PERITONEAL DIALYSIS: PRESENT AND FUTURE

Bari, March 2010

Simon Davies University Hospital of North Staffordshire, Stoke-on-Trent Institute for Science and Technology in Medicine Keele University, UK

Looking into the future...

The next president.... Of ISPD?

What are the challenges for PD?

• Developing the therapy to enable an aging, increasingly multimorbid dialysis population to have the opportunity for home-based treatment • Creating the clinical evidence for best practice – infection – Fluid management – Membrane injury

RCTs: Nephrology vs 12 Specialties

Strippoli et al J Am Soc Nephrol 15:411-9, 2004

Coverage of Nephrology RCTs (1966 to 2002).

Strippoli et al J Am Soc Nephrol 15:411-9, 2004

PD Publications: RCTs vs Others

1000 900 800 700 600 500 400 300 200 100 0

3-6%

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Year Other RCT

Scope

• Extending the role of PD • High/Rapid transport – a problem solved • Residual concerns over salt and water balance in PD? • Monitoring and preserving the membrane

Scope

• Extending the role of PD – Part of a central line avoidance strategy – Extending choice - Assisted PD • High/Rapid transport – a problem solved • Residual concerns over salt and water balance in PD • Monitoring and preserving the membrane

Examples of integration: the patient specific perspective

Pre-emptive Tx PD Bridge 2 nd Tx PD Start Tx PD Start Satellite-based HD Home HD Tx Minimal Care HD 2 nd Tx PD Bridge Centre-based HD Assisted Home PD

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

European view – EDTA 2008

Health Professionals Perspective

Patient perspective: Specific factors leading to modality selection

• •

Those choosing PD (20/20 active choice):

– –

flexibility of schedule (19 patients), convenience of performing CPD in their own home (19 patients),

–

the option of doing dialysis at night while sleeping (8 patients). Those choosing HD (8/20 active choice):

–

desirability of having a planned schedule (7 patients)

–

letting nurses or other take care of them (5 patients)

Wuerth et al, PDI, 2002

Barriers to doing PD

Oliver MJ et al , KI, 2007

Is assisted PD viable?

• Standard approach in many situations – e.g. nursing homes, extended families, visiting/community nurses (e.g. France) • Specific programmes e.g. Denmark, J Povlsen Oliver MJ et al , KI, 2007

Danish experience: retrospective review of older patients on PD

• • • Retrospective review of new patients 2000-4 – 100 incident patients >65 yrs old (65-88 yrs) – survived for >2 years 52 patients had unplanned start defined as starting PD <9 days after catheter insertion 58 patients required assistance – Caregivers visit patients twice a day – 32 unplanned start Povlsen & Ivarson, PDI 2008

Age of PD patients in France

Verger et al, Kid Int 2006

•

Retrospective study of 1613 patients >75 years old who started dialysis between 1.1.2000 and 31.12.2005

•

Mean age at dialysis initiation was 81.9 ± 4.5 years

•

89% on CAPD

•

81.8% required assistance

• Flexible PD catheter insertion arrangements • Motivation and ownership by ward staff (not just the PD team) • Access to continued care with aAPD

2008 Is rapid initiation of peritoneal dialysis feasible in un-planned dialysis patients? A single center experience Thierry Lobbedez, Angelique Lecouf, Maxence Ficheux, Patrick Henri, Bruno Hurault de Ligny, Jean-Philippe Ryckelynck Survival (months) in unplanned patients (NS) PD (n=34) HD (n=26)

In the future...

• We will break down the barriers to doing PD, including age, professional bias, patient bias, social, financial...

• There will be an egalitarian approach to enabling all patients to benefit from what PD has to offer • Evidence, evidence, evidence...

Scope

• Extending the role of PD • High/Rapid transport – a problem solved – Identification as a risk factor – Understanding the mechanism – Improved outcomes • Residual concerns over salt and water balance in PD • Monitoring and preserving the membrane

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

Smit, Thesis, 2003, KI, 2005 Asghar & Davies, KI, 2008

Early in the exchange transport status has opposite effects on UF By 4 hours most of the variability in aquaporin UF can be explained by transport status Asghar & Davies, KI, 2008

-1 -1.5

-2 -2.5

-3 1 0.5

0 0.4

-0.5

0.5

R² = 0.603

0.6

0.7

0.8

0.9

Solute Transport (D/Pcreat)

Asghar & Davies, KI, 2008

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

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

Survival of high (rapid) transport patients is better on APD

P = 0.01

Johnson, D. ANZDATA, NDT, 2010

Scope

• Extending the role of PD • High/Rapid transport – a problem solved • Residual concerns over salt and water balance in PD – Are PD patients fluid loaded – How does this relate to cardiac function?

• Monitoring and preserving the membrane

Initial application of BIA suggested that PD patients were over-hydrated.

