PREVENTION OF HEMODIALYSIS VASCULAR ACCESS STENOSIS
Alfred K Cheung
University Of Utah, 75 South 2000 East, Salt Lake City, Ut 84112
Grant 5R01HL067646-08 from National Heart, Lung, And Blood Institute
Abstract: Stenosis caused by neointimal hyperplasia (NH) often occurs focally at the anastomoses of arteriovenous (AV) grafts used for hemodialysis, leading to thrombosis and occlusion. This is a competitive renewal resubmission for a project to develop novel sustained drug delivery systems that could be injected percutaneously and allow local delivery of anti-proliferative drugs to prevent graft stenosis. The Bioengineering area is "Clinical Medicine, Therapeutics and Drug Delivery". Using a unique polymeric drug depot (ReGel) to deliver paclitaxel perivascularly, we have demonstrated the feasibility of this approach in a canine model. We have now perfected a porcine model and demonstrated the sustained, quantifiable delivery of dipyridamole and rapamycin from the perivascular depot into the vessel walls over weeks. The 4 specific aims in this renewal are to (1) optimize sustained-release polymer gel systems for local delivery of specific anti-proliferative drugs based on each drug´s physicochemical, pharmacokinetic and pharmacodynamic properties; (2) develop and validate finite element models to predict the long-term pharmacokinetics of drugs administered perivascularly using sustained-delivery systems at the anastomoses of AV grafts; (3) identify drugs that are safe and efficacious in preventing stenosis at the graft anastomoses when administered using sustained-delivery systems; (4) adapt and refine 3D imaging modalities, including magnetic resonance angiography (MRA), for more accurate quantification of stenosis progression and drug efficacy at the graft anastomoses in the porcine model. There are 6 Leading Investigators in 5 departments (1) R. Rathi, MacroMed, Inc. (development of polymers for drug delivery); (2) S. Kern, Depts. of Pharmaceutics and Bioengineering and M. Kirby, Scientific Computing & Imaging Institute (pharmacokinetic modeling and validation in tissues); (3) D. Blumenthal, Dept. of Pharmacology & Toxicology (characterization of in vitro drug efficacy and mechanism of action); (4) A. Cheung, Dept. of Medicine, U. of Utah (animal experiments and clinical correlation) who also serves as the PI and Project Manager; (5) D. Parker, Dept. of Radiology (MRA imaging development and 3D reconstruction of NH morphology). This multidisciplinary team, using an integrative systems approach, is essential for the development of innovative methods to solve an important clinical problem. It will also offer excellent opportunities for trainees of various disciplines to interact with each other in a collaborative manner. It is highly likely that, within this 5-year proposal, the results of this project can be applied to pilot clinical studies
Keywords: 3-D; 3-Dimensional; Address; Algorithms; Anastomosis; Anastomosis - action; Animal Experiments; Animals; Anzatax; Area; Arteries; Arteriovenous Anastomosis; Arteriovenous Shunt; Asotax; Biomedical Engineering; Blood Vessels; Body Tissues; Bristaxol; CAT Scan, X-Ray; CAT scan; CT X Ray; CT scan; Canine Species; Canis familiaris; Cell Culture Techniques; Characteristics; Clinical; Clinical Medicine; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Computed Tomography; Computer Assisted; Computer Systems Development; Computerized Axial Tomography (Computerized Tomography); Computerized Tomography, X-Ray; Constriction, Pathologic; Constriction, Pathological; Data; Development; Development, Computer Systems; Dialysis; Dialysis procedure; Diffusion; Dipyramidole; Dipyridamole; Discipline; Dogs; Drug Delivery; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug Targetings; Drug Transport; Drug usage; Drugs; EMI scan; Editorial Comment; Editorial Comment (PT); Elements; Ethanol, 2, 2`, 2``, 2```-((4, 8-di-1-piperidinylpyrimido(5, 4-d)pyrimidine-2, 6-diyl)dinitrilo)tetrakis-; Ethene, tetrafluoro-, homopolymer; FEP; FLR; Failure (biologic function); Family suidae; Funding; Future; Gel; Goals; Grant; Hemodialyses; Hemodialysis; Hyperplasia; Hyperplastic; Image; Imaging Procedures; Imaging Techniques; In Vitro; Individual; Industry; Institutes; Investigators; Lesion; MRI Angiography; Magnetic Resonance Angiography; Mammals, Dogs; Math Models; Medical Device; Medical Sciences, Clinical; Medication; Medicine; Methods; Microbeads; Microspheres; Modeling; Monitor; Morphology; NIH; National Institutes of Health; National Institutes of Health (U.S.); Outcome; PTFE; Paclitaxel; Paclitaxel (Taxol); Patients; Persantin; Persantine; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmaceutics; Pharmacodynamics; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Pharmacology and Toxicology; Pharmacy (field); Physiologic arteriovenous anastomosis; Pigs; Polymers; Polytef; Polytetrafluoroethylene; Postdoc; Postdoctoral Fellow; Praxel; Preparation; Prevention; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Published Comment; Radiology; Radiology Specialty; Radiology, General; Rapamune; Rapamycin; Research; Research Associate; Research Personnel; Researchers; Safety; Science of Medicine; Sirolimus; Stenosis; Students; Suidae; Swine; System; System, LOINC Axis 4; Systems Development; TFE; Taxol; Taxol (Old NSC); Taxol A; Taxol Konzentrat; Technics, Imaging; Testing; Therapeutic; Thrombosis; Tissue Model; Tissues; Tomodensitometry; Tomography, Xray Computed; Training; Translating; Translatings; United States National Institutes of Health; Utah; Validation; Vascular Graft; Veins; Venous; Viewpoint; Viewpoint (PT); Work; X-Ray Computed Tomography; antiproliferative drugs; base; bioengineering; bioengineering/biomedical engineering; canine; catscan; clinical investigation; complex biological systems; computed axial tomography; computer aided; computerized axial tomography; computerized tomography; copolymer; design; designing; dialysis therapy; domestic dog; drug efficacy; drug use; drug/agent; failure; imaging; imaging modality; in vivo; innovate; innovation; innovative; language translation; local drug delivery; mathematical model; mathematical modeling; meetings; multidisciplinary; novel; pharmacokinetic model; physiologic anastomosis; porcine; post-doc; post-doctoral; prevent; preventing; programs; reconstruction; scientific computing; success; suid; vascular; vascular smooth muscle cell proliferation
Project start date: 2001-04-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PAR-04-023
5R01HL067646-08 (2010): $1114245
Sponsored Links Excellgen http://Excellgen.com
PREVENTION OF HEMODIALYSIS VASCULAR ACCESS STENOSIS
Alfred K Cheung, Professor
University Of Utah, 75 South 2000 East, Salt Lake City, Ut 84112
Grant 5R01HL067646-07 from National Heart, Lung, And Blood Institute
Abstract: Stenosis caused by neointimal hyperplasia (NH) often occurs focally at the anastomoses of arteriovenous (AV) grafts used for hemodialysis, leading to thrombosis and occlusion. This is a competitive renewal resubmission for a project to develop novel sustained drug delivery systems that could be injected percutaneously and allow local delivery of anti-proliferative drugs to prevent graft stenosis. The Bioengineering area is "Clinical Medicine, Therapeutics and Drug Delivery". Using a unique polymeric drug depot (ReGel) to deliver paclitaxel perivascularly, we have demonstrated the feasibility of this approach in a canine model. We have now perfected a porcine model and demonstrated the sustained, quantifiable delivery of dipyridamole and rapamycin from the perivascular depot into the vessel walls over weeks. The 4 specific aims in this renewal are to (1) optimize sustained-release polymer gel systems for local delivery of specific anti-proliferative drugs based on each drug´s physicochemical, pharmacokinetic and pharmacodynamic properties; (2) develop and validate finite element models to predict the long-term pharmacokinetics of drugs administered perivascularly using sustained-delivery systems at the anastomoses of AV grafts; (3) identify drugs that are safe and efficacious in preventing stenosis at the graft anastomoses when administered using sustained-delivery systems; (4) adapt and refine 3D imaging modalities, including magnetic resonance angiography (MRA), for more accurate quantification of stenosis progression and drug efficacy at the graft anastomoses in the porcine model. There are 6 Leading Investigators in 5 departments (1) R. Rathi, MacroMed, Inc. (development of polymers for drug delivery); (2) S. Kern, Depts. of Pharmaceutics and Bioengineering and M. Kirby, Scientific Computing & Imaging Institute (pharmacokinetic modeling and validation in tissues); (3) D. Blumenthal, Dept. of Pharmacology & Toxicology (characterization of in vitro drug efficacy and mechanism of action); (4) A. Cheung, Dept. of Medicine, U. of Utah (animal experiments and clinical correlation) who also serves as the PI and Project Manager; (5) D. Parker, Dept. of Radiology (MRA imaging development and 3D reconstruction of NH morphology). This multidisciplinary team, using an integrative systems approach, is essential for the development of innovative methods to solve an important clinical problem. It will also offer excellent opportunities for trainees of various disciplines to interact with each other in a collaborative manner. It is highly likely that, within this 5-year proposal, the results of this project can be applied to pilot clinical studies
