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Technological Advances in Technological Advances in RRT: Five Years and BeyondRRT: Five Years and Beyond
ESRD: State of the Art and Charting the ESRD: State of the Art and Charting the
Challenges for the FutureChallenges for the FutureApril 26April 26thth, 2009, 2009
Boston, MassachusettsBoston, Massachusetts
Allen R. Nissenson, MD, FACPAllen R. Nissenson, MD, FACPEmeritus Professor of MedicineEmeritus Professor of Medicine
David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLAChief Medical OfficerChief Medical Officer
DaVita Inc.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
HomeWearable
Frequency Thrice weekly
Every other dayDaily
LengthShort (2 hours)
Conventional (4 hours)Long (nocturnal) (8 hours)
ModalityHemodialysis
HemofiltrationHemodiafiltration
HemoperfusionPeritoneal dialysis
Blood Purification Techniques for Chronic Kidney Failure
Location In-center
HomeWearable
Frequency Thrice weekly
Every other dayDaily
Length Short (2 hours)
Conventional (4 hours)Long (nocturnal) (8 hours)
ModalityHemodialysis
HemofiltrationHemodiafiltration
Hemoperfusion
Conventional Diffusive Therapy in the U.S.
Redefining Adequacy of Renal Replacement Therapy
Electrolyte and Acid/base control
Anemia status Nutritional status
Middle molecule clearance
Small moleculeclearance
Adequacy
Well being/Quality of
life
Sleep qualityVolume 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, 1975Colton 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
Middle Molecule Clinical Importance
2-microglobulin Dialysis-related amyloidosis
Parathyroid hormone Pruritus, erythropoiesis inhibition
Polyamines Erythropoiesis inhibition
Homocysteine Cardiovascular disease risk factor; pro-oxidant;inflammation
Neurotoxic compounds(guanidines)
Impairment of peripheral nerve function; associated withperipheral neuropathy and dementia
Appetite suppressants Impaired appetite; malnutrition; compromised immunefunction
AGE modified compounds Tissue structure modification; enzyme alteration;inflammation
Complement factors Inflammation, compromised immune function
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 69:2087–2093, 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
CRRT
Glomerulus
Renal Tubule
RBI -01A
Glomerulus
Renal Tubule
RBI -
Immune ModulationImmune Modulation Host defense systemHost defense system Antigen presentationAntigen presentation Cytokine productionCytokine production
Metabolic/endocrine functionsMetabolic/endocrine functions Hormone production Hormone production Vitamin productionVitamin production Ca, Phos homeostasisCa, Phos homeostasis
Waste ControlWaste Control
Fluid BalanceFluid 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 Fluorescence microscopy of epithelial cells on culture plate epithelial cells on culture plate nuclei (blue), actin nuclei (blue), actin cytoskeleton (green)cytoskeleton (green)
Renal Epithelial Cells in Culture
Renal Epithelial Cells in Hollow Fiber
Fluorescence microscopy – Fluorescence microscopy – cross section of cells on hollow cross section of cells on hollow fiber nuclei (blue), actin fiber nuclei (blue), actin cytoskeleton (green)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 MOFICU patients with ARF and MOF Randomized 2 : 1Randomized 2 : 1 CVVH + RAD vs. CVVH aloneCVVH + RAD vs. CVVH alone Open labelOpen label Up to 72 h of RAD therapyUp to 72 h of RAD therapy
Kaplan-Meier Survival CurveKaplan-Meier Survival Curve Through 180 Days (ITT Population)
Log-rank p-value = 0.0381
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
LeukocyteTissue
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. In search of a 24 hours per day artificial kidney. Lande AJ, Roberts M, and Pecker EA. Lande AJ, Roberts M, and Pecker EA. J DialysisJ Dialysis 1977; 1: 805-823 1977; 1: 805-823..
Neff’s Wearable
Hemofilter
Leg Bag
Neff, MS et al Trans Amer Soc Artif Intern Organs, 25:71-73, 1979
Murisasco’s Wearable
A
V
Heparin
Hemofilter
Filter
Cartridge
PumpsKidney
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/hr2 L/hr
4 L/hr 4 L/hr
2 L/hr
Fluid Removal Pouch
Pump
Patient’s Peritoneal Cavity
Enrichment Pouch
Vent
Wearable Artificial Kidney
The Wearable Artificial Kidney (WAK) The Wearable Artificial Kidney (WAK) Blood CircuitBlood CircuitUS patent 6,960,179US patent 6,960,179
Flow probe to Dialyzerexternal flow meter
Heparin Bubble detectorPump 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
Tubing color code:
Black: Electrolyte supplementYellow: Dialysate to regenerating systemBrown: BicarbonateGreen: Dialysate from regenerating system Electronics/cables are shown in gray
Dialyzer
Blood-leak/bubble detector, pump power-up and Dialysate alarm/shutoff system Battery regeneratingWAK pump system
Blood-leak-detecting probe
The Wearable Artificial Kidney V1.2Dialysate Circuit
US Patent No. 6,960,179 and other patents pending.
