Physioneal

1
MEMBRANE LIFE
London May 2003
2
Objectives

• Link the preservation of membrane integrity with
  maintaining patients on PD for longer periods of
  time
• Link the chemistry of solutions with the
  structural changes within the peritoneal
  membrane, and associated clinical changes

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What determines the biocompatibility of PD
Solutions

• Ph
• Buffer System
• Osmolality
• Concentration of Glucose
• Potential for formation of advanced glycation end
  products (AGE)
• Presence of glucose degradation products (GDPs)
• The combination of these factors for a particular
  PD solution is said to define its
  biocompatibility profile

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Advanced Solutions Portfolio
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Extraneal is a peritoneal dialysis solution
with Icodextrin instead of glucose as the
primary osmotic agent
- THE LONG DWELL SOLUTION -
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Characteristics of Icodextrin an alternative
osmotic agent
Reduced carbohydrate load
Sustained UF
Reduced AGE Low GDPs
Isosmolar(282 mOsm/kg)
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Extraneal PD Solution
Characteristics

• Isosmolar to serum (282 mOsm/kg)
• UF equivalent to 4.25 dextrose
• Sustained positive net UF for gt14 hr
• Gentle ultrafiltration
• One bag per day (long dwell)

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Ultrafiltration Kinetics of Icodextrin Exchanges
1600
1200
Dextrose 4.25
800
Net Ultrafiltration (ml)
400
Icodextrin 7.5
0
Dextrose 1.5
-400
-800
Time (minutes)
Ho-dac-Pannekeet et al, KI, 1996
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Reduced carbohydrate absorption
Reduced carbohydrate absorption with icodextrin
at 8 hours
100
80
60
Carbohydrate Absorption (g)
Carbohydrate Absorption ()
40
20
0
Glucose n7
Icodextrin n11
Glucose n7
Icodextrin n11
Glucose Concentration 3.86
Mistry C D, et al., KI 1994 46 496-503
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UF with Icodextrin and Glucose within and
without peritonitis episodes

Ultrafiltration (ml)
plt0.01
Gokal et al, PDI 15 226-230, 1995.
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• DIALYSIS AND NUTRITION
• IN ONE BAG -

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What is Nutrineal?
Nutrineal is a peritoneal dialysis solution
with amino acids instead of glucose which
integrates dialysis and nutritional
supplementation
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Nutrineal Characteristics

• Amino acids as osmotic agent
• No glucose
• No change in dialysis procedures
• More physiological pH (6.7)
• Osmolality equivalent to 1.36 glucose
• Clearance equivalent to 1.36 glucose
• PD 4 formulation

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Nutrineal Composition
Essential Amino Acids Non-Essential
Amino Acids Electrolytes Valine - 1.393
g Arginine - 1.071 g Na 132
mmol/L Leucine - 1.020 g Alanine - 0.951 g
Ca 125 mmol/L Isoleucine - 0.850 g Proline -
0.595 g Mg 0.25 mmol/L Methionine - 0.850
g Glycine - 0.510 g Cl 105 mmol/L Lysine
- 0.955 g Serine - 0.510 g Histidine -
0.714 g Tyrosine - 0.300 g Threonine - 0.646
g Phenylalanine - 0.570 g Tryptophane - 0.270
g
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What is the Purpose of Using Nutrineal?

• Nutrineal is primarily a dialysis solution
  designed
• To act as an amino acid supplement for protein
  malnourished PD patients
• To replenish normal peritoneal amino acid /
  protein losses which may prevent protein
  malnutrition in the longer term
• As a non-glucose based dialysis solution which
  could be useful for diabetic and obese patients

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Delivering 25 of daily protein intake
In just one exchange, an amino acid-based PD
solution can deliver 25 of the target Daily
Protein Intake

• With an absorption rate of 70-80 over 4-6 hours,
  one exchange of 2L Amino Acid solution provides
  approximately 18g of AAs to an average, stable,
  60kg patient that is 0.3 g/kg body weight/day,
  which represents 25 of the 1.2 g/kg body
  weight/day target intake1
• Recommended dosage for adults one 2L or
  2.5L bag/day