Keywords: 3-D; 3-Dimensional; Address; Algorithms; Anastomosis; Anastomosis - action; Animal Experiments; Animals; Anzatax; Area; Arteries; Arteriovenous Anastomosis; Arteriovenous Shunt; Asotax; Biomedical Engineering; Blood Vessels; Body Tissues; Bristaxol; CAT Scan, X-Ray; CAT scan; CT X Ray; CT scan; Canine Species; Canis familiaris; Cell Culture Techniques; Characteristics; Clinical; Clinical Medicine; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Computed Tomography; Computer Assisted; Computer Systems Development; Computerized Axial Tomography (Computerized Tomography); Computerized Tomography, X-Ray; Constriction, Pathologic; Constriction, Pathological; Data; Development; Development, Computer Systems; Dialysis; Dialysis procedure; Diffusion; Dipyramidole; Dipyridamole; Discipline; Dogs; Drug Delivery; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug Targetings; Drug Transport; Drug usage; Drugs; EMI scan; Editorial Comment; Editorial Comment (PT); Elements; Ethanol, 2, 2`, 2``, 2```-((4, 8-di-1-piperidinylpyrimido(5, 4-d)pyrimidine-2, 6-diyl)dinitrilo)tetrakis-; Ethene, tetrafluoro-, homopolymer; FEP; FLR; Failure (biologic function); Family suidae; Funding; Future; Gel; Goals; Grant; Hemodialyses; Hemodialysis; Hyperplasia; Hyperplastic; Image; Imaging Procedures; Imaging Techniques; In Vitro; Individual; Industry; Institutes; Investigators; Lesion; MRI Angiography; Magnetic Resonance Angiography; Mammals, Dogs; Math Models; Medical Device; Medical Sciences, Clinical; Medication; Medicine; Methods; Microbeads; Microspheres; Modeling; Monitor; Morphology; NIH; National Institutes of Health; National Institutes of Health (U.S.); Outcome; PTFE; Paclitaxel; Paclitaxel (Taxol); Patients; Persantin; Persantine; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmaceutics; Pharmacodynamics; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Pharmacology and Toxicology; Pharmacy (field); Physiologic arteriovenous anastomosis; Pigs; Polymers; Polytef; Polytetrafluoroethylene; Postdoc; Postdoctoral Fellow; Praxel; Preparation; Prevention; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Published Comment; Radiology; Radiology Specialty; Radiology, General; Rapamune; Rapamycin; Research; Research Associate; Research Personnel; Researchers; Safety; Science of Medicine; Sirolimus; Stenosis; Students; Suidae; Swine; System; System, LOINC Axis 4; Systems Development; TFE; Taxol; Taxol (Old NSC); Taxol A; Taxol Konzentrat; Technics, Imaging; Testing; Therapeutic; Thrombosis; Tissue Model; Tissues; Tomodensitometry; Tomography, Xray Computed; Training; Translating; Translatings; United States National Institutes of Health; Utah; Validation; Vascular Graft; Veins; Venous; Viewpoint; Viewpoint (PT); Work; X-Ray Computed Tomography; antiproliferative drugs; base; bioengineering; bioengineering/biomedical engineering; canine; catscan; clinical investigation; complex biological systems; computed axial tomography; computer aided; computerized axial tomography; computerized tomography; copolymer; design; designing; dialysis therapy; domestic dog; drug efficacy; drug use; drug/agent; failure; imaging; imaging modality; in vivo; innovate; innovation; innovative; language translation; local drug delivery; mathematical model; mathematical modeling; meetings; multidisciplinary; novel; pharmacokinetic model; physiologic anastomosis; porcine; post-doc; post-doctoral; prevent; preventing; programs; reconstruction; scientific computing; success; suid; vascular; vascular smooth muscle cell proliferation
Project start date: 2001-04-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: PAR-04-023
5R01HL067646-07 (2009): $1103993
5R01HL067646-06 (2008): $1050526
5R01HL067646-05 (2007): $1045217
5R01HL067646-03 (2004): $887386
Grants awarded to Alfred K Cheung
TRAINING PROGRAM IN NEPHROLOGY RESEARCH
Alfred K Cheung
University Of Utah, 75 South 2000 East, Salt Lake City, Ut 84112
