Prevention Of Membrane Damage In Patient With Peritoneal Dialysis

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Prevention Of Membrane Damage In Patient With Peritoneal Dialysis Powered By Docstoc
					  Chronic Peritoneal Damage In
  Patients On Peritoneal Dialysis
   and its Prevention with New
   Peritoneal Dialysis Solutions

Mufazzal Ahmad, Joanne Bargman, Dimitrios G Oreopoulos
                Department of Nephrology
          University of Toronto, Ontario, Canada
                Outline

   Peritoneal membrane damage on PD
   Possible etiological factors in PDF
   New PDFs
   Evidence for prevention of membrane
    damage with New PDFs
Peritoneal Changes on Long Term PD


                            Laproscopy


                            Light
                            Microscopy


                           Electron
                           Microscopy
  Technique Failure in Long Term PD
  Source        Recurrent     UF     Solute Leak/ Other/ Choice/
                Peritonitis Failure Removal Cathet Clinical   Not
                    %         %     Failure % er %    %     managin
                             Membrane Failure                 g%
Maiorca et al      48             22             11       12           13
   1991
 Lupo et al        29             16              8       13           11
   1994
Maiorca et al      37        9         9          4       13           37
   1996
Kawaguchi et       13        23        ---        2       44           15
  al 1997
Stoke study        54        27        ---        2       ---          17
   1998

                                             Davies SJ et al KI 1998
           Conventional PDF

     PDF           Dianeal       Stay safe Gambro Std
 Manufacturer       Baxter       Fresinius   Gambro
 Glucose (%)     1.36 -3.86%,   1.5%-4.25% 1.5%- 3.88%
Lactate mmol/L        40            35         40
      pH              5.5           5.5        5.5
  Osmolality       344-483        340-368    353-492
Peritoneal Changes & PD Duration




    Submesothelial Compact
       Zone Thickness
                      Williams et al JASN 2002
Peritoneal Changes & PD Duration




 Peritoneal Neoangiogenesis & Vasculopathy
                            Williams et al JASN 2002
    Functional changes & PD Duration

 More rapid absorption of the glucose
during the dwell
 Reduction in ultrafiltration capacity
(increased risk of UFF)
 Progressive increase in solute
transport with time

                 Davies et al KI 1998: 2207-17
Peritoneal Damage- Sequence of events
            Bioincompatible PDF

               Peritoneal injury

                  Loss of UF

     More hypertonic bioincompatible PDF

         More severe peritoneal Injury


           More severe loss of UF

            Discontinuation of PD
Long-term Structural & Functional Alterations
   in Peritoneal Membrane (Hypothesized)
                        Uremia

                                 PDF

                Peritoneal cells injury


                 TGFβ, FGF, VGEF


             Fibrosis                Angiogenesis

                                   Increased effective
                                 peritoneal surface area


                                 Increased permeability to
                                  small solute & Glucose


                                          UF Failure


             Peritoneal Membrane Failure               Toshio et al KI 2002
Etiological Factors
  • Glucose
  • GDPs
  • AGEs
  • Hyperosmolality
  • Lactate
  • Acidity
    Limitation of Literature
  Only few studies comparing the
  effect of one factor in presence
  and absence of all other etiological
  factors
 Specific role & importance of each
  factor
Glucose – A Saint or Sinner
Glucose based PDF
   • Effective
   • Safe
   • Readily metabolised
   •Source of calorie
   • Inexpensive
   • Standard of care
   • Unphysiological
   • Not “ideal”
                 Glucose Toxicity
                                                Effect on
             Patho-physiological Changes        peritoneal
                                                membrane
HPMC          Altered complement synthesis  Inflammation
              Increased TGFβ, Laminin,      Fibrosis
             fibronectin                     Altered
              Alter fibrinolytic system    membrane
              Increased apoptosis          permeamability

Fibroblast    Increased proliferation             Fibrosis
              Increased extracellular matrix


                              Sitter T et al PDI 2005
Longitudinal Changes In Peritoneal Solute Transport
   & Glucose Exposure In Long Term Survivors




