technological advances in rrt five years and beyond课件

Technological Advances in RRT: Five Years and Beyond,ESRD: State of the Art and Charting the Challenges for the Future April 26th, 2009 Boston, Massachusetts Allen R. Nissenson, MD, FACP Emeritus Professor of Medicine David Geffen School of Medicine at UCLA Chief Medical Officer DaVita Inc.,Epidemic of CKD High mortality in CKD period (CVD) Growing ESRD population with increasing complexity Stagnant ESRD outcomes (mortality, morbidity, QOL) Incremental improvements in technology over 3 decades,The Problem,Delivers 10-15% GFR equivalency Is pro-inflammatory Is intrusive on patient life-style Is associated with significant intradialytic complications and interdialytic symptoms,Current ESRD Therapy,Poor survival High morbidity Marginal quality of life,Current ESRD Therapy,“Maintenance dialysis on the whole is non-physiological and can be justified only because of the finiteness of its alternative.”,Dr Benjamin Burton Director AKCUP, NIDDK Journal of Dialysis, 1976,“Satisfied with what we have wrought in this field, we will pile small improvements on top of other minor advances in dialysis technology.”,Dr Benjamin Burton Director AKCUP, NIDDK Journal of Dialysis, 1976,High efficiency/high flux membranes Biocompatible membranes Alterations in internal dialyzer geometry to increase efficiency On-line replacement solution production for continuous therapies for ARF or hemofiltration for ESRD On-line monitoring of dialysis dose and vascular access function,ADVANCES AT THE MARGIN!,Recent Technological Advances in RRT,Kidney Functions,Filtration Transport Metabolism Endocrine,Location In-center Home Wearable,Frequency Thrice weekly Every other day Daily,Length Short (2 hours) Conventional (4 hours) Long (nocturnal) (8 hours),Modality Hemodialysis Hemofiltration Hemodiafiltration Hemoperfusion Peritoneal dialysis,Blood Purification Techniques for Chronic Kidney Failure,Location In-center Home Wearable,Frequency Thrice weekly Every other day Daily,Length Short (2 hours) Conventional (4 hours) Long (nocturnal) (8 hours),Modality Hemodialysis Hemofiltration Hemodiafiltration Hemoperfusion,Conventional Diffusive Therapy in the U.S.,Redefining Adequacy of Renal Replacement Therapy,Well being/Quality of life,Sleep quality,Volume control,Blood pressure control,Meyer T & Hostetter T: N Engl J Med 357:1316-1325, 2007,Diffusion (Dialysis) vs. Convection (Hemofiltration),Best for small-molecule clearance,Best for middle-molecule clearance,Henderson LW et al: J Lab Clin Med 85:372-391, 1975 Colton CK et al: J Lab Clin Med 85:355-71, 1975,Menu of Convective Therapies,Hemofiltration 3x/week vs. daily Pre- vs. post-dilution Hemodiafiltration 3x/week vs. daily Pre- vs. post- vs. mid-dilution,Principal Components of Hemofiltration _,McCarthy J et al: Semin Dialysis 16:199-207, 2003,= dose,Pyrogen free,Known and Putative Middle Molecules Cleared by Hemofiltration,Dhondt, Kidney Int 2000; Macdougall, Kidney Int 2001; McCarthy, Semin Dialysis 2003,Relative Risk of Mortality by Dialysis Modality,Adjusted for age, sex, dialysis vintage, comorbid conditions, weight, catheter use, hemoglobin, albumin, nPCR, cholesterol, triglycerides, Kt/V, erythropoietin, MCS, and PCS,Canaud B et al: Kidney Int 69:20872093, 2006,Rabindranath KS et al: Cochrane Database of Systematic Reviews 2008,Meta-Analysis of Convective vs. Diffuse Therapies for ESRD,Meta-Analysis of Convective vs. Diffuse Therapies for ESRD,Authors conclusions “We were unable to demonstrate whether convective modalities have significant advantages over HD with regard to clinically important outcomes of mortality, dialysis-related hypotension and hospitalization. More adequately-powered good quality RCTs assessing clinically important outcomes (mortality, hospitalization, quality