Grant 5T32DK070557-04 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This proposal is for support of a Nephrology Training Program at the University of Utah Health Sciences Center for four postdoctoral positions, involving both Ph.D.´s and M.D.´s, over a five year period. The Nephrology Training Program consists of several groups of investigators who extensively interact. There are 14 preceptors and 18 collaborators involved. Many investigators are located within the Divisions of Adult and Pediatric Nephrology, however there are investigators in the Departments of Human Genetics, Pathology, Medical Informatics, Physiology, Neurobiology and Anatomy, and Bioengineering, as well as the Divisions of Cardiology, Endocrinology, Pulmonary and Epidemiology. The major research groups are organized into those investigating 1) collecting duct biology, involving the roles of endothelins, nitric oxide, prostaglandins, reactive oxygen species and the purinergic system in regulating collecting duct and medullary function in health and in hypertension; 2) acute renal failure, studying the pathophysiology of ischemic, drug-induced, and toxin-induced acute renal failure models; 3) progression of chronic renal failure, studying the mechanisms of renal fibrosis in models of diabetic nephropathy, chronic cyclosporine nephropathy, and mesangial proliferative GN; 4) renal development, emphasizing relevant transcriptional regulatory pathways; and 5) ESRD and chronic renal insufficiency, involving analysis of outcomes, interventions and pathobiology. Trainees can become involved in either clinical or basic research projects. All trainees will experience a multidimensional approach to their training. Clinical research trainees are enrolled in the K-30 program wherein they are exposed to a wide variety of clinical research projects. Basic researcher trainees experience a large faculty group with complementary research interests. All trainees spend at least two years devoted to research
Keywords: Nephrology; Research; Training Programs
Project start date: 2007-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-06-468
5T32DK070557-04 (2010): $100047
5T32DK070557-03 (2009): $116420
CLINICAL OUTCOME OF HEMODIALYSIS IN UTAH
Alfred K Cheung, Professor Of Medicine
University Of Utah 75 South 2000 East Salt Lake City, Ut 84112
Grant 5U01DK049252-08 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: The mortality rate of U.S. chronic hemodialysis patients is higher than that in other industrialized nations. Available data suggest that this high mortality rate is partially a result of inadequate delivery of dialysis. The MMHD is a prospective, randomized, multicenter, two-by-two factorial trial sponsored by NIDDK to determine if increasing the amount of delivered dialysis (as assessed by a two-pool, variable-volume urea kinetic model) and using high flux biocompatible dialysis membranes would improve the clinical outcome of these patients. This application describes the University of Utah Dialysis Program (together with the Salt Lake City VA Medical Center dialysis unit) and proposes that this Program participates as a Clinical Center in the MMHD Full Scale Study. The University of Utah Dialysis Program consists of 7 dialysis units, some of which are located in suburban communities, that have common administrative and medical guidelines originating from the University headquarters. The VA-unit is also closely affiliated and has similar protocols. The investigators in this proposal have significant expertise in their respective areas. Both the institution and the investigators have a long tradition in laboratory and clinical dialysis research. They have recently performed several clinical studies involving patients from the different dialysis units within the Program. The P.I. has also participated in several multicenter clinical trials with centers outside Utah. The ESRD population in this Program has been growing. The number of in-center hemodialysis patients, as of December 31, 1993, was 237, of which 37% were diabetic. The majority of these patients are Caucasian (78%), but there is a significant fraction (5%) of Native Americans. This Program will recruit approximately 108 patients during the first 18 months of the Study and randomly allocate 60 of them to 4 hemodialysis treatment strategies that differ in the amount of delivered dialysis and/or the type of dialysis membrane. Sixty patients will be maintained throughout the study by using a "recruit to replace" strategy. Many of the medical and technical aspects of therapy, including nutritional intake, will be standardized during the baseline and a 60 month follow-up period. The primary outcome is death of the patient; secondary outcomes include non-access related hospitalization, hospitalization for heart disease or infection, and declining serum album in. The results from this trial will guide hemodialysis therapy in the future.
