Technological Advances in RRT: Five Years and Beyond

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!!!
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Kidney Functions

• Filtration
• Transport
• Metabolism
• Endocrine

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Blood Purification Techniques for Chronic Kidney
Failure
Location In-center Home Wearable
Frequency Thrice weekly Every other day Daily
Modality Hemodialysis Hemofiltration Hemodiafiltra
tion Hemoperfusion Peritoneal dialysis
Length Short (2 hours) Conventional (4
hours) Long (nocturnal) (8 hours)
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Conventional Diffusive Therapy in the U.S.
Location In-center Home Wearable
Frequency Thrice weekly Every other day Daily
Modality Hemodialysis Hemofiltration Hemodiafiltra
tion Hemoperfusion
Length Short (2 hours) Conventional (4
hours) Long (nocturnal) (8 hours)
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Redefining Adequacy of Renal Replacement Therapy
Sleep quality
Volume control
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 85372-391,
1975 Colton CK et al J Lab Clin Med 85355-71,
1975
Meyer T Hostetter T N Engl J Med
3571316-1325, 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

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Principal Components of Hemofiltration___________
__________________________
Pyrogen free
dose
McCarthy J et al Semin Dialysis 16199-207, 2003
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Known and Putative Middle Molecules Cleared by
Hemofiltration
Dhondt, Kidney Int 2000 Macdougall, Kidney Int
2001 McCarthy, Semin Dialysis 2003
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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 6920872093, 2006
17
Meta-Analysis of Convective vs. Diffuse Therapies
for ESRD
Rabindranath KS et al Cochrane Database of
Systematic Reviews 2008
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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
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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

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Renal Bio-Replacement Therapy Advantages
Current Treatment RBT
Waste Control ? ? Fluid Balance ? ?

• Immune Modulation
• Host defense system ?
• Antigen presentation ?
• Cytokine production ?
• Metabolic/endocrine functions
• Hormone production ?
• Vitamin production ?
• Ca, Phos homeostasis ?

RBI-01 replicates the structure and function of
the nephron
Humes HD et al Personal communication, 2009
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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 gt4000
cell-containing hollow fibers
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• 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

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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.
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F40 vs. BRECS-d
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Immunoregulatory Role of Renal Epithelial Cells

• In vitro experiments demonstrating inhibitory
  activity of renal epithelial cells on the innate
  immunologic system

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SIRS
Leukocyte Activation
Endothelial Dysfunction
Capillary Leak Poor Tissue Perfusion
Leukocyte Tissue Infiltration
Ischemic Toxic Tissue Injury
Multiorgan Dysfunction
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Selective Cytopheretic Inhibitory Device

• Membrane device that replicates renal epithelial
  cells inhibitory immunologic effects

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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

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Clinical Development Plan

• ESRD Pro-inflammatory markers
• ARF Confirmatory mortality trial
• Severe sepsis 28 day mortality

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In search of a 24 hours per day artificial
kidney.
Lande AJ, Roberts M,
and Pecker EA. J Dialysis 1977 1 805-823.
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Neffs Wearable
Hemofilter
Leg Bag
Neff, MS et al Trans Amer Soc Artif Intern
Organs, 2571-73, 1979
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Murisascos Wearable
A
Heparin
Hemofilter
Pumps
Kidney
Cartridge
V
Filter
Bladder
Murisasco, A. et al. Trans Amer Soc Artif Intern
Organs. 32567-571, 1986
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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
Patients Peritoneal Cavity
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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