                                                         Increased Peritoneal
        Increasing solute transport n=9
                                                         Exposure to Glucose
                          stable solute transport n=13
                                                         Preceded Increase
                                                         in Solute Transport




                                      Simon J Davis et al JASN 2001
Glucose – Indirect Toxicity
   GDPs
   AGEs

   Hyperosmolarity

   Relative contribution in
   relation to glucose ?
Glucose Degradation Products
          (GDPs)
      GDPs In PDF
 GDPs    formed during heat
  sterilization & storage of PDF
 GDPs not only damage directly,
  also trigger the AGE formation
                 GDPs
           GDPs               Conc (µmol/L)
3,4-Dideoxyglucosone-3-ene    9- 22
Formaldehyde                  6-15
Acetaldehyde                  120- 420
3-Deoxyglucosone              118-154
Glyoxal                       3-14
2-Furaldehyde                 0.05-2
5-Hydroxytmethylfuraldehyde   6- 30
Methylglyoxal                 2-23
                         GDPs
                                              Effect on
            Patho-physiological Changes       peritoneal
                                              membrane
HPMC         Reduced proliferation, viability  Reduced wound
             Impair cellular attachment       healing
             Increased VCAM1, IL6, IL8,        Inflammation

             Modulate AGER,                    Fibrosis

             Increased VEGF                   Neoangiogenesis

Peritoneal  Reduced respiratory burst        Impaired
Macrophage capacity                           peritoneal defence
Leucocyte      Increased rolling leucocyte      Inflammation


                               Sitter T et al PDI 2005
      GDPs In PDF

 More cytotoxic than glucose
 Cytotoxicity is dose
 dependent
              Mortier et al KI 2004
Advanced Glycosylation
 End Products (AGEs)
                       AGEs
           Patho-physiological       Effect on peritoneal
           Changes                   membrane
HPMC        Increased VGEF          Neoangiogenesis
            Increased PAI1          Altered
                                    Fibrinolysis
Peritoneum  Inflammatory cytokines  Inflammation
            Upregulation adhesion  Impair UF
           molecule
              Increased TGFβ           Fibrosis


                           Sitter T et al PDI 2005
          AGEs
 Alter structural integrity of
  membrane protein
 Extent of AGEs
  accumulation correlated
   Fibrosis
   Vascular sclerosis
   UF loss

               Honda et al NDT 1999
Hyperosmolarity
              Hyperosmolarity
Patho-physiological           Effect on peritoneal
Changes                       membrane
Inhibition of integrin          Delayed wound healing
mediated MC migration
   Increased aquaporin 1        Impair UF
 Increased PG E2 synthesis      Increased protein loss
 Increased TGFβ                 Fibrosis



                              Sitter T et al PDI 2005
Glucose Systemic Toxicity in PD
 Systemic absorption of glucose
 Hyperinsulinemia

 Decrease appetite & protein intake

 Dyslipidemia

 Obesity
Acidity (pH)
      Low pH is not the major culprit
Mice model
Compared bicarbonate/lactate-buffered PDF of
physiological pH Vs acidic pH (pH 5.2)
    Morphological
    Cellular Changes
    Angiogenesis
                              No significant
    Fibrosis
                              difference
    Glucose Absorption
    Ultrafiltration Capacity
Acidic PDF neutralized within 15 to 20 minutes
Lactate Buffer
              Lactate Buffer (Animal Model)
                    Heat-sterilized PDF   Filter-sterilized PDF



  Glucose                                                         Glucose
  Lactate                                                         Lactate
  GDPs


  Lactate
• MC Damage
• Neoangiogenesis
• Inflammation
• Fibrosis




                      Lactate Buffer            Control
                                                      Zareie et al NDT 2003
    Newer PDF- Goals
  Reduce/ Eliminate GDPs
 Reduce/ Eliminate Glucose
  (better osmotic agent)
 Neutral pH

