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Chronic Kidney Disease: Inflammation and Oxidative Stress in Pathogenesis and Clinical Course

Wednesday, December 14, 2011

The New York Academy of Sciences

Presented By

 

According to the National Kidney Foundation, 26 million adults in the US currently have chronic kidney disease (CKD). Although CKD results from various etiologies, diabetes mellitus and hypertension are the major causes of this disease in the US. Diabetes mellitus, which can lead to diabetic nephropathy, is the single leading cause of kidney failure in the US, accounting for approximately 45% of patients who begin treatment for kidney failure each year. (For example, in 2001 more than 40,000 people with diabetes developed kidney failure.) Although ACE inhibitors and ARBs are the current standard of care for CKD, they do not cure the disease, and patients progressively lose kidney function while on these medications, albeit significantly less rapidly than if left untreated. For many years the prevailing view of the pathogenesis of CKD has been that declines in glomerular filtration rate (GFR) that lead to end-stage renal disease (ESRD) are caused by an irreversible loss of nephrons to fibrotic disease. However, a substantial body of epidemiological and structural data in diabetic patients with CKD has failed to establish a cause-effect relationship between fibrosis-mediated nephron loss and declining renal function. An emerging view is that CKD in diabetic patients is a disease of chronic inflammation and oxidative stress characterized by reduced nephron function secondary to endothelial dysfunction, mesangial expansion, and other inflammatory processes without significant fibrosis-mediated nephron loss. This suggests that the pathological basis of CKD in diabetic patients is, in part, chronic renal inflammation with an etiology similar to chronic vascular inflammation in cardiovascular disease. This explains why most diabetics with CKD also have cardiovascular disease and more frequently succumb to this comorbidity. As such, novel therapeutics that target inflammatory pathways in the kidney and vasculature may have utility in improving CKD outcomes. Evidence supporting the role of inflammation in the development and progression of CKD, together with recent results of clinical trials of an innovative drug that modulates inflammatory pathways in diabetic patients with CKD, will be presented at this symposium.

Networking reception to follow.

Registration Pricing

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Agenda

* Presentation times are subject to change.


Wednesday December 14, 2011

1:00 PM

Opening Remarks
Jennifer Henry, PhD, The New York Academy of Sciences
George B. Zavoico, PhD, MLV

1:15 PM

Oxidative Stress in CKD, the Nature, Mechanisms, and Consequences
Nick Vaziri, MD, University of California, Irvine, CA

1:55 PM

NGAL Defends the Urinary System by Chelating Iron
Jonathan N. Barasch, MD, PhD, Columbia University Medical Center

2:35 PM

The Burden of Chronic Kidney Disease: An Unmet Clinical Need
David G. Warnock, MD, University of Alabama at Birmingham, AL

3:15 PM

Coffee Break

3:40 PM

Bardoxolone Methyl: An Emerging Treatment for Chronic Kidney Disease
Colin Meyer, MD, Reata Pharmaceuticals, Inc.

4:20 PM

Panel Discussion
All speakers, moderated by George B. Zavoico, PhD, MLV

5:00 PM

Networking Reception

Speakers

Organizers

Colin Meyer, MD

Reata Pharmaceuticals, Inc.

Dr. Meyer is the Vice President, Product Development of Reata Pharmaceuticals and joined the company as its second employee. Dr. Meyer's primary role is to develop and implement strategies to move product candidates expeditiously through all stages of development. His duties include overseeing preclinical development, clinical pharmacology, and working with Reata's senior leadership team to design and implement development strategies for drug candidates. Dr. Meyer received a B.S. in chemistry with specialization in biochemistry and a B.A. in biology from the University of Virginia. He received an M.D. from the University of Texas Southwestern Medical School and an M.B.A. from Southern Methodist University Cox School of Business.

