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Detecting Nephrotoxicity Using Early Markers and Imaging Tools - Header

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7:45 am Registration and Morning Coffee

Understanding Mechanisms
of Nephrotoxicity

8:45 Chairperson’s Opening Remarks

Kendall Frazier, DVM, Ph.D., DAVCP, DABT, Director, Cellular and Molecular Pathology, Safety Assessment, GlaxoSmith Kline 

8:55 Cisplatin Nephrotoxicity and Renal Protective Strategies     

Zheng Dong, Ph.D., Professor, Department of Cellular Biology and Anatomy, Medical College of Georgia  

Cisplatin, a widely used chemotherapy drug, has major side effects in normal tissues, notably nephrotoxicity in kidneys. Research during last few years has delineated several signaling pathways leading to renal tubular damage and kidney injury in cisplatin nephrotoxicity, including a rapid DNA damage response. Importantly, cisplatin may activate different signaling pathways in normal tissues and tumors. Targeting these pathways may uncover clinically effective strategies for kideny protection without diminishing the chemotherapy efficacy of cisplatin in tumors.    

9:25 Primary Cell Cultures from Human and Rat Proximal Tubule as Models to Study Mechanisms of Acute Kidney Injury     

Lawrence H. Lash, Ph.D., Professor, Associate Chair, Pharmacology, School of Medicine, Wayne State University

Our laboratory has developed several in vitro models from rat and human kidney, using both non-specific toxic chemicals and specific nephrotoxicants, including halogenated solvents, analgesics, and antibiotics. One focus has been the metabolism and toxicity of the halogenated solvent trichloroethylene (TRI), which is a significant environmental contaminant that has the kidney as one target organ. Molecular approaches and proteomics have been integrated into our in vitro toxicology models to explore the role of specific proteins and examine the influence of disease processes, such as diabetic nephropathy and reduced nephron mass, on renal toxicological responses.      

9:55 Networking Coffee Break

Monitoring and Assessing Kidney Injury

10:25 Current Use of Renal Biomarkers in Early Drug Development 

Diann Weddle, Ph.D., D.V.M., Senior Pathologist, Pre-Clinical Safety, Abbott Laboratories 

An overview of renal toxicology will be presented including a discussion of use and limitations of current biomarkers. Key concepts will be further emphasized through case examples. Within the last year, the Predictive Safety Testing Consortium’s Nephrotoxicity Working Group submitted a qualification package for multiple renal biomarkers to the FDA and EMEA and received clearance for limited use in nonclinical and clinical drug development. Conclusions and recommendations from the submission will be summarized.  

10:55 Pre-Clinical Biomarkers of Nephrotoxicity: Applications in Drug Discovery and Development     

Eric Blomme, D.V.M., Ph.D., D.A.C.V.P., Senior Project Leader, Abbott Laboratories

This presentation will build upon the preceding presentation discussing the current use of renal biomarkers in early drug development. Specifically, several case examples will be used to illustrate how biomarkers of renal toxicity can be applied in drug discovery and development to increase probability of success and make better decisions on compounds at earlier stages. Data on performance characteristics for several of these biomarkers in rats will be presented.

11:25 Integrative Assessment of Drug-Induced Kidney Function Changes and Acute Injury Using an Automated Blood Sampling and Telemetry (ABST) System     

Yafei Chen, M.D., M.S., Scientist Safety Pharmacology, Global Safety Assessment, AstraZeneca Pharmaceuticals

~20% of hospital admissions are caused by nephrotoxic drugs due to acute kidney injury. Current preclinical methods are insufficient to detect and predict drug-induced changes in kidney function and/or kidney injury (DIKI). We will describe an integrated pharma-cology platform representing a convergence of automated blood sampling with telemetry (ABST) for simultaneous assessment of cardiovascular, renal hemodynamic and excretory functions, and nephron site-specific DIKI biomarkers in surgically prepared conscious rats. This integrated preclinical approach provides multiple translational markers for risk management in early clinical development.

11:55 Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own



1:30 pm Chairperson’s Remarks

W. Brian Reeves, M.D., F.A.C.P., Chief, Division of Nephrology, Professor and Vice Chair, Medicine, Penn State College of Medicine     

1:35 FEATURED PRESENTATION: Establishing the Context for Introducing New Safety Biomarkers into Clinical Trials  

Stephen FurlongStephen Furlong, Ph.D., Safety Science Lead, U.S., Patient Safety, AstraZeneca

There has been rapid progress in developing new safety biomarkers for monitoring organ toxicity. Some of these new markers have already been qualified for use in supporting pre-clinical studies. Efforts to qualify these new safety biomarkers for use in human clinical trials are also underway. This presentation will explore recent experiences with organ-specific markers and strategies and challenges for progressing these markers for support of clinical trials. 

2:05 Clinical Evaluation and Qualification of Kidney Safety Biomarkers: A Collaboration between Two Consortia

Maria Vassileva, Ph.D., Scientific Program Manager, The Biomarkers Consortium, Foundation for the NIH

The Biomarkers Consortium (BC), a public private partnership managed by the Foundation for the NIH, is preparing to launch an important project expected to generate the data needed to advance the regulatory acceptance of new biomarkers appropriate for monitoring kidney safety in the clinic, and reaching alignment on how these biomarkers could improve clinical diagnoses of drug-induced acute kidney injury during drug development and patient therapy with aminoglycosides in patients with cystic fibrosis and cisplatin in patients with head and neck cancer. This project is a collaboration between the BC and the Predictive Safety Testing Consortium of the Critical Path Institute.

2:35 Urinary Cytokines as Biomarkers of Nephrotoxicity     

W. Brian Reeves, M.D., F.A.C.P., Chief, Division of Nephrology, Professor and Vice Chair, Medicine, Penn State College of Medicine 

Inflammation is a critical component of drug-induced acute kidney injury. In response to injury, renal epithelial cells elaborate a variety of chemokines and cytokines which alter epithelial cell function and also lead to the recruitment and/or activation of inflammatory cells in the kidney. Levels of cytokines increase in the urine early after kidney injury and may provide a window to the inflammatory processes ongoing within the kidney.     

3:05 Sponsored Presentations (Opportunities Available)

3:35 Grand Opening Refreshment Break in the Exhibit Hall

4:35 Rapid Point-of-Care GFR: Technique, Diagnostic and Therapeutic Advantages     

Bruce A. Molitoris, M.D., Director, Division of Nephrology and Professor of Medicine, Indiana University

Glomerular filtration rate (GFR) is the most important measure of kidney function. Although many ways exist to measure GFR, there is no acceptable rapid point-of-care technique. Therefore, we have developed a fluorescent based ratiometric technique in dogs and pigs using an LED-based detection device and an intravenous optical catheter by using a non-filterable large red fluorescent dextran and a small kidney freely filterable FITC dextran. In less than one hour accurate GFRs are obtained in many conditions including acute kidney injury (AKI). We believe this has clinically important diagnostic and therapeutic advantages in AKI and chronic kidney disease.

5:05 PANEL DISCUSSION: Renal Injury Markers and How Effectively Can They Be Used?

Moderator: W. Brian Reeves, M.D., F.A.C.P., Chief, Nephrology; Professor and Vice Chair, Medicine, Penn State College of Medicine 

5:35 - 6:30 Happy Hour in the Exhibit Hall


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