 Total/ partial substitution of
  lactate
     Newer PDF
   Low GDP/Neutral pH
   Bicarbonate/ Lactate
   Bicarbonate
   Icodextrin
   Amino acid
                      New PDFs
     PDF         BicaVera       Trio     Physioneal Nutrineal Extraneal
Manufacturer      Fresinius   Gambro       Baxter    Baxter    Baxter
Osmotic agent      Glucose   Glucose Glucose 1.1% AA       7.5%
                 1.5%-4.25% 1.5 - 3.9% 1.36 -3.86%      Icodextrin
 Bicarbonate          34      None          25     None   None
   mmol/L
Lactate mmol/L     None        39-41        15         40        40
      pH            7.0        5.5-6.5      7.4       6.7       5.5
  Osmolality      340-350     356-482     344-483     369       284
Switch from Conventional to Low GDP PDF
             (Animal Model)
       Better UF
       Less
           VEGF
           AGEs
           TGFβ
           Fibrosis

                   Mortier et al KI 2005
          Euro Balance Trial
 Multicenter, open, randomized,
  crossover with parallel arm design trial
 Compared conventional PDF to Low
  GDPs, neutral pH PDF (Balance)
     Increased  CA 125, Procollagen peptide
     Decreased HA
     ? Significance & long term effect of
      surrogate marker
                        William et al KI 2004
      Euro Balance Trial- RRF
                  SPDF Balance p value Balance SPDF p value
                  (n=36) (n=36)         (n=35) (n=35)
U Cr Cl (L/day)    4.9    5.2     0.09    4.5    3.5    0.007
U U Cl (L/day)     3.8    3.9    0.022    3.7    2.7    0.007
  UF ml/day       1350    995    0.0003   1025   1185   0.026
 Weight (kg)      70.0   71.25    0.06    78.0   78.0   0.80
     SBP           135    130     0.93    130    133    0.66
     DBP           80     81      0.92     80    81     0.74

    Better RRF, No clinical sign of overhydration
            ? High Extracellular volume – Less UF
            ? Decrease Cytokines, AGEs, GDPs
                               William et al KI 2004
           Low GDPs
Double/ Triple Chamber Bag PDF
 Separates  glucose
  from the buffer
  during heat sterilization
 Less Carmalization

 Physiologic pH

 Markedly Reduced GDPs
Bicarbonate based PDF
      Bicarbonate is better
 Natural physiological buffer
 Abolish peritoneal bicarbonate loss

 Better peritoneal macrophage,
  mesothelial cell and neutrophil
  functions
 Better viability and cytokine release

                  Topley N, PDI 1997
How much is too much
Supraphysiological Bicarbonate

    Supraphysiological pCo2

? Paradoxical intracellular acidosis
       Metabolic alkalosis

Long term effects (ABD, VC) ?
              Cancarini et al PDI 1998
B/L 25/15 Vs B 38 - Peritoneal
    Macrophage Function

      L 40
      B 38
      B/L 25/15




    Mackenzie et al JASN 1998: 1499-1506
PMN Migratory Capacity & B/L PDF
 PMN Migration




  Lactate        20.8   16.7   12.5     15.0     6.7
Bicarbonate      10.0   15.0   20.0     17.0     27.0
          pH     7.0    7.0    7.0      7.2      7.4

                                      Schambye et al PDI 1993
              Balance Trial
   Multicenter, retrospective observational study,
    Incident, Korean, CAPD pts
   Patient & Technique Survival –
     Standard, Lactate, Heat-sterilized PDF (n=551)
                         Vs
     Low GDP, Neutral-pH PDF (Balance) (n=611)

    Treated upto 30 months

                          Lee et al PDI 2005
Balance Trial – Patient Survival

                          Balance PDF
                                        74%
                           SPDF
                                        62%




  RR of Death on Balance 0.75 (0.56-0.99)

                    Lee et al PDI 2005
     Balance Trial – Criticism
   Retrospective, Nonrandomized study
   Selection bias & Center effect
   ~30% pts switching from control arm to
    treatment arm
   Younger pts in treatment arm
                     Lee et al PDI 2005
B/L 25/15 (Physioneal)
 Physiological pH & pCO2
 Reduced Lactate

 Reduced GDPs

 Good control of uremic acidosis

 Improved UF
              Tranaeus A PDI 2000
          B/L 25/15 Vs Lactate 40

Multicenter RCT
106 pts
6 month
Dialysate CA 125
(Mesothelial cell
mass)