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Target DPI
1 Jones MR, et al., PDI, 199818(2)210-216
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Delivering 25 of daily protein intake
Lean body mass ( of standard weight) and
patient survival
The relationship between malnutrition and
increased morbidity and mortalityin dialysis is
well known
100
gt73
90
Surviving
80
63-73
70
lt63
60
24
0
6
12
18
Months
Nutrineal Recommended dosage for adults one 2L
or 2.5L bag/day
Adapted from McCusker FX, et al., Kidney Int
Suppl, 199656S56-61
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(No Transcript)
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A Natural Solution for a Natural Membrane
Bicarbonate/Lactate PD Solutions

• Physioneal? offers a
• physiological pH
• physiological bicarbonate concentration
• physiological pCO2
• reduced level of GDPs

Coles GA., et al., NDT 1998 133165-3171 Mactier
RA., et al., KI 1998 531061-1067 McKenzie R.,
et al., JASN 1998 91499-1506 Topley N., et
al., JASN 1999 10, 230A (A1169)
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Physioneal Bicarbonate-buffered PD Solution
-
Product Description

• Ca and Mg separated from bicarbonate during
  sterilization to prevent precipitate formation
• Dextrose separation during sterilization results
  in very low levels of GDPs
• pH 7.4

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Physioneal biocompatibility

• Physioneal and peritoneal host defence
• Physioneal and membrane integrity

HA Hyaluronic Acid
CA125 Cancer Antigen 125
N106 Duration 6 months
Jones S., et al., Kidney Int 2001591529-1538
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Physioneal for improved therapy comfort
McGill Pain Questionnaire
Total Weighted Pain Rating Index
12
10
8
Total weighted pain rating index
6
4
2
0
Conventional lactate
Experimental 38mM
Physioneal solution
solution
bicarbonate solution
PD solution tested
Mactier RA., et al., KI 1998 531061-1067
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Mechanisms for Bio-incompatibility

• The modulation of peritoneal cell function
• Cellular stress mechanisms
• Carbonyl stress breakdown products of glucose
  react with proteins to form a series of
  biologically active compounds
• 3. Inhibition of peritoneal cell function and
  reduction in cell viability

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PD Solution Biocompatibility
pH and buffer system
Biocompatibility Factors
GDP cytotoxicity
Hyperosmolality
AGE
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Glucose exposure and inflammation
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How do GDPs impact on peritoneal membrane
function
Heat Sterilisation
Glucose
Glucose Degradation Products (GDPs)
Filter
Heat
Proteins
AGE Formation
Modulation of Cell function
Fibrosis
Inflammation
Angiogenesis
Membrane structural and functional alterations
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Extraneal and GDPs Ueda et al, 2000 Kidney Int
58 2518-2524
ltConcentration (?M)gt
1.36 Glucose Extraneal
Glyoxal 6.2 0.5 1.7 0.2
Methyl-glyoxal 7.8 0.6 1.8 0.2
3-deoxyglucosone 47.2 4.3 3.5 0.4
Total reactive carbonyl compounds 64.7
8.7 25.7 4.1
Extraneal contains significantly lower levels of
carbonyl stress compounds even versus
conventional 1.36 glucose solution
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In vitro GDP concentration Methylglyoxal  
8.0
7.0
6.0
5.0
Methylglyoxal umol/L
4.0
3.0
2.0
1.0
0.0
Glucose
Glucose
Glucose
Physioneal
Physioneal
Physioneal
Icodextrin
Amino Acids
3.86
2.27
1.36
3.86
2.27
1.36
Schalkwijk et al, Perit Dial Int,
200020(6)796-798
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How does glucose impact on peritoneal membrane
function
700

Glucose Osmolality
Glucose

600
Mannitol

500


400
TGF-b1 (pg/105 HPMC)
300
Cellular activation
200
100
0
VEGF
TGF-b1
5
10
20
40
60
100
Concentration (mM)
Angiogenesis
Fibrosis
Membrane structural and functional alterations
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Glycation of Albumin with Extraneal
In vitro study of glycation of albumin with
Extraneal Millar et al., J Am Soc Nephrol, 1995
1
0
0
1.36 glucose

