1. Present and Future of Peritoneal Dialysis
Simon Davies
University Hospital of North Staffordshire,
Stoke-on-Trent
Institute for Science and
Technology in Medicine
Keele University, UK

2. Scope Where are we now with peritoneal dialysis?
Role of the therapy
Infection
Small solute clearance
What problems do we need to solve in the future and what is the current progress?
Fluid management
Longer term membrane integrity

3. Examples of integration: the patient specific perspective
Pre-emptive Tx
PD Bridge
2nd Tx
PD Start Tx
Minimal Care HD
2nd Tx
PD Start
Home HD
Satellite-based HD Tx
PD Bridge
Centre-based HD
Assisted Home PD

4. USRDS comparison of modality survival:
Adjusted Patient Survival
Incident U.S. Medicare Patients ( )
N=398,940
Proportional hazards model with adjustment for demographics, baseline comorbidity, and baseline GFR, albumin, Hgb, BMI as captured on Medical Evidence Form 2728
Adjusted Median Life Expectancy:
HD: 35.1 months
PD: 33.8 months
Vonesh et al (Kid Int 70:S3-S11, 2006)

5. Patients prefer to choose Some have no choice
1,347 patients included
Patients prefer to choose
Some have no choice
Given choice: Elderly less likely to choose PD
Am J Kidney Dis 2004; 43:891-9

6. Choice summary
Patients have preferences and would like these to be considered
Dialysis modality choice is largely based on life-style
Home versus Centre is more important in this context than HD v PD
Choice is associated with greater patients satisfaction
Older patients can be disenfranchised of a home choice

7. Infection Peritonitis rates much improved Regular audit of:
Disconnect systems
Range from 1 in 24 to 1 in 60 months
Regular audit of:
Culture techniques (>80% +ve culture)
Patient technique
Primary cure rate (>80%)
Antibiotic regimes and sensitivites

8. ISPD Guidelines 2005
Prevention, Prevention, Prevention….

9. Hospitalization rates for septicemia

10. Each 250 ml of urine volume reduced risk by 36%
CAN-USA Study:
2-year survival
Each 250 ml of urine volume reduced risk by 36%

11. Country Kt/V Creatinine Cl CARI Australia 1.6 (min) or 50 60
‘Rationale’ updated 2006
Country Kt/V Creatinine Cl
Transport status: Low/LA HA/High
CARI Australia (min) or
CSN Canada (min)
EBPG Europe (min) and 45
K-DOQI US (min)
Renal Association 1.7 (min) or

13. Comparison of studies:
2-year survival
Hong Kong
EAPOS
CANUSA
ADEMEX
NECOSAD
Kt/V urea

14. Comparison of two approaches to dialysis prescription: RCT
Demetriou, et al KI, 2006

15. Randomised cross-over design, n=22
 10%
 27%
Demetriou, et al KI, 2006

16. Scope Where are we now with peritoneal dialysis?
Role of the therapy
Infection
Small solute clearance
What problems do we need to solve in the future and what is the current progress?
Fluid management
Longer term membrane integrity

17. Predictors of survival in PD patients
2° analysis of ADEMEX Study, CJASN, 2008

18. Cox proportional models for survival by BP on PD according to subsequent transplant status
Non transplanted n =1535 ,p =0.001; transplanted n =526, p=0.24
UK Renal Registry, Am J Kid Dis, 2007

19. Markers of cardiac damage predict fluid overload and cardiovascular death in PD and HD
LV Mass, LV function, Troponin T and n-proBNP (independent) predictors of cardiac fluid overload in PD patients
Wang, AM, et al; KI, 2006, & JASN, 2006
Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients
Zocalli, C. et al, JASN, 2001

20. Should there be an ultrafiltration target?
European guidelines suggest minimum UF of 1 litre
EAPOS suggests <750ml ( 50 mmol/day of sodium) associated with problems – what is the mechanism?
Low salt and water intake? Likely
Worsening nutrition? Indirect evidence
Poor BP control? NO
Poor fluid status – no data
Inflamed patients (association – cause or effect?)
Poor membrane function? Partial explanation

21. The membrane as a cause of poor ultrafiltration and poor volume management
High solute transport
(Type 1 UF failure)
Poor osmotic conductance
(Type II UF failure)

22. Meta-analysis of studies linking solute transport to survival
Brimble, KS JASN 2006

23. Why might high transport be associated with worse outcomes?
Worse ultrafiltration
Early loss of osmotic gradient causing less efficient aquaporin mediated UF
More rapid fluid reabsorption in long dwell via the small pores
Increased protein losses
Association with membrane inflammation

24. Icodextrin as a tool to improve fluid status
Plum, AJKD 2002
Wolfson, AJKD, 2002
Konings, KI, 2003

25. * * * * * * ** * * ¶ ¶ ¶ Drained body weight TBW Volume (BIA)
TBW Volume (deuterium)
ECF Volume (BIA)
Between Group: *=P<0.01, **=P<0.05; Longitudinal, ¶=P<0.001
Davies, et al, JASN, 2003