George Zavoico, PhD

MLV

George B. Zavoico, PhD, is Managing Director, Research, and a Senior Equity Research Analyst at MLV, a boutique investment bank and institutional broker-dealer based in New York. He has over 6 years of experience as a life sciences analyst writing research on publicly traded equities. Prior to MLV, he was an equity analyst with Westport Capital Markets and Cantor Fitzgerald. Prior to working as an analyst, Dr Zavoico established his own consulting company serving the biotech and pharmaceutical industries by providing competitive intelligence and marketing research, due diligence services, and guidance in regulatory affairs. He also wrote extensively on healthcare and the biotech and pharmaceutical industries for periodicals targeting the general public and industry executives. Dr Zavoico began his career as a Senior Research Scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals, Inc. and T Cell Sciences, Inc. (now Celldex Therapeutics, Inc.). He has a BS in Biology from St. Lawrence University and PhD in Physiology from the University of Virginia and has held post-doctoral positions at the University of Connecticut Health Sciences Center and Brigham and Women’s Hospital and Harvard Medical School.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Jonathan N. Barasch, MD, PhD

Columbia University Medical Center

Jonathan Barasch MD PhD studied organic and biochemistry at Dartmouth College and then completed medical and graduate studies at Columbia where he is an Associate Professor of Medicine and Cell Biology. He studies growth factors in the embryonic and adult kidney focusing on iron transport.

Colin Meyer, MD

Reata Pharmaceuticals, Inc.

Dr. Meyer is the Vice President, Product Development of Reata Pharmaceuticals and joined the company as its second employee. Dr. Meyer's primary role is to develop and implement strategies to move product candidates expeditiously through all stages of development. His duties include overseeing preclinical development, clinical pharmacology, and working with Reata's senior leadership team to design and implement development strategies for drug candidates. Dr. Meyer received a B.S. in chemistry with specialization in biochemistry and a B.A. in biology from the University of Virginia. He received an M.D. from the University of Texas Southwestern Medical School and an M.B.A. from Southern Methodist University Cox School of Business.

Nick Vaziri, MD

University of California, Irvine

Dr. Vaziri, MD, is emeritus professor of medicine, physiology and biophysics at the University of California, Schools of Medicine and Biological Science, Irvine, California. He is former chair of the Department of Medicine and past president of the School of Medicine’s academic senate at the University of California Irvine. He is a Master and a Laureate of the American College of Physicians, past president of the Western Association of Physicians, past president of the American Paraplegia Society, and recipient of numerous prestigious awards. He serves on the editorial board of several scientific journals.

Dr Vaziri has authored close to 500 original papers and 150 invited book chapters, reviews, and editorials. He has made seminal contributions to the understanding of the molecular mechanisms of lipid disorders, oxidative stress and inflammation in chronic renal disease.

David Warnock, MD

University of Alabama at Birmingham

Dr. Warnock's focus is on the factors, genetic and environmental that contribute to hypertension and chronic kidney disease. The spectrum extends from basic studies of salt and water transport systems to population based studies of the prevalence of CKD and the association with stroke and heart disease. Another focus is inherited disorders of renal function, with a current emphasis on the renal manifestations of Fabry disease. Over 40 patients with Fabry disease have been identified in Alabama and approximately 20 of them have been started on Enzyme Replacement Therapy.

A major part of current nephrology practice is focused on management of kidney disease in adults with type 2 diabetes mellitus, the most common cause of end-stage renal disease in many parts of the world. Dr. Warnock participated as an investigator in the phase 2B studies of bardoxolone methy in the treatment of moderate to severe chronic kidney disease in type 2 diabetics (N Engl J Med 365: 327-336, 2011), and now serves as a Senior Medial Advisor to Reata Pharma in Irving, Texas as bardoxolone methyl moves forward into the phase 3 outcome study (BEACON Trial) in partnership with Abbott Pharmaceuticals.

