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.

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


Short Pore Length

Low Pressure


“Zero” Tortuosity

Nanomembrane

TOPVIEW

0.0025 mμ thick

Low Pressure


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

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.

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