Keywords: chronic renal failure, hemodialysis, human morbidity, human mortality, human therapy evaluation, outcomes research, biomaterial evaluation, cardiovascular disorder, clinical trial, cooperative study, infection, medical complication, nutrition, serum albumin, blood chemistry, human subject
Project start date: 1994-09-30
Project end date: 2004-08-31
5U01DK049252-08 (2001): $292251
5U01DK049252-07 (2000): $245457
5U01DK049252-06 (1999): $245457
5U01DK049252-05 (1998): $233776
5U01DK049252-04 (1997): $226679
5U01DK049252-02 (1995): $194397
Prevention Of Hemodialysis Vascular Access Stenosis
Alfred K Cheung, Professor Of Medicine
University Of Utah 75 South 2000 East Salt Lake City, Ut 84112
Grant 2R01HL067646-04A1 from National Heart, Lung, And Blood Institute IRG: ZRG1
Abstract: Stenosis caused by neointimal hyperplasia (NH) often occurs focally at the anastomoses of arteriovenous (AV) grafts used for hemodialysis, leading to thrombosis and occlusion. This is a competitive renewal resubmission for a project to develop novel sustained drug delivery systems that could be injected percutaneously and allow local delivery of anti-proliferative drugs to prevent graft stenosis. The Bioengineering area is "Clinical Medicine, Therapeutics and Drug Delivery". Using a unique polymeric drug depot (ReGel) to deliver paclitaxel perivascularly, we have demonstrated the feasibility of this approach in a canine model. We have now perfected a porcine model and demonstrated the sustained, quantifiable delivery of dipyridamole and rapamycin from the perivascular depot into the vessel walls over weeks. The 4 specific aims in this renewal are to (1) optimize sustained-release polymer gel systems for local delivery of specific anti-proliferative drugs based on each drug s physicochemical, pharmacokinetic and pharmacodynamic properties; (2) develop and validate finite element models to predict the long-term pharmacokinetics of drugs administered perivascularly using sustained-delivery systems at the anastomoses of AV grafts; (3) identify drugs that are safe and efficacious in preventing stenosis at the graft anastomoses when administered using sustained-delivery systems; (4) adapt and refine 3D imaging modalities, including magnetic resonance angiography (MRA), for more accurate quantification of stenosis progression and drug efficacy at the graft anastomoses in the porcine model. There are 6 Leading Investigators in 5 departments (1) R. Rathi, MacroMed, Inc. (development of polymers for drug delivery); (2) S. Kern, Depts. of Pharmaceutics and Bioengineering and M. Kirby, Scientific Computing and Imaging Institute (pharmacokinetic modeling and validation in tissues); (3) D. Blumenthal, Dept. of Pharmacology and Toxicology (characterization of in vitro drug efficacy and mechanism of action); (4) A. Cheung, Dept. of Medicine, U. of Utah (animal experiments and clinical correlation) who also serves as the PI and Project Manager; (5) D. Parker, Dept. of Radiology (MRA imaging development and 3D reconstruction of NH morphology). This multidisciplinary team, using an integrative systems approach, is essential for the development of innovative methods to solve an important clinical problem. It will also offer excellent opportunities for trainees of various disciplines to interact with each other in a collaborative manner. It is highly likely that, within this 5-year proposal, the results of this project can be applied to pilot clinical studies.