Plum et al, NDT 2001

Relationship between plasma albumin and tertiles of bioimpedance ratios (ECF:TBW)

45 43 41 39

HD n=59 ANOVA P=0.065

37 35 33

PD n=68

31 29 27

ANOVA P=0.001

25 1 2 3

Increasing over-hydration/muscle wasting Tan BK, Chan C and Davies SJ, Sem Dial, 2010 in press

BIA predicted and D dilution measured TBW in PD patients

Percentage body fat

Predictors of discrepancy between measured and estimated TBW- PD

Standardised β Covariate

Constant Plasma albumin CRP Solute transport Comorbid Score Use of Icodextrin Plasma sodium Dialysate sodium loss Urine sodium loss -0.56

-0.31

0.09

0.096

0.225

-0.211

0.125

0.049

t

1.76

-3.04

-1.65

0.50

0.60

1.21

-1.32

0.79

0.29

Significance

0.089

0.005

0.109

0.62

0.55

0.24

0.197

0.43

0.77

Multivariate analysis: R=0.674, ANOVA P=0.011

Plasma volumes in PD patients are within normal limits

Fluid distribution in PD patients according to plasma albumin

Plasma albumin <31.4 g/dL Plasma albumin >31.4 g/dL 95% CI of difference P value (unpaired t test) N Gender split (M:F) Difference between measured TBW D and estimated TBW BIA (L) ECW:TBW ratio 20 8:12 3.55

0.495

26 18:8 0.94

0.472

0.61 to 4.6

0.049

0.012

0.036

Plasma Volume (ml) Corrected plasma volume (ml/m 2 ) Plasma Volume (% different from predicted) 2551 1463 -0.94

2820 1482 -3.4

-0.001 to 0.05

-124 to 661 -135 to 173 -12.2 to 7.2

NS NS NS

Comparing the heart of PD patients with normal and symptomatic HT

Baseline Results LV EF (%) LVMI (g/m 2 ) LAVI (ml/m 2 ) Left atrial pressure (E/e’) PD Pat 58 ±6 113.0

± 29.6# Symptomatic HT non-renal 61 ±6 89.5

± 31.5

Controls 62 ±8 75.7

± 21.9

31.6

±12.8 10.2

±3.3

29.9

11.7

± 10.5

±4.1

23.6

7.9

± 8.0

±2.0

p-value * 0.114

<0.001

0.024

0.001

# post-hoc Tukey comparing PD and HFNEF patients * p<0.05 One-Way-Anova comparing patients and healthy controls LV EF = left ventricular ejection fraction, LVMI = left ventricular mass index, LAVI =left atrial volume index

Comparing the heart of PD patients with normal and symptomatic HT

Results Apical Rotation ( º) Basal Rotation ( º) Longitudinal Function (%) Chamber Stiffness (1/ms 2 ) PD Pat 9.6

± 3.7

-6.3

± 2.7# 1.9

±1.6 Symptomatic HT non-renal 8.7

± 3.4

-8.6

± 3.0

-18.8

±2.2 -18.9

± 3.4

1.5

± 0.7

Controls 13.5

± 3.4

-8.0

± 3.1

-21.0

± 2.9

1.4

± 0.6* p-value * <0.001

0.024

0.012

0.205

# p<0.05 (Tukey test) comparing PD and HFNEF patients * p<0.05 One-Way-Anova comparing patients and healthy controls

Fluid status measures according to HFNEF Status

ECF:TBW ratio Corrected Plasma Volume (ml) Plasma albumin (g/l) Measured OH index (L) ECF/height (L/m) Log CRP (mg/ml) Age (years) Gender Ratio (M:F) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg)

Normal (n= 16)

0.47

1372 31.3

2.38

9.84

0.81

58.8

50:50 26 140.7

81.8

HFNEF (n=12)

0.47

1565 32.7

3.0

10.45

0.56

60.6

50:50 26 142.2

79.9

P

NS 0.035

NS NS NS NS NS NS NS NS NS

Predicting the variance in corrected plasma volume from cardiac indices LVMI: Area under ROC 0.746, CI = 0.540-0.948; LAVI Area under ROC 0.825, CI = 0.645-1.006; E/e’: Area under ROC 0.484, CI = 0.203-0.765

What is the fluid status of PD patients?

• BIA and isotope studies tend to suggest they are either absolutely or relatively volume expanded • Plasma volume not expanded • ECF excess predicts survival and is   albumin or  inflammation • Hearts in PD patients resemble those of patients with symptomatic hypertension and are not related to ‘whole-body’ measures of fluid excess • No validated studies on how to use BIA as a clinical tool

In the future...

• We will have validated tools to assess and optimally manage the fluid status of PD patients • Evidence, evidence, evidence...