David Gene Warnock was born in Parker, Arizona on March 5, 1945. He received a BA degree in 1966 from the University of California at Berkeley and received his MD degree in 1970 from the University of California, San Francisco. His clinical training was completed at the University of California, San Francisco, including a 1 year research fellowship with Isidore Edelman, MD in the Cardiovascular Research Institute. Following a fellowship with Maurice Burg, MD at the NIH, Dr. Warnock returned to UCSF as a faculty member. He served as the Section Chief at the San Francisco VA Medical Center during the last 5 years of his appointment at UCSF. Following a sabbatical with Bernard Rossier, MD at the Institute of Pharmacology in Lausanne, Switzerland, Dr. Warnock was recruited to UAB, and served as the Director of Nephrology from 1988 to 2008. Dr. Warnock served at the Director of the Office of Human Research at UAB from May 1, 2005 through September 30, 2008. He spent a 6-month sabbatical in 2008 at the College de France in Paris with Frederic Jaisser and Pierre Corvol. Dr. Warnock’s research interests include acid-base physiology, sodium transport mechanisms, chronic kidney disease, diabetes and kidney disease, and inherited renal diseases.

Sponsors

For sponsorship opportunities please contact Carmen McCaffery at cmccaffery@nyas.org or 212.298.8642.

Promotional Partners

Fistula First

The Journal of Clinical Investigation

Grant Support

Genzyme Corporation

Abstracts

Oxidative Stress in CKD, the Nature, Mechanisms and Consequences
Nick Vaziri, MD, University of California, Irvine, CA

Oxidative stress is a constant feature of chronic kidney disease (CKD). Oxidative stress in CKD is both a cause and a consequence of inflammation. Oxidative stress and inflammation are the major mediators of progression of renal disease and the associated cardiovascular complications, anemia, neurological disorders, cachexia, and accelerated aging etc. Oxidative stress in CKD is due to a combination of increased production of reactive oxygen species (ROS) and impaired antioxidant system. Increased ROS production in CKD is caused by upregulation/activation of ROS-producing enzymes, mitochondrial dysfunction, uncoupling of NO synthase, increased tissue iron stores, and activation of leukocyte/macrophages & resident cells (Inflammation) among others. Increased ROS production in CKD is compounded by the failure of the antioxidant defense system which is, in part, due to the impaired activation of Nrf2 (the master regulator of genes encoding numerous antioxidant and cytoprotective molecules), anemia, HDL deficiency and dysfunction, among others. This presentation is intended to provide an overview of the nature, mechanisms and adverse consequences of oxidative stress and its constant companion, inflammation, in CKD.
 

NGAL Defends the Urinary System by Chelating Iron
Jonathan N. Barasch, MD, PhD, Columbia University Medical Center

A member of the Lipocalin Superfamily, named Lipocalin-2 or Neutrophil-Gelatinase-Associated Lipocalin (NGAL) or Siderocalin was expressed at very low levels in blood and urine at steady state, but it was dramatically stimulated by the common causes of acute kidney injury (AKI). The level of protein expression in fact predicted both the severity and the duration of AKI in humans and animals (Mori, JCI, 2005; Nickolas, Annals of Internal Medicine, 2008). Consistently, NGAL/Siderocalin expression was also associated with an elevated burden of tubulo-interstitial damage in later stages of chronic kidney diseases (CKD), rather than with reversible glomerular damage (Paragas, JASN, 2009). Quantitative analysis of NGAL/Siderocalin expression using bioluminescence reporters and stringent molecular identification demonstrated that unexpected distal tubular segments were the source of urinary and serum NGAL/Siderocalin (Paragas, Nature Med, 2011). The expression was under the control of TLR4 signaling in the case of bacterial stimuli, but the mechanism of its induction by aseptic stimuli has remained unknown. Secreted NGAL/Siderocalin recognized a Gram negative bacterial siderophore, called Enterochelin (Ent). The interaction (identified by Roland Strong, Fred Hutchinson Cancer Research Center) interrupted iron transfer from the host to bacteria by removing Ent::Fe+3 in a protein complex (NGAL/Siderocalin::Ent::Fe+3), resulting in bacteriostasis. Chelation of the metabolic product catechol (NGAL/Siderocalin::catechol3:: Fe+3) may mimic the siderophore (Bao, Nature Chem Biol, 2010) and act locally at the site of injury in the urogenital system. NGAL/Siderocalin also has growth regulatory activities in kidney mesenchyme (Yang, Molecular Cell, 2002) and cysts (Viau JCI, 2010), but the mechanisms of action are unclear since only the megalin clearance receptor is documented (Mori JCI, 2005). In sum, NGAL/Siderocalin expression is one of the earliest and most intensive indicators of kidney tubulo-interstital damage. It is a binding protein for iron associated siderophores resulting in bacteriostasis. Activities such as cystic growth will require the identification of receptor mediated signaling.
 