of life) are needed.”,Rabindranath KS et al: Cochrane Database of Systematic Reviews 2008, Issue 1,Some Challenges for Adopting Convective Therapies in the U.S.,Set-Up Logistics Costs Clearance by Regulatory Agencies (e.g. FDA, AAMI) Nurse/Physician Education Reimbursement,Immune Modulation Host defense system Antigen presentation Cytokine production Metabolic/endocrine functions Hormone production Vitamin production Ca, Phos homeostasis ,Waste Control Fluid Balance ,Current Treatment RBT,Renal Bio-Replacement Therapy Advantages*,RBI-01 replicates the structure and function of the nephron,Humes HD et al: Personal communication, 2009,Fluorescence microscopy of epithelial cells on culture plate nuclei (blue), actin cytoskeleton (green),Renal Epithelial Cells in Culture,Renal Epithelial Cells in Hollow Fiber,Fluorescence microscopy cross section of cells on hollow fiber nuclei (blue), actin cytoskeleton (green),Therapy Delivered in Hollow Fiber Cartridges,Conventional CVVH cartridge system with 4000 cell-containing hollow fibers,Therapy is Provided By Cells In Conventional Delivery System,Phase II Study Design ICU patients with ARF and MOF Randomized 2 : 1 CVVH + RAD vs. CVVH alone Open label Up to 72 h of RAD therapy,Kaplan-Meier Survival Curve,Kaplan-Meier Survival Curve Through 180 Days (ITT Population),The Cox Proportional Hazard ratio was 0.49 indicating that the risk of death for patients in the CVVH + RBT group was 50% of that observed in the CVVH alone group.,F40 vs. BRECS-d,Immunoregulatory Role of Renal Epithelial Cells,In vitro experiments demonstrating inhibitory activity of renal epithelial cells on the innate immunologic system,SIRS,Leukocyte Activation,Endothelial Dysfunction,Multiorgan Dysfunction,Ischemic & Toxic Tissue Injury,Capillary Leak & Poor Tissue Perfusion,Leukocyte Tissue Infiltration,Selective Cytopheretic Inhibitory Device,Membrane device that replicates renal epithelial cells inhibitory immunologic effects,PreClinical Studies Summary,Efficacy of Simplified Pump System Extracorporeal Blood Circuit Reduction of Leukocyte Activation Markers Reduction of Circulating Neutrophil Activation Parameters Decreased Systemic Capillary Leak Diminished Activated Leukocyte Tissue Accumulation Enhanced Survival Time,Clinical Development Plan,ESRD : Pro-inflammatory markers ARF : Confirmatory mortality trial Severe sepsis: 28 day mortality,In search of a 24 hours per day artificial kidney. Lande AJ, Roberts M, and Pecker EA. J Dialysis 1977; 1: 805-823.,Neffs Wearable,Hemofilter,Leg Bag,Neff, MS et al Trans Amer Soc Artif Intern Organs, 25:71-73, 1979,Murisascos Wearable,A,V,Heparin,Hemofilter,Filter,Cartridge,Pumps,Kidney,Bladder,Murisasco, A. et al. Trans Amer Soc Artif Intern Organs. 32:567-571, 1986,Pump,Sorbent Cartridge,Sterilizing Filter,Fibrin Filter,Double Lumen Catheter,2 L/hr,2 L/hr,4 L/hr,4 L/hr,2 L/hr,Fluid Removal Pouch,Pump,Patients Peritoneal Cavity,Enrichment Pouch,Vent,Wearable Artificial Kidney,The Wearable Artificial Kidney (WAK) Blood Circuit US patent 6,960,179,Flow probe to Dialyzer external flow meter,Heparin Bubble detector Pump pump power-up and bag alarm/shutoff system Battery Shuttle pump,Color Code Red: Blood from patient Blue: Blood to patient Gray: Electronics White: Heparin,Pump/bag color code: Black: Electrolyte Yellow: Waste (UF) Brown: Bicarbonate,Dialyzer,Blood-leak/bubble detector, pump power-up and Dialysate alarm/shutoff system Battery regenerating WAK pump system,Blood-leak-detecting probe,The Wearable Artificial Kidney V1.2 Dialysate Circuit US Patent No. 6,960,179 and other patents pending.,The Wearable Artificial Kidney V1.2 US Patent No. 6,960,179 and other patents pending.,The Wearable Artificial Kidney 8 hours of dialysis, in anesthetized uremic pigs,Removal of 2M from Healthy Human Blood,First Human Trial of Ambulatory Hemodialysis Royal Free Hospital, London, UK, 2007,8 end stage kidney failure subjects. Established on regular hemodialysis. 