Scope

• Extending the role of PD • High/Rapid transport – a problem solved • Residual concerns over salt and water balance in PD • Monitoring and preserving the membrane – Maintain better treatment – Avoid EPS – Understand the underlying mechanisms of membrane injury and thus treatment strategies

Start PD Increasing solute transport IL-1/IL-6 VEGF Variability in membrane function •Effective contact area •Osmotic conductance Increasing vascularity Increase in blood flow Loss RRF Glucose/GDP Peritonitis Dissociation of solute transport and osmotic conductance EPS

?

? TGF EMT Ultrafiltration failure Progressive fibrosis Additional trigger Stop PD Peritonitis Visceral involvement

What are the mediators/potential biomarkers?

• Protein leak • CA125 • IL-6 • VEGF  = fibrosis,  = inflammation/EPS mesothelial cell health local production   transport local production   transport • TGF-β driver of EMT • MCP-1, CCL18 local production ?fibrosis

• Hyaluronan ? Membrane health/healing • Fibrinolytic system • CRP systemic inflammation  EPS

IL-6, inflammation and membrane function • 32 incident patients • retrospectively selected • Systemic v.

local IL-6 correlate at baseline and 12 months • Both with   at one year solute transport • ?comorbidity

• ?RRF

Pecoits-Filho, PDI, 2006

IL-6 Genotype

Dialysate IL-6 Levels Solute Transport

Global Fluid Study

Longitudinal evaluation of peritoneal membrane function and effluent markers of peritoneal membrane structural integrity in Peritoneal Dialysis patients

Study Design

• Prospective study of membrane function, systemic and local inflammatory markers • Multi-centre (19) from Belgium, Canada, Israel, Hong Kong, Korea and UK • Incident and prevalent cohorts • Pre-defined endpoints (patient and technique survival, change in membrane function, peritonitis)

Initial analysis of biomarkers

• Paired dialysate and plasma samples, IFN-

γ

IL-1β, IL-6, TNF-α • Initial sample from both incident and prevalent cohorts • 10 centres selected on basis of best data integrity (5 UK, 3 Korea, 2 Canada) ,

Multivariate modelling

• DP Cr with centre effect

Centre Gender Albumin Dialysate IL6 Day of test

p value <0.001

Incident

partial eta squared 0.176

0.020

<0.001

0.016

0.053

<0.001

0.015

0.103

0.017

p value <0.001

0.021

0.048

<0.001

Prevalent

partial eta-squared

Urine volume

<0.001

0.030

Not significant - Comorbidity, diabetes, age, diastolic BP, MAP, PP, BMI, Type of PD, plasma cytokines, other dialysate cytokines

0.166

0.026

0.019

0.120

Multivariate modelling

• Dialysate IL-6 with centre effect

Centre DP Cr Plasma IL-6 Plasma TNF Plasma IFN Dialysate TNF Dialysate IFN Dialysate IL1 Urine volume Type of PD

(APD higher) p value <0.001

Incident

partial eta squared 0.179

<0.001

0.076

<0.001

0.052

p value <0.001

Prevalent

partial eta squared 0.151

<0.001

0.102

0.022

0.017

0.002

0.020

0.001

0.009

0.001

0.020

0.029

0.048

0.022

0.037

0.023

0.010

EPS vs Controls

• • • • Linear mixed model (HLM) for PD IL6 – IL6 increases with time in both groups, p<0.001

– D/P Cr and UF both positive independent predictors – Random intercept, fixed slopes – no convergence with random slopes – Estimated marginal means • EPS 200.4 pg/min vs Controls 76.7pg/min, p=0.016

For plasma IL-6, EPS not significant with random intercept For plasma IFN-γ, EPS 3.09 vs controls 4.29 pg/ml, p=.05 with random intercept Plasma TNF not significant

Global Fluid Study Initial conclusions:

• • • • • Cross sectional analysis indicates un-coupling of local (PD membrane) from systemic inflammation Local IL-6 production is strongly associated with membrane transport characteristics IL-6, especially in prevalent patients is associated with a more active local cytokine network Systemic inflammation is associated with age, comorbidity, albumin Reduced UF Capacity in prevalent patients is associated with lower IL-6 and detectable IFN  independent of solute transport characteristics

In the future...

• We will have biomarkers that help clinicians recognise peritoneal membrane injury • We will understand the mechanisms of damage and have treatments to prevent this • Evidence, evidence, evidence

Acknowledgements

Cian Chan Barbara Engel Ramzana Asghar Biju John Kay Tan Frauke Wenzelburger David Smith FRS Patrik Spanel Chris McIntyre John Sanderson

Renal Discoveries Extramural Grant Programme

Acknowledgements

Collaborators and colleagues

EAPOS Group Bengt Rippe Daniele Venturoli Ray Krediet Denise Sampimon Ramzana Asghar Lily Mushahar Kit Huckvale Biju John Jeff Perl PD staff and patients Titus Augustine Paul Brenchley

Biopsy Registry

John Williams Nick Topley Kate Craig

GLOBAL Fluid Study

Nick Topley James Chess Mark Lambie Charlotte James Study Investigators