, utility has been questioned in the obese population. OBJECTIVE: To evaluate differences in estimates of kidney function in obese patients and implications for drug dosing. METHODS: This was a retrospective study of adult inpatients with a body mass index ≥30 kg/m2 and stable kidney function. Patients were categorized based on creatinine clearance (CrCl): group 1-CrCl ≥ 60 mL/min and group 2-CrCl 15 to 59 mL/min. Mean estimates of kidney function and recommended doses of 8 renally eliminated medications were compared. RESULTS: For the 166 patients included, mean estimates using CG, MDRD, and CKD-EPI for group 1 were 87 (23) mL/min, 91 (21) mL/min, and 96 (23) mL/min, respectively. Group 2 estimates were 42 (13) mL/min, 51 (15) mL/min, and 51 (16) mL/min, respectively. MDRD and CKD-EPI estimates were significantly higher than CG in 125 (75%) and 140 (84%) patients, respectively. Dose discrepancies were most often due to higher dose recommendations using MDRD or CKD-EPI compared to CG. CONCLUSION: Careful consideration of the method used to estimate kidney function, the method used for developing dosing recommendations, and the risk-benefit profile is warranted when designing drug regimens in obese individuals.
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Affiliation(s)
- Emily A Higdon
- 1 Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA
| | - Lauren A Kimmons
- 2 Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA
| | - Benjamin T Duhart
- 3 Department of Clinical Pharmacy, The University of Tennessee, Memphis, TN, USA
| | - Joanna Q Hudson
- 3 Department of Clinical Pharmacy, The University of Tennessee, Memphis, TN, USA.,4 Department of Medicine (Nephrology), The University of Tennessee, Memphis, TN, USA
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Frazee E, Rule AD, Lieske JC, Kashani KB, Barreto JN, Virk A, Kuper PJ, Dierkhising RA, Leung N. Cystatin C-Guided Vancomycin Dosing in Critically Ill Patients: A Quality Improvement Project. Am J Kidney Dis 2017; 69:658-666. [PMID: 28131530 DOI: 10.1053/j.ajkd.2016.11.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 11/10/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND The aim of the study was to determine whether a vancomycin dosing algorithm based on estimated glomerular filtration rate from creatinine and cystatin C levels (eGFRcr-cys) improves target trough concentration achievement compared to an algorithm based on estimated creatinine clearance (eCLcr) in critically ill patients. STUDY DESIGN This prospective quality improvement project evaluated intensive care unit (ICU) patients started on intravenous vancomycin using one of 2 different strategies. Dosing regimens were selected and implemented after an individualized goal trough range was established (10-15 or 15-20mg/L). Steady-state goal trough achievement was compared between treatment arms with and without adjustment for potential confounders. SETTING & PARTICIPANTS 3 medical and surgical ICUs at a single tertiary medical center. QUALITY IMPROVEMENT PLAN During January 2012 to October 2013, vancomycin was dosed according to eCLcr using the Cockcroft-Gault formula (control arm). During December 2013 to May 2015, a multidisciplinary quality improvement team implemented a novel vancomycin dosing algorithm according to eGFRcr-cys using the CKD-EPI equation (intervention arm). OUTCOME Steady-state initial goal vancomycin trough concentration achievement. MEASUREMENTS & RESULTS More patients in the intervention arm (67 of 135 [50%]) achieved therapeutic trough vancomycin levels than in the control arm (74 of 264 [28%]; OR, 2.53; 95% CI, 1.65-3.90; P<0.001). Improved trough achievement was maintained even after adjustment for age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) III score, fluid balance, baseline CLcr, surgical admission diagnosis, presence of sepsis, and goal trough concentration range (adjusted OR, 2.79; 95% CI, 1.76-4.44; P<0.001). Clinical outcomes were similar between groups. LIMITATIONS Nonrandomized, incomplete algorithm compliance. CONCLUSIONS A vancomycin dosing nomogram based on eGFRcr-cys significantly improved goal trough achievement compared to eCLcr among ICU patients with stable kidney function. Further studies are warranted to characterize the relationship between use of cystatin C-guided dosing and clinical outcomes.