The Burden of Chronic Kidney Disease: An Unmet Clinical Need
David G. Warnock, MD, University of Alabama at Birmingham, AL

CKD in patients with diabetes is associated with chronic inflammation and oxidative stress, glomerular endothelial dysfunction, mesangial-cell contraction and glomerular fibrosis and decline in kidney function. Bardoxolone methyl, an antioxidant inflammation modulator (AIM), activates the Keap1–Nrf2 pathway, with subsequent up-regulation of a multitude of cytoprotective genes. The structure and activity profile of bardoxolone methyl resemble those of the cyclopentenone prostaglandins, endogenous Nrf2 activators that promote the resolution of inflammation. Like cyclopentenone prostaglandins, bardoxolone methyl exerts anti-inflammatory effects by inhibiting the proinflammatory nuclear factor κB pathway. In a previous phase 2 trial, we found that daily administration of bardoxolone methyl for 8 weeks significantly increased the estimated glomerular filtration rate (GFR). In a randomized, placebo-controlled 52-week Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) study, we assessed the effects of three doses of bardoxolone methyl on the estimated GFR at 24 and 52 weeks in patients with CKD and type 2 diabetes. In an ongoing prospective, double-blind placebo control trial (BEACON; clinicaltrials.gov NCT01351675), the effects of bardoxolone methyl are being examined in adult patients with type 2 diabetes mellitus and severe CKD with eGFR < 30 mL/min/1.73 m2. The BEACON study is designed to assess the efficacy of bardoxolone methyl relative to placebo in delaying progression to end-stage renal disease (ESRD) and cardiovascular deaths in patients with Stage 4 CKD and type 2 diabetes receiving standard of care. Secondary outcome measures include:

  • Rate of change in eGFR over the duration of the study
  • Time to first hospitalization for heart failure
  • Time to first event in the composite cardiorenal endpoint defined as:
    • Cardiovascular death
    • Non-fatal myocardial infarction
    • Non-fatal stroke
    • Hospitalization for heart failure

Recruitment for the BEACON Trial will be completed in 2012.
 

Bardoxolone Methyl: An Emerging Treatment for Chronic Kidney Disease
Colin Meyer, MD, Reata Pharmaceuticals, Inc.

Bardoxolone methyl is the lead molecule in Reata's portfolio of Antioxidant Inflammation Modulators (AIMs). The AIMs are potent inducers of the transcription factor Nrf2, an important biological target that controls the production of many of the body's antioxidant and detoxification enzymes, and inhibitors of NF-kB, a central transducer of inflammatory signaling. Because oxidative stress and inflammation occur throughout the course of chronic kidney disease (CKD) and are known to contribute to loss of kidney function, agents that activate the Nrf2 pathway in patients with CKD may provide a novel method for preserving or improving kidney function. This talk will review the pharmacology of bardoxolone methyl and recent clinical results. Rationale and design for the ongoing multi-national phase 3 study will also be discussed.
 

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