Keywords: arteriovenous shunt surgery, artery stenosis, drug delivery system, drug screening /evaluation, gel, graft versus host disease, growth inhibitor, hemodialysis, histocompatibility, nonhuman therapy evaluation, postoperative complication, angiography, longitudinal animal study, pharmacokinetics, vascular smooth muscle, clinical research, human subject, magnetic resonance imaging, swine, tissue /cell culture
Project start date: 2001-04-01
Project end date: 2011-08-31
2R01HL067646-04A1 (2006): $1048737
MATURATION OF HEMODIALYSIS ARTERIOVENOUS FISTULAS
Alfred K Cheung
University Of Utah, 75 South 2000 East, Salt Lake City, Ut 84112
Grant 5U01DK082222-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Many arteriovenous fistulas (AVFs) suffer thrombosis or fail to mature and become usable. The Univ. of Utah will participate as a Clinical Center to conduct a prospective multi-center observational cohort study, investigating factors associated with the failure of AVF to mature. Major hypotheses are(1) The usability of native AVF in CKD and dialysis patients can be predicted by a number of pre-, peri- and post-operative factors. (2) Defining these factors will allow the development of algorithms that are superior to physical examination alone in predicting AVF usability. (3) The blood flow rate and depth of the AVF determined by ultrasound at certain post-placement time points can serve as a surrogate for the usability of AVF. Specific Aims are to (1) determine the pre-, peri- and post-operative local and/or systemic factors associated with AVF failure and the prevalence of these factors; (2) identify and evaluate intermediate outcomes as potential surrogates for AVF usability; (3) participate in the design and execution of the multi-center study. Other Aims are to (4) determine the medical complications associated with the unusable AVF; (5) propose as ancillary studies the values of very early (3-hr) ultrasound results, plasma inflammation markers and novel platelet markers as predictors of AVF failure. Strengths of this application are (1) a dedicated, multi-disciplinary team of researchers, with experience in clinical care of dialysis patients and AVF, and in clinical and laboratory research related to vascular access and kidney diseases; (2) a sizable independent academic dialysis program under the direction of the PI that would ensure maximum cooperation from the dialysis staff; (3) as Co-investigators, a surgical team that integrates vascular surgery with interventional radiology, vascular diagnostic tests and research; (4) integration of clinical and laboratory research that should facilitate the exploration of novel biological principles and therapies. Successful development of a prediction algorithm for AVF failure will help to guide the clinical practice of whether, when and how to place, monitor and/or implement corrective actions for the AVF. Identification of risk factors for usability failure and establishment of an objective biological surrogate for usability would facilitate the design of interventional trials targeting modifiable factors. Further, the pursuit of novel factors may promote the understanding of the pathogenesis of AVF failure that could potentially lead to new therapeutic strategies
Keywords: Algorithms; Ancillary Study; Arteriovenous Aneurysm; Arteriovenous fistula; Biological; Bizzozero`s corpuscle/cell; Blood; Blood Plasma; Blood Platelets; Blood Vessels; Blood flow; Characteristics; Chronic; Clinical; Clinical Trials Design; Coagulants; Cohort Studies; Comorbidity; Concurrent Studies; Deetjeen`s body; Development; Diagnosis, Ultrasound; Diagnostic tests; Dialysis; Dialysis patients; Dialysis procedure; Echography; Echotomography; Ensure; FLR; Failure (biologic function); Fistula; Future; Goals; Hayem`s elementary corpuscle; Heel; Hemodialyses; Hemodialysis; Human Resources; Individual; Interventional radiology; Investigators; Kidney Diseases; Laboratory Research; Lead; Location; Manpower; Marrow platelet; Measures; Mediating; Medical Imaging, Ultrasound; Medical Inspection; Methods and Techniques; Methods, Other; Monitor; Natural History; Nephropathy; Operation; Operative Procedures; Operative Surgical Procedures; Outcome; Outcome Measure; Pathogenesis; Patients; Pb element; Physical Examination; Plasma; Platelets; Plethysmography; Population; Post-Operative; Postoperative; Postoperative Period; Predictive Factor; Prevalence; Programs (PT); Programs [Publication Type]; Renal Disease; Research; Research Personnel; Researchers; Reticuloendothelial