                     Jones et al KI 2001
B/L 25/15 Vs Lactate 40 – Dialysate Hyluronic Acid
         (Inflammation/wound healing)




                        Jones et al KI 2001
    B/L 25/15 Vs L 40
 Increase muscle mass
 Improved appetite & overall
  wellbeing
 Equivalent peritoneal urea & Cr
  clearances
 Safe & Well tolerated
               Tranaeus A PDI 2000
          Infusion Pain
 DRCT
 B/L 25/15 Vs B 38 Vs L 40

 Validated McGill Pain Questionnaire

 B/L 25/15 & B 38 PDF significantly
  reduced pain compared to lactate
 Trend for lower pain score with B/L
  25/15 compared to pure bicarbonate
                     Mactier et al KI 1998
             Peritonitis
 Prospective European PD solution
  registry (n=1762)
 Significantly lower rate of peritonitis
  in B/L 25/15 Vs Conventional PDF
 Significantly lower peritonitis
  duration
    Non-randomized data
    Only abstract published

              Sporsen et al PDI 2002 (abstract)
                                  Bicarbonate/ Lactate PDFs

        Less GDPs & AGEs
           Physiologic pH                                          Good Correction of Acidosis
       Better Cellular function




                                                                Improved Appetite & Muscle mass
Better preservation of dialysate marker                          Reduced Systemic inflammation
       Improve immune defense                                     Better Response to infection




                                           Peritonitis rate?
                                           Nutritional Status
                                           Preserved RRF?




                             Improval of peritoneal membrane viability
                                  Reduced mortality & morbidity



                                          Roberto Pecoits- Filho KI 2003
Icodextrin
Composition of Icodextrin PDF
Components           Icodextrin PDF
Glucose g/L          —
Icodextrin g/L       75
Sodium mEq/L         132
Chloride mEq/L       96
Calcium mEq/L        3.5
Magnesium mEq/L      0.5
Lactate mEq/L        40
Osmolality mOsm/kg   282
pH                   5.2
           Icodextrin
 Reduce  glucose exposure –
  reduce UF problems – Less
  hypertonic exchanges
 Less AGEs

 Extend technique survival in UFF
                   Wilkie et al PDI 1997
 GDPs- Icodextrin Vs Glucose PDF

   GDPs         Glucose     Icodextrin
  μmol/L        (1.36 %)      (7.5%)     p value

     Glyoxal      6.2±0.5      2.6±1.2     <0.01

Methylglyoxal     7.8±0.6      1.9±0.5    <0.001

       3-DG      47.2±4.3      4.1±0.7    <0.001

  Total RCOs     64.7±8.7     26.4±4.5     <0.01

                            Cooker et al KI 2002
Icodextrin- Systemic Benefits
     Less  Hyperinsulinemia
     Insulin resistance

     Dyslipidemia

     Hyperleptinemia
    Icodextrin- Sustained & Better UF than 1.5% &
       2.5% dextrose in long & long- long dwell
                      1200
                      1000
                       800
                                                              7.5% Icodextrin
                       600
        Net UF (ml)




                       400
                                                              4.25% Dextrose
                       200
                                                              2.5% Dextrose
                         0
                      -200
                                                              1.5% Dextrose
                      -400
                      -600
                      -800
                             0   2   4   6        8      10   12     14         16
                                             Time (hr)
Ho-Dac-Pannekeet et al, Kid Int 1996; 50:979-86               Negative Ultrafiltration
Douma et al, Kid Int 1998; 53:1014-21
Icodextrin Vs 4.25% Dextrose in APD
    12-16 Hrs dwell, H & HA PET
      Peritoneal Ultrafiltration



                             7.5% Icodextrin




                            4.25% Dextrose




              Salim Mujais et al JASN 2005
Negative Net UF




      Salim Mujais et al JASN 2005
        Long-dwell carbohydrate absorption &
          UF efficiency ratio (net UF volume
               [mL]/g CHO absorbed)
                       4.25% Dextrose         7.5% Icodextrin
                          CHO        UFE      CHO                  UFE
                       Absorbed (g) (ml/g) Absorbed (g)           (ml/g)
     Week 1             76.7 (91.3%)   5.1   56.0 (35.3%)         10.5*