The Wearable Artificial Kidney V1.2US Patent No. 6,960,179 and other patents pending.
Results V 1.0 V 1.1 Units
Effective urea clearance 24.1+2.4 39.8+2.7 [mL/min]
Effective creatinine clearance 25.1+2.3 40.9+2.3 [mL/min]
Total urea removal 12.4+2.8 15.3+4.4 [g]
Total creatinine removal 0.9+0.2 1.7+0.2 [g]
Total phosphate removal 0.8+0.2 1.83+0.7 [g]
Total potassium removal 80.5+19.5 150.5+16.7 [mmol]
Extrapolated standard Kt/V 6.9+1.9 7.7+0.5
The Wearable Artificial Kidney8 hours of dialysis, in anesthetized uremic pigs8 hours of dialysis, in anesthetized uremic pigs
Removal of β2M from Healthy Human Blood
y = 79.29x-0.78
R2 = 0.90.0
200.0
400.0
600.0
800.0
1000.0
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0
Time (hr)
Blo
od
B2
MC
on
ce
ntr
ati
on
(u
g/L
)
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. 2007The Lancet. 2007
Time (hrs) pre 2 4 6 8
Na(mEq/L)
133±2.7
134±1.5
135±1.9
135±2.0
135±2.6
K(mEq/L)
4.2±0.3
4.4±0.5
4.1±0.3
4.1±0.5
4.1±0.5
iCa(mEq/L)
2.20±1.8
2.22±0.2
2.26±0.2
2.28±0.2
2.22±0.2
pH 7.35±0.1
7.35±0.06
7.35±0.07
7.33±0.05
7.36±0.05
Bicarb(mEq/L)
24.9±3.7
23.3±3.2
22.2*±2.8
22.1±2.4
22.0±3.3
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. 2007The Lancet. 2007
Kidney International. 2008Kidney International. 2008
Claudio Ronco, MD Hans Dietrich Polaschegg, PhD Hans Dietrich Polaschegg, PhD Andrew Davenport, MD
Masoud Beizai, PhD Carlos Ezon, MD Masoud Beizai, PhD Carlos Ezon, MD
Ambulatory Ultrafiltration: a step toward reduced clinical
dependence*
Artificial Organs Research Laboratory, Columbia University
andVizio Medical Devices LLC
Leonard E: Personal communication, 2009
The TechnologyBlood 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.
From patient To patient
Filtered sheath is separated from blood stream through an array of nanofilters that catch errant cells.
Ambulatory Blood PurificationThe 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 Nanotechnologyassembly of new moleculesassembly of molecules into machinesmodification of existing materials
Top-Down Nanotechnologymaking today’s toys smallerthe old technology approach gettingbetter
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 mμ 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 patient’s 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
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
0 10 20 30 40 50 60
Pore Size
N
Hydraulic Permeability
Blood Contact with Silicon Membranes
Bioartificial Proximal Nephron
Hemofilter
Blood
Blood
Urine
Proximal Tubule Cells
Continuously Functioning Artificial Nephron (CFAN)
Artery Vein
G-membrane
T-membrane
Waste
High Flux +Selectivity = Small Size
CFAN-1 vs. Dialysis (Mathematical Simulation)
U.S. 4hr dialysis
Japan 5hr dialysis
CFAN-1 filtration
U.S. 4hr TAC=67.3 mg/dL
Japan 5hr
TAC=58.0 mg/dL
CFAN-1
TAC=26.7 mg/dL
TAC Urea Achieved vs. Filtration Time (Mathematical Simulation)
Modality Treatment
(Per week) Assumed Dialyzer
Clearance (ml/min)
Qb (ml/min)
B2M TAC (mg/dL)
Standard 4hr-3days 43 300 7.92 Standard 4hr-3days 78 300 5.25
Short Daily 2hr-7days 43 300 6.50 Short Daily 2hr-7days 78 300 3.96 Nocturnal 8hr-7days 37 200 1.94 Nocturnal 8hr-7days 66 200 1.24
HNF-1 12hr-7days NA 100 0.69 HNF-1 18hr-7days NA 100 0.40 Normal Level
<0.27
B2-Microglobulin TAC (Mathematical Simulation)
text
text
Waste Bag
Keypadand
Display
DisposableFilter Cartridge
HighCapacityBattery
HNF
VascularAccess
CFAN Wearable System
A Wearable Continuously Functioning Artificial Nephron
Design Concept
Recent Progress
Synthesis of pores for in vitro testing
Fabrication of membrane with pores
Scale-up methodology in final stages of development
Key Collaborators
Martin Edelstein, PhD, Co-founder Biophiltre, LLC Chemistry; instrumentation; software; pharmaceutical development; quality assurance; FDA filings
Richard Watts, PhD, CTOPhysiology; medical instrumentation; manufacturing
Gayle Pergamit, Co-founder Biophiltre, LLC Marketing; business modeling; startup entrepreneurship
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