26. L H
P=0.009
P = NS
Stoke PD Study: Influence of solute transport category on survival on PD before and after specific strategies to reduce problems of high transport status: KI, 2006

27. Fluid Management Algorithm:
Identify problem:
Clinical fluid overload/BP/BIA/inflammation
Low 24 UF (remember overfill in CAPD)
High Solute transport or reduced UF capacity
Assess Na intake and restrict if appropriate
Use icodextrin and APD to optimise prescription in high transporters – avoid reabsorption
Use ACE/AII blockade and/or diuretics to:
maintain RRF
Avoid excessive hypertonic glucose
Treat BP if otherwise euvolaemic
Increase UF if below 750 ml/transfer to HD

28. Future of fluid management in PD
Assessment of fluid status
BIA
ECHO
Biomarkers
Improving salt and water removal
Low sodium solutions
Combination solutions

29. What is the relationship between cardiac function, fluid status and BNP in PD?
Detailed ECHO studies in PD patients:
LVMI correlates with:
systolic BP,
corrected plasma volume,
and ECW:height
but not with ECW:TBW ratio or CRP.
LAVI correlates with:
corrected plasma volume and BNP
but not with BP, ECW:height, ECW:TBW or CRP.

30. Baseline Results LV EF (%) LVMI (g/m2) LAVI (ml/m2) E/A E/E’pw ratio
PD Pat
(n=17)
HT non-renal Pat (n=17)
p-value #
Controls
LV EF (%)
58±7
61±9
0.237
62±8
LVMI (g/m2)
113.1±33.5
81.3±29.6
0.012
84±20*
LAVI (ml/m2)
27.8±11.1
28.7±8.2
0.772
22.9±8.4
E/A
0.7±0.14
0.87±0.2
0.008
0.83±0.18*
E/E’pw ratio
10.4±3.6
10.2±4.0
0.885
7.5±1.8*

31. Davies et al, NDT, 2009

32. Combining icodextrin and glucose to optimise Na removal
Freida, P. PDI 2007

33. Scope Where are we now with peritoneal dialysis?
Role of the therapy
Infection
Small solute clearance
What problems do we need to solve in the future and what is the current progress?
Fluid management
Longer term membrane integrity

34. Davies, SJ, KI, 2004 34

35. Longitudinal changes in membrane function
■ = stable UF
□ = UF failure
Davies, SJ, KI, 2004

36. Smit, Thesis, 2004

37. Capillaries and Post Capillary Venules
Aquaporin I
Capillaries and Post Capillary Venules

38. Epithelial to mesenchymal transition

39. Evidence of Epithelial-to-Mesenchymal Transition of Mesothelial Cells in Peritoneal Tissue of Patients Undergoing Continuous Ambulatory Peritoneal Dialysis
María Yáñez-Mó, Enrique Lara-Pezzi, Rafael Selgas et al., New England J Med, 2005

40. Davies, KI, 2004

41. Glucose >1.36% 12 months Glucose =1.36% 24 months Glucose onlyml ml
Glucose >1.36%
12 months
Glucose =1.36%
24 months ml ml
Glucose only
No peritonitis
peritonitis
using icodextrin

42. Increasing solute transport
Variability in membrane function
Effective contact area
Osmotic conductance
Start PD
Increasing solute transport
IL-1/IL-6
VEGF
Increasing vascularity
Increase in blood flow
Dissociation of solute transport and osmotic conductance
? TGF
EMT
Progressive fibrosis
Loss RRF
Glucose/GDP
Peritonitis
Ultrafiltration failure ?
Additional trigger
Stop PD
Peritonitis
Visceral involvement
EPS

43. > 1000 patients. Paired dialysate and plasma samples, IFN-γ , IL-1β, IL-6, TNF-α
Dialysate IL-6 levels ~x10 plasma (despite dilution by dialysate).
IFN, IL-1 usually low/undetectable, but can be elevated above plasma
Dialysate cytokines auto correlate:
IL-1 with IFN r=0.43, P<0.0001
IL-1 with TNF r=0.45, P<0.0001
IL-6 with TNF r=0.45, P<0.0001
IFN with TNF r=0.48, P< etc

44. INCIDENT
PREVALENT
Dialysate IL-6 pg/ml
Plasma IL-6 pg/ml

45. Preserving and monitoring the membrane
Avoid excess glucose exposure
Low GDP solutions
Regular monitoring of membrane function (PET) and effluent biomarkers
Switch to HD if type 2 UF failure

46. Acknowledgements Collaborators and colleagues Biopsy Registry
EAPOS Group
Bengt Rippe
Daniele Venturoli
Ray Krediet
Denise Sampimon
Ramzana Asghar
Lily Mushahar
Kit Huckvale
Biju John
Jeff Perl
PD staff and patients
Biopsy Registry
John Williams
Nick Topley
Kate Craig
GLOBAL Fluid Study
Nick Topley James Chess Mark Lambie Charlotte James
Study Investigators