     Week 2              77.7 (92.%)   4.7   56.3 (35.6%)         10.9*

* P < 0.001 versus 4.25% dextrose
                                             Salim Mujais et al JASN 2005
Disadvantage- Icodextrin
   Mesothelial dysplastic changes &
    lipid peroxidation
                   Gotloib et al Nephron 2002
Amino acid based PDF
    Amino acid PDF
PDF               Nutrineal
Glucose (%)       None
Sodium mmol/L     132
Calcium mmol/L    1.25
Magnesium         0.25
mmol/L
Chloride mmol/L   108
Bicarbonate       None
mmol/L
Lactate mmol/L    40
pH                6.7
Osmolality        369
                  1.1% AA
HPMC Proliferation- AA Vs Glucose PDF


                                                        Control

                                                       AA PDF

                                                        Glucose
                                                       Spent
                                                       Dialysate



Better preservation of peritoneal ultrastructure, Viability &
protein synthesis in HPMC
                            Chan TM et al NDT 2003
       Amino Acid PDF
 Improve malnutrition
 Decreased AGEs & RAGE
  Expression
                   Mortier et al KI 2004

       mesothelial cell mass
 Better
 (CA 125)   Mortikainen et al PDI 2005
AA Vs Conventional PDF
  Animal Model
  Reduced
    • Immune activation
    • Angiogenesis
    • Fibrosis
    • Mesothelial damage
                     Zareie et al PDI 2005
         Pyruvate based PDF

   Less peritoneal fibrosis & angiogenesis
     Cytoprotective & Antioxidant effect
     Disadvantage: Instability in aqueous solution

                             Wu et al Artif Organs 2003
                             Shostak et al Nephron 2000
         Carnitine based PDF
   1.5% Carnitine based PDF Vs 3.86%
    Glucose Vs Icodextrin
   HPMC & Rabbit model
   Low mesothelial toxicity & better growth
   Higher phospholipids secretion
   Better preserved peritoneal membrane
              Gaggiotti et al Int J Artif Organs 2005
Combination of newer PDF
4 exchanges of Conventional PDF
                  Vs
1-AA +1-Icodextrin +2 B/L 25/15
    Decrease IP Glucose load
    High dialysate CA125
         Dialysis adequacy
         UF
         Weight             No Difference
         BP


                             le Poole et al PDI 2005
   Advantages & Disadvantages of The New PDFs

New PDFs                   Advantages                       Disadvantages

Bicarbonate     Normal pH & pCO2                      Glucose based
with Lactate    Dialysate CA 125 ↑, & Hyaluronan ↓    Lactate-buffered
                Lactate exposure ↓                    Costly
                GDP exposure ↓
                Inflow pain ↓
               ? Peritonitis incidence ↓

 Icodextrin     Ultrafiltration ↑                     Low pH,
                Better control of ECV & BP            Lactate-buffered
                Iso-osmolar                           Once daily (long dwell)
                Glucose, GDP & AGEs exposure ↓        Glucose & Amylase assay
                Hyperglycemia ↓                       Dysplastic Changes
                Dyslipidemia ↓                        Costly

Amino acid      25% of target protein (Amino acid)    Lactate-buffered
               without phosphate intake                Once-twice daily
                Protein synthesis ↑                   Metabolic Acidosis (mild)
                Glucose, GDP & AGEs exposure ↓↓       Costly
                Conclusion
   New PDF - Impressive result in
     In-vitro studies

     Animal studies

     Surrogate markers CA 125, HA, TGFβ

   Effect on hard end points
     Membrane histology/ Failure
                                   Still awaited
     Technique & Patient survival
   Investigating Effect(iveness) of
              New PDF
• Long-term follow-up controlled studies with
  “hard” end-points
        • Patient Survival, Peritonitis rates
        • UFF, RRF & QOL
• Such studies will also establish the validity
  of surrogate end-points
  • Until long-term studies become available
     – use surrogate end-points
                       F.J. Van Ittersum PDI 2005
Questions & Clarifications

				
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