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Technological Advances in RRT: Five Years and Beyond

Technological Advances in RRT: Five Years and Beyond. ESRD: State of the Art and Charting the Challenges for the Future April 26 th , 2009 Boston, Massachusetts Allen R. Nissenson, MD, FACP Emeritus Professor of Medicine David Geffen School of Medicine at UCLA Chief Medical Officer

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Technological Advances in RRT: Five Years and Beyond

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  1. 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.

  2. The Problem • 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

  3. Current ESRD Therapy • Delivers 10-15% GFR equivalency • Is pro-inflammatory • Is intrusive on patient life-style • Is associated with significant intradialytic complications and interdialytic symptoms

  4. Current ESRD Therapy • Poor survival • High morbidity • Marginal quality of life

  5. Dr Benjamin Burton Director AKCUP, NIDDK Journal of Dialysis, 1976 “Maintenance dialysis on the whole is non-physiological and can be justified only because of the finiteness of its alternative.”

  6. 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.”

  7. Recent Technological Advances in RRT • 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!!!

  8. Kidney Functions • Filtration • Transport • Metabolism • Endocrine

  9. Blood Purification Techniques for Chronic Kidney Failure Location In-center Home Wearable Modality Hemodialysis Hemofiltration Hemodiafiltration Hemoperfusion Peritoneal dialysis Frequency Thrice weekly Every other day Daily Length Short (2 hours) Conventional (4 hours) Long (nocturnal) (8 hours)

  10. Conventional Diffusive Therapy in the U.S. Location In-center Home Wearable Modality Hemodialysis Hemofiltration Hemodiafiltration Hemoperfusion Frequency Thrice weekly Every other day Daily Length Short (2 hours) Conventional (4 hours) Long (nocturnal) (8 hours)

  11. Redefining Adequacy of Renal Replacement Therapy Volume control Sleep quality Blood pressure control Well being/Quality of life

  12. 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 Meyer T & Hostetter T: N Engl J Med 357:1316-1325, 2007

  13. Menu of Convective Therapies • Hemofiltration • 3x/week vs. daily • Pre- vs. post-dilution • Hemodiafiltration • 3x/week vs. daily • Pre- vs. post- vs. mid-dilution

  14. Principal Components of Hemofiltration_____________________________________ Pyrogen free = dose McCarthy J et al: Semin Dialysis 16:199-207, 2003

  15. Known and Putative Middle Molecules Cleared by Hemofiltration Dhondt, Kidney Int 2000; Macdougall, Kidney Int 2001; McCarthy, Semin Dialysis 2003

  16. 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 69:2087–2093, 2006

  17. Meta-Analysis of Convective vs. Diffuse Therapies for ESRD Rabindranath KS et al: Cochrane Database of Systematic Reviews 2008

  18. 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

  19. 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

  20. Immune Modulation Host defense system  Antigen presentation  Cytokine production  Metabolic/endocrine functions Hormone production  Vitamin production  Ca, Phos homeostasis  CRRT RBI RBI - - 01A Glomerulus Glomerulus Renal Tubule Renal Tubule Renal Bio-Replacement Therapy Advantages* Current TreatmentRBT Waste Control   Fluid Balance   RBI-01 replicates the structure and function of the nephron Humes HD et al: Personal communication, 2009

  21. Therapy is Provided By Cells In Conventional Delivery System Therapy Delivered in Hollow Fiber Cartridges 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) Fluorescence microscopy of epithelial cells on culture plate nuclei (blue), actin cytoskeleton (green) Conventional CVVH cartridge system with >4000 cell-containing hollow fibers

  22. 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

  23. 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.

  24. F40 vs. BRECS-d

  25. Immunoregulatory Role of Renal Epithelial Cells • In vitro experiments demonstrating inhibitory activity of renal epithelial cells on the innate immunologic system

  26. SIRS Leukocyte Activation Endothelial Dysfunction Capillary Leak & Poor Tissue Perfusion Leukocyte Tissue Infiltration Ischemic & Toxic Tissue Injury Multiorgan Dysfunction

  27. Selective Cytopheretic Inhibitory Device • Membrane device that replicates renal epithelial cells’ inhibitory immunologic effects

  28. 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

  29. Clinical Development Plan • ESRD : Pro-inflammatory markers • ARF : Confirmatory mortality trial • Severe sepsis: 28 day mortality

  30. In search of a 24 hours per day artificial kidney. Lande AJ, Roberts M, and Pecker EA. J Dialysis 1977; 1: 805-823.

  31. Neff’s Wearable Hemofilter Leg Bag Neff, MS et al Trans Amer Soc Artif Intern Organs, 25:71-73, 1979

  32. Murisasco’s Wearable A Heparin Hemofilter Pumps Kidney Cartridge V Filter Bladder Murisasco, A. et al. Trans Amer Soc Artif Intern Organs. 32:567-571, 1986

  33. Wearable Artificial Kidney Sterilizing Filter Vent Sorbent Cartridge Enrichment Pouch Fibrin Filter Fluid Removal Pouch Pump 2 L/hr 2 L/hr 2 L/hr Pump 4 L/hr 4 L/hr Double Lumen Catheter Patient’s Peritoneal Cavity

  34. The Wearable Artificial Kidney (WAK) Blood Circuit US patent 6,960,179 Heparin Bubble detector Pump pump power-up and bag alarm/shutoff system Battery Shuttle pump Flow probe to Dialyzer external flow meter Color Code Red: Blood from patient Blue: Blood to patient Gray: Electronics White: Heparin

  35. Tubing color code: Black: Electrolyte supplement Yellow: Dialysate to regenerating system Brown: Bicarbonate Green: Dialysate from regenerating system Electronics/cables are shown in gray The Wearable Artificial Kidney V1.2Dialysate Circuit US Patent No. 6,960,179 and other patents pending. Blood-leak/bubble detector, pump power-up and Dialysate alarm/shutoff system Battery regenerating WAK pump system Dialyzer Blood-leak-detecting probe Pump/bag color code: Black: Electrolyte Yellow: Waste (UF) Brown: Bicarbonate

  36. The Wearable Artificial Kidney V1.2US Patent No. 6,960,179 and other patents pending.

  37. The Wearable Artificial Kidney 8 hours of dialysis, in anesthetized uremic pigs

  38. Removal of β2M from Healthy Human Blood

  39. 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. First Human Trial of Ambulatory Hemodialysis Royal Free Hospital, London, UK, 2007 The Lancet. 2007

  40. 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

  41. Kidney International. 2008

  42. Claudio Ronco, MD Hans Dietrich Polaschegg, PhD Andrew Davenport, MD MasoudBeizai, PhD Carlos Ezon, MD

  43. Ambulatory Ultrafiltration: a step toward reduced clinical dependence* Artificial Organs Research Laboratory, Columbia University and Vizio Medical Devices LLC Leonard E: Personal communication, 2009

  44. 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. From patient To patient Filtered sheath is separated from blood stream through an array of nanofilters that catch errant cells. Sheath circulates through hollow-fiber second stage, which removes excess fluid at 2 cc/min. Sheath circulates continuously, back to the first stage array.

  45. 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

  46. 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.

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