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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
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The Wearable Artificial Kidney V1.2US Patent No.
6,960,179 and other patents pending.
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The Wearable Artificial Kidney 8 hours of
dialysis, in anesthetized uremic pigs
Results V 1.0 V 1.1 Units
Effective urea clearance 24.12.4 39.82.7 mL/min
Effective creatinine clearance 25.12.3 40.92.3 mL/min
Total urea removal 12.42.8 15.34.4 g
Total creatinine removal 0.90.2 1.70.2 g
Total phosphate removal 0.80.2 1.830.7 g
Total potassium removal 80.519.5 150.516.7 mmol
Extrapolated standard Kt/V 6.91.9 7.70.5
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Removal of ß2M from Healthy Human Blood
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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
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Electrolyte and Acid-Base Changes During
Treatment with the WAK
Time (hrs) pre 2 4 6 8
Na(mEq/L) 1332.7 1341.5 1351.9 1352.0 1352.6
K(mEq/L) 4.20.3 4.40.5 4.10.3 4.10.5 4.10.5
iCa(mEq/L) 2.201.8 2.220.2 2.260.2 2.280.2 2.220.2
pH 7.350.1 7.350.06 7.350.07 7.330.05 7.360.05
Bicarb(mEq/L) 24.93.7 23.33.2 22.22.8 22.12.4 22.03.3
Serum sodium (Na), potassium (K), ionized calcium
(iCa), bicarbonate (Bicarb) and pH p lt0.05 vs
prevalue.
The Lancet. 2007
43
Kidney International. 2008
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46

• Claudio Ronco, MD
  Hans Dietrich Polaschegg, PhD
  Andrew Davenport, MD

Masoud Beizai, PhD


Carlos Ezon, MD
47
Ambulatory Ultrafiltration a step toward reduced
clinical dependence

• Artificial Organs Research Laboratory, Columbia
  University
• and
• Vizio Medical Devices LLC

Leonard E Personal communication, 2009
48
The Technology
Blood flows at 30 cc/min in a very thin
(microfluidic) layer (lt50 ?m thick) for a very
short time (lt1 sec) between two sheath layers,
achieving rapid molecular equilibrium.
Extracorporeal volume is lt 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.
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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
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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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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

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WHY A MONOMOLECULAR MEMBRANE?

• Specific
• Monomolecular Membranes from
• Molecular constructs

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WHY A MONOMOLECULAR MEMBRANE?

• Short Pore Length

Low Pressure
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WHY A MONOMOLECULAR MEMBRANE?

• Zero Tortuosity

TOPVIEW
Nanomembrane
0.0025 µm thick
Low Pressure
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WHY A MONOMOLECULAR MEMBRANE?
Biocompatibility?
56

• 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
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Arrythmia Care as a Paradigm for the 21st Century
?
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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

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Control of Pore Geometry
N
Pore Size
Narrower pore size distribution larger mean
pore size Large mean pore size higher
hydraulic permeability High hydraulic
permeability no blood pump
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Hydraulic Permeability
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Blood Contact with Silicon Membranes
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Bioartificial Proximal Nephron
Blood
Urine
Proximal Tubule Cells
Blood
Hemofilter
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Continuously Functioning Artificial Nephron
(CFAN)
G-membrane
Artery
Vein
T-membrane
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High Flux Selectivity Small Size
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CFAN-1 vs. Dialysis (Mathematical Simulation)
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TAC Urea Achieved vs. Filtration Time
(Mathematical Simulation)
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B2-Microglobulin TAC (Mathematical Simulation)
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CFAN Wearable System
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A Wearable Continuously Functioning Artificial
Nephron
Design Concept
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Recent Progress

• Synthesis of pores for in vitro testing
• Fabrication of membrane with pores
• Scale-up methodology in final stages of
  development

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Key Collaborators
Martin Edelstein, PhD, Co-founder Biophiltre,
LLC Chemistry instrumentation software
pharmaceutical development quality assurance
FDA filings Richard Watts, PhD, CTO Physiology
medical instrumentation manufacturing Gayle
Pergamit, Co-founder Biophiltre, LLC Marketing
business modeling startup entrepreneurship
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Conclusions

1. Current outcomes of ESRD patients on RRT are
   unacceptable
2. In the short term logistical improvements in RRT
   are likely (HF/HDF, daily, wearable)
3. In the long term creative approaches that emulate
   natural kidneys offer the true hope of improving
   clinical outcomes and quality of life of patients
   with ESRD