System, Blood; Reticuloendothelial System, Platelets; Reticuloendothelial System, Serum, Plasma; Risk; Risk Factors; Serum, Plasma; Specific qualifier value; Specified; Surgeon; Surgical; Surgical Interventions; Surgical Procedure; Techniques; Thrombocytes; Thrombosis; Time; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Test; Ultrasound, Medical; Utah; Venous; biomarker; clinical care; clinical practice; demographics; design; designing; diagnostic ultrasound; dialysis therapy; experience; failure; heavy metal Pb; heavy metal lead; inflammatory marker; kidney disorder; medical complication; new therapeutics; next generation therapeutics; novel; novel therapeutics; personnel; programs; prospective; renal disorder; skills; sonogram; sonography; sound measurement; surgery; thrombocyte/platelet; ultrasound; ultrasound imaging; ultrasound scanning; usability; vascular
Project start date: 2008-09-10
Project end date: 2013-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: RFA-DK-07-007
5U01DK082222-03 (2010): $323463
Sponsored Links Excellgen http://Excellgen.com
5U01DK082222-02 (2009): $320483
3U01DK082222-02S1 (2009): $339630
ACTIVATION OF NEUTROPHILS BY DIALYSIS MEMBRANES
Alfred K Cheung, Professor Of Medicine
University Of Utah
75 South 2000 East
salt Lake City, Ut 84112
Grant 5R01DK045575-02 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: As a consequence of interactions with the dialysis membrane, neutrophils are activated and undergo degranulation during hemodialysis using all types of membranes. Previous studies have suggested that the release of neutrophil granular proteolytic enzymes into plasma contributes to the protein catabolic state in the dialysis patient. The mechanisms by which intradialytic degranulation occurs are, however, unknown. Since complement is also activated during hemodialysis, it has been postulated that the complement activation product, C5a, mediates most of the intradialytic neutrophil alterations, such as degranulation and oxygen radical production. Evidence supporting this hypothesis is, however, lacking and clinical studies have found a poor correlation between complement activation and plasma levels of neutrophil granular proteins during hemodialysis. In order to understand the mechanisms of dialysis induced-neutrophil degranulation, we have used an in vitro model in which isolated neutrophils are stimulated by cuprophan membranes and plasma. Our results have shown that cuprophan membrane-induced degranulation is dependent on plasma, and is mediated by both complement-dependent and complement-independent mechanisms. We also showed that C5a alone is insufficient to account for the complement portion of the degranulating activity. Further, the noncomplement factor does not appear to be a previously described substance that is known to induce neutrophil degranulation. In this application, we propose to i) determine the interactions between proteins that are bound to cuprophan membrane during plasma exposure and proteins that are present in the fluid-phase which result in neutrophil degranulation; ii) identity the complement proteins and neutrophil surface complement receptors that mediate the degranulation; iii) identify the noncomplement plasma factor that mediates the degranulation; iv) study the capacity of various types of commonly used dialysis membranes to support the activation of the noncomplement plasma proteins that stimulate neutrophil degranulation, and to examine if this capacity correlates with the complement activating potential of the membranes. We anticipate that these studies will elucidate the mechanisms by which hemodialysis induces neutrophil activation and degranulation. In addition, they will define a novel complement-independent mechanism by which neutrophils can be stimulated to degranulate that may be applicable to other inflammatory states
Keywords: artificial membrane, biomaterial interface phenomena, hemodialysis, leukocyte activation /transformation, neutrophil antibody receptor, complement, complement receptor human tissue, radioimmunoassay, western blotting
Project start date: 1992-09-30
Project end date: 1995-09-29
5R01DK045575-02 (1993): $155823
1R01DK045575-01 (1992): $153436
CLINICAL OUTCOME OF HEMODIALYSIS IN UTAH
Alfred K Cheung, Professor Of Medicine
Internal Medicineuniversity Of Utah
75 South 2000 East
salt Lake City, Ut 84112
Grant 5U01DK049252-03 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Project start date: 1994-09-30
Project end date: 2001-08-31
5U01DK049252-03 (1996): $207879