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Affiliation(s)
- Erin Frazee
- Department of Pharmacy, Mayo Clinic, Rochester, MN.
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Division of Epidemiology, Mayo Clinic, Rochester, MN
| | - John C Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | | | - Abinash Virk
- Division of Infectious Diseases, Mayo Clinic, Rochester, MN
| | | | - Ross A Dierkhising
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
| | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
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Kane-Gill SL, Achanta A, Kellum JA, Handler SM. Clinical decision support for drug related events: Moving towards better prevention. World J Crit Care Med 2016; 5:204-211. [PMID: 27896144 PMCID: PMC5109919 DOI: 10.5492/wjccm.v5.i4.204] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 09/17/2016] [Accepted: 10/18/2016] [Indexed: 02/06/2023] Open
Abstract
Clinical decision support (CDS) systems with automated alerts integrated into electronic medical records demonstrate efficacy for detecting medication errors (ME) and adverse drug events (ADEs). Critically ill patients are at increased risk for ME, ADEs and serious negative outcomes related to these events. Capitalizing on CDS to detect ME and prevent adverse drug related events has the potential to improve patient outcomes. The key to an effective medication safety surveillance system incorporating CDS is advancing the signals for alerts by using trajectory analyses to predict clinical events, instead of waiting for these events to occur. Additionally, incorporating cutting-edge biomarkers into alert knowledge in an effort to identify the need to adjust medication therapy portending harm will advance the current state of CDS. CDS can be taken a step further to identify drug related physiological events, which are less commonly included in surveillance systems. Predictive models for adverse events that combine patient factors with laboratory values and biomarkers are being established and these models can be the foundation for individualized CDS alerts to prevent impending ADEs.
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Einhorn D, Mende CW. COMBINING CREATININE-BASED eGFR WITH CYSTATIN C-BASED EGFR TO BETTER ASSESS RENAL FUNCTION IN PATIENTS WITH DIABETES AND CHRONIC KIDNEY DISEASE 3A: IMPLICATIONS FOR DRUG SELECTION AND DOSAGE IN TYPE 2 DIABETES. Endocr Pract 2016; 21:1301-2. [PMID: 26509856 DOI: 10.4158/ep15821.ed] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Cystatin C Falsely Underestimated GFR in a Critically Ill Patient with a New Diagnosis of AIDS. Case Rep Nephrol 2016; 2016:9349280. [PMID: 27293926 PMCID: PMC4886077 DOI: 10.1155/2016/9349280] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 04/26/2016] [Indexed: 01/02/2023] Open
Abstract
Cystatin C has been suggested to be a more accurate glomerular filtration rate (GFR) surrogate than creatinine in patients with acquired immunodeficiency syndrome (AIDS) because it is unaffected by skeletal muscle mass and dietary influences. However, little is known about the utility of this marker for monitoring medications in the critically ill. We describe the case of a 64-year-old female with opportunistic infections associated with a new diagnosis of AIDS. During her course, she experienced neurologic, cardiac, and respiratory failure; yet her renal function remained preserved as indicated by an eGFR ≥ 120 mL/min and a urine output > 1 mL/kg/hr without diuresis. The patient was treated with nephrotoxic agents; therefore cystatin C was assessed to determine if cachexia was resulting in a falsely low serum creatinine. Cystatin C measured 1.50 mg/L which corresponded to an eGFR of 36 mL/min. Given the >60 mL/min discrepancy, serial 8-hour urine samples were collected and a GFR > 120 mL/min was confirmed. It is unclear why cystatin C was falsely elevated, but we hypothesize that it relates to the proinflammatory state with AIDS, opportunistic infections, and corticosteroids. More research is needed before routine use of cystatin C in this setting can be recommended.
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