Extraneal
7
5
Increase in Glycation
Above Control
5
0
2
5
0
1
0
20
4
0
Time (Days)
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Osmolality of Standard vs. Advanced PD Solutions
Mistry et al, 1994
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The transport of solutes and fluid
High transporters An increase in surface
area/permeability leading to greater glucose
absorption and a more rapid dissolution of the
osmotic gradient
Normal peritoneal vessel
Vascular alterations
80
70
60
50
40
number of vessels/field
30
20
10
0
0
2-25
gt25
Peritoneal sclerosis
10mm
Months CAPD
Mateijsen et al. PDI, 19 517-525, 1999
Net result
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High transport outcome
High transporters Efficient membranes for small
solute clearancebut may have difficulty with
ultrafiltration, especially during the long dwell
Impact on outcomes in PD
Recent studies (Davis1 and Churchill2) have
shown that high transporters had a worse
prognosis probably due to more difficulty with
fluid balance management
Surviving
Time in Months
1 Davis et al. KI 1999 Vol 54 p 2207 2217 2
Churchill et al JASN 1998 - Vol 9 1285 - 1292
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Which of these factors is thought to
influence/cause the peritoneal membrane to become
more permeable ? 1 time on PD2 glucose 3
GDPs 4 hyperosmolality 5 other dialysate
components
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Morphological changes in the peritoneal membrane
100mm
100mm
Normal parietal peritoneum
Parietal peritoneum gt5 years PD
The Peritoneal Biopsy Registry
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The Peritoneal Biopsy Registry
Median thickness of sub-mesothelial compact zone
2000
Donor v All p0.00001 (Kruskal-Wallis)
HD v PD p0.0049 (Kruskal-Wallis)
1500
PD p0.0049 (Kruskal-Wallis)
1000
Membrane Thickness (microns)
500
0
n
16
15
11
24
54
37
23
8
25-48 months
73-96 months
HD
Uraemic
Donor
49-72 months
0-24 months
97 months
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Loss of Ultrafiltration

• Caused by the following changes in the
  Peritoneums
• structure
• Degenerative changes in blood vessels and
  vascular walls (neo-angiogenesis occlusion)
• Fibrosis of sub-mesothelial layer
• Loss of mesothelium

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Glucose absorption
PD patients are estimated to absorb 100-300 g of
glucose/day1
Increased circulating insulin
Atherogenesis
Hypertonic glucose solutions
Hyperlipidaemia
Continual absorption of glucose
1 Martis et al, in Owen et al, Dialysis
Transplantation A companion to Brenner
Rectors The Kidney, 2000179-198.
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Local effects High glucoseLow pH
Lactate Hyperosmolarity
Systemic effects Glucose absorption Fluid
solute removal
Improving membrane patient life

• Nutritional status appetite
• Fluid balancegtBPgtCVD
• Metabolic alterations
• Atherosclerosis
• Comfort (reducing POI)

• Structure
• Vascular changes
• Membrane tissue
• Function
• High peritoneal transport rate
• Loss of UF capacity

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Modeled peritoneal glucose exposure
Additive effects that can be achieved by using
a combination of Physioneal?, Icodextrin Amino
Acid Solutions
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CAPD DwellsDay time 3 X 5 hours Overnight 1
X 9 hours
14
12
10
Peritoneal glucose exposure (g.min/ml)
8
6
4
2
0
3 X 1.36 G
3 X 1.36 P
3 X 1.36 P
2 X 1.36 P
1 X 3.86 G
1 X 3.86 P
1 X ICO
1 X AA
1 X ICO
Holmes et al. PDI 200020(2)S37-S41
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In vitro GDP concentration Methylglyoxal  
8.0
7.0
6.0
5.0
Methylglyoxal umol/L
4.0
3.0
2.0
1.0
0.0
Glucose
Glucose
Glucose
Physioneal
Physioneal
Physioneal
Icodextrin
Amino Acids
3.86
2.27
1.36
3.86
2.27
1.36
Schalkwijk et al, Perit Dial Int,
200020(6)796-798
42
Modeled total carbohydrate absorption
Additive effects that can be achieved by using
a combination of Physioneal?, Extraneal?
Nutrineal?
140
CAPD DwellsDay time 3 X 5 hours Overnight 1
X 9 hours
120
100
80
Total CHO absorption (g/24/h)
60
40
20
0
3 X 1.36 G
3 X 1.36 P
3 X 1.36 P
2 X 1.36 P
1 X 3.86 G
1 X 3.86 P
1 X E
1 X N
1 X E
Holmes et al PDI 200020(2)S37-S41
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QUIZ TIME!!!
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Improved PD solution biocompatibility
pH and buffer system
GDP cytotoxicity
Hyperosmolality
Biocompatibility Factors
Glycation, Amadori and AGE