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.
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
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
Current ESRD Therapy
 Poor survival
 High morbidity
 Marginal quality of life
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.”
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.”
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!!!
Kidney Functions




Filtration
Transport
Metabolism
Endocrine
Blood Purification Techniques for
Chronic Kidney Failure
Location
In-center
Home
Wearable
Modality
Hemodialysis
Hemofiltration
Hemodiafiltration
Hemoperfusion
Peritoneal dialysis
Length
Short (2 hours)
Conventional (4 hours)
Long (nocturnal) (8 hours)
Frequency
Thrice weekly
Every other day
Daily
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)
Redefining Adequacy of Renal
Replacement Therapy
Volume control
Small molecule
clearance
Sleep quality
Middle molecule
clearance
Electrolyte and
Acid/base control
Adequacy
Blood pressure
control
Well
being/Quality of
life
Anemia status Nutritional status
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
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
_____________________________
________
Pyrogen
free
= dose
McCarthy J et al: Semin Dialysis 16:199-207, 2003
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 with
peripheral neuropathy and dementia
Appetite suppressants
Impaired appetite; malnutrition; compromised immune
function
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
Meta-Analysis of Convective vs.
Diffuse Therapies for ESRD
Rabindranath KS et al: Cochrane Database of Systematic Reviews 2008
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
Renal Bio-Replacement Therapy
Advantages*
Current
Treatment
Waste Control
Fluid Balance


RBT
CRRT


RBI --01A
Immune Modulation
Host defense system
Antigen presentation
Cytokine production
Metabolic/endocrine functions
Hormone production
Vitamin production
Ca, Phos homeostasis
Glomerulus






Renal Tubule
RBI-01 replicates the structure and
function of the nephron
Humes HD et al: Personal communication, 2009
Therapy is Provided By Cells In
Conventional Delivery System
Renal Epithelial
Cells in Culture
Fluorescence microscopy of
epithelial cells on culture plate
nuclei (blue), actin
cytoskeleton (green)
Renal Epithelial Cells
in Hollow Fiber
Therapy Delivered in
Hollow Fiber Cartridges
Fluorescence microscopy –
cross section of cells on hollow
fiber nuclei (blue), actin
cytoskeleton (green)
Conventional CVVH
cartridge system with
>4000 cell-containing
hollow fibers
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)
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
Capillary Leak
&
Poor Tissue Perfusion
Leukocyte
Tissue
Infiltration
Ischemic & Toxic Tissue Injury
Multiorgan Dysfunction
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
 ARF
: Pro-inflammatory markers
: 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.
Neff’s Wearable
Hemofilter
Leg Bag
Neff, MS et al Trans Amer Soc Artif
Intern Organs, 25:71-73, 1979
Murisasco’s Wearable
A
Heparin
Hemofilter
V
Pumps
Kidney
Cartridge
Filter
Bladder
Murisasco, A. et al. Trans Amer Soc Artif Intern Organs. 32:567-571, 1986
Wearable Artificial Kidney
Sterilizing Filter
Sorbent
Enrichment
Pouch
Vent
Cartridge
Fibrin Filter
Pump
2 L/hr
4 L/hr
2 L/hr
2 L/hr
Pump
4 L/hr
Double Lumen
Catheter
Patient’s Peritoneal Cavity
Fluid
Removal
Pouch
The Wearable Artificial Kidney (WAK)
Blood Circuit
US patent 6,960,179
Heparin
Pump
and bag
Bubble detector
pump power-up
alarm/shutoff system
Shuttle pump
Flow probe to
external flow meter
Color Code
Red: Blood from patient
Blue: Blood to patient
Gray: Electronics
White: Heparin
Dialyzer
Battery
The Wearable Artificial Kidney V1.2
Dialysate 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
Tubing color code:
Black: Electrolyte supplement
Yellow: Dialysate to regenerating system
Brown: Bicarbonate
Green: Dialysate from regenerating system
Electronics/cables are shown in gray
Blood-leak-detecting probe
Pump/bag color code:
Black: Electrolyte
Yellow: Waste (UF)
Brown: Bicarbonate
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
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]
6.9+1.9
7.7+0.5
Extrapolated standard Kt/V
Blood B2M
Concentration (ug/L)
Removal of β2M from Healthy
Human Blood
1000.0
800.0
600.0
400.0
y = 79.29x -0.78
R2 = 0.9
200.0
0.0
0.0
1.0
2.0
3.0
4.0
Time (hr)
5.0
6.0
7.0
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
Time (hrs)
pre
2
4
6
8
Na
133
134
135
135
135
(mEq/L)
±2.7
±1.5
±1.9
±2.0
±2.6
K
4.2
4.4
4.1
4.1
4.1
(mEq/L)
±0.3
±0.5
±0.3
±0.5
±0.5
iCa
2.20
2.22
2.26
2.28
2.22
(mEq/L)
±1.8
±0.2
±0.2
±0.2
±0.2
pH
7.35
7.35
7.35
7.33
7.36
±0.1
±0.06
±0.07
±0.05
±0.05
Bicarb
24.9
23.3
22.2*
22.1
22.0
(mEq/L)
±3.7
±3.2
±2.8
±2.4
±3.3
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
Masoud Beizai, PhD
Hans Dietrich Polaschegg, PhD
Andrew Davenport, MD
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.
From patient
To patient
Filtered sheath is separated
from blood stream through an
array of nanofilters that catch
errant cells.
Sheath circulates through hollowfiber 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 today’s 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
TOPVIEW
Nanomembrane
0.0025 μm 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
1.2
1
0.8
0.6
N
0.4
0.2
0
-0.2 0
10
20
30
40
50
60
Pore Size
Narrower pore size distribution = larger mean pore size
Large mean pore size = higher hydraulic permeability
High hydraulic permeability = no blood pump
Hydraulic Permeability
Blood Contact with Silicon Membranes
Bioartificial Proximal Nephron
Blood
Urine
Proximal
Tubule Cells
Blood
Hemofilter
Continuously Functioning Artificial Nephron
(CFAN)
G-membrane
Artery
Vein
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)
B2-Microglobulin TAC
(Mathematical Simulation)
Modality
Treatment
(Per week)
Standard
4hr-3days
Standard
4hr-3days
Short Daily 2hr-7days
Short Daily 2hr-7days
Nocturnal
8hr-7days
Nocturnal
8hr-7days
HNF-1
12hr-7days
HNF-1
18hr-7days
Normal
Level
Assumed
Dialyzer
Clearance
(ml/min)
43
78
43
78
37
66
NA
NA
Qb
(ml/min)
B2M TAC
(mg/dL)
300
300
300
300
200
200
100
100
7.92
5.25
6.50
3.96
1.94
1.24
0.69
0.40
<0.27
CFAN Wearable System
Va scular
A cce ss
K eypa d
and
D isplay
D isposa ble
Filter Cartridge
te x t
t ext
W aste B ag
H igh
C apacit y
B attery
HNF
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, CTO
Physiology; 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