4 glomerulonephritis 3 polycystic kidney disease 1 obstructive uropathy. 5 male / 3 female mean age 51.7 years range 26-67,4-8 hours treatment time. Prospective non-randomized pilot study, designed as proof of concept. Approved by the UK Medicines Health Regulation Authority (MHRA) and Ethics Committee Alpha, at University College Hospital, London.,The Lancet. 2007,Electrolyte and Acid-Base Changes During Treatment with the WAK,Serum sodium (Na), potassium (K), ionized calcium (iCa), bicarbonate (Bicarb) and pH * p 0.05 vs prevalue.,The Lancet. 2007,Kidney International. 2008,Claudio Ronco, MD Hans Dietrich Polaschegg, PhD Andrew Davenport, MD,Masoud Beizai, PhD Carlos Ezon, MD,Ambulatory Ultrafiltration: a step toward reduced clinical dependence*,Artificial Organs Research Laboratory, Columbia University and Vizio Medical Devices LLC,Leonard E: Personal communication, 2009,The Technology,Blood flows at 30 cc/min in a very thin (microfluidic) layer (50 m thick) for a very short time (1 sec) between two sheath layers, achieving rapid molecular equilibrium. Extracorporeal volume is 5cc.,Sheath circulates through hollow-fiber second stage, which removes excess fluid at 2 cc/min. Sheath circulates continuously, back to the first stage array.,Ambulatory Blood Purification,The Problems Safety Patient involvement Anticoagulation Decremented function Decreased clinical oversight Blood access,The Response Modern microelectronic control, monitoring, alarming data-logging. Only for some patients. Almost no blood contact, indirect filtration from sheath fluid minimizes anticoagulation requirement. Frequent change-out with patient/system assessment. System is firmly tied to clinical support. Good antecedents but not yet demonstrated.,An achievable forward step toward stand-alone ambulatory ESRD therapy,The Approach,Ambulatory ultrafiltration to achieve dry weight at all times. Concomitant reduction in dialysis to 2 per week Inspection, change-out during dialysis sessions,The Advantages,Removes major cause of discomfort, unsteadiness in patients. Decreases time lost in therapy. Facilitates dialysis; allows focus on solute removal. Allows frequent monitoring of extra-clinical care. Increases capacity of dialysis unit for additional patients. Addresses new guidelines on fluid management. Solves problems within current cost containment rules.,Approaches to the creation of Nanotechnology,Bottom-Up Nanotechnology assembly of new molecules assembly of molecules into machines modification of existing materials Top-Down Nanotechnology making todays toys smaller the old technology approach getting better,WHY A MONOMOLECULAR MEMBRANE?,Specific Monomolecular Membranes from Molecular constructs,WHY A MONOMOLECULAR MEMBRANE?,Short Pore Length,Low Pressure,WHY A MONOMOLECULAR MEMBRANE?,“Zero” Tortuosity,Nanomembrane,TOPVIEW,0.0025 m thick,Low Pressure,WHY A MONOMOLECULAR MEMBRANE?,Biocompatibility?,Microelectromechanical systems (MEMS)*,The Advantages of a Silicon Nanopore Membrane,Miniaturization Uniform pore size and shape Reduced hydraulic resistance Inert, non-toxic, biocompatible,Fissell WH et al. J Membrane Science 326: 58, 2009,Arrythmia Care as a Paradigm for the 21st Century,?,“3Rs of 21st Century”,Relocate the site of care from the clinic to the home or the patients own body Reduce disposables Rely on automated sensing and control structures to free up health care professionals from role of passive monitors,Control of Pore Geometry,Narrower pore size distribution = larger mean pore size Large mean pore size = higher hydraulic permeability High hydraulic permeability = no blood pump,Pore Size,N,Hydraulic Permeability,Blood Contact w