Simon DaviesUniversity Hospital of North Staffordshire,

Stoke-on-TrentInstitute for Science andTechnology in Medicine

Keele University, UK

PERITONEAL DIALYSIS: PRESENT AND FUTURE

Bari, March 2010

The next president.... Of ISPD?

Looking into the future...

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

0100200300400500600700800900

1000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Year

Cit

atio

ns

OtherRCT

3-6%

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 2nd Tx

PD Start Home HD

Centre-based HD

Assisted Home PD

PD Start Tx Minimal Care HD

2nd Tx

Satellite-based HD Tx PD Bridge

1,347 patients includedPatients prefer to chooseSome have no choiceGiven 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?

Oliver MJ et al , KI, 2007

• Standard approach in many situations – e.g. nursing homes, extended families, visiting/community nurses (e.g. France)

• Specific programmes e.g. Denmark, J Povlsen

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

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

2008

PD (n=34)

HD (n=26)

Survival (months) in unplanned patients (NS)

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

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

R² = 0.603

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

0.4 0.5 0.6 0.7 0.8 0.9

Rate

flu

id r

eab

so

rpti

on

(m

l/m

in)

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

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

P=0.009 P = NS

L

H

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

Johnson, D. ANZDATA, NDT, 2010

P = 0.01

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

Plum et al, NDT 2001

Relationship between plasma albumin and tertiles of

bioimpedance ratios (ECF:TBW)

25

27

29

31

33

35

37

39

41

43

45

1 2 3

Pla

sma a

lbu

min

g/l

Increasing over-hydration/muscle wasting

HD n=59

PD n=68

ANOVA P=0.065

ANOVA P=0.001

Tan BK, Chan C and Davies SJ, Sem Dial, 2010 in press

BIA predicted and D dilution measured TBW in PD patients

TB

W/w

eig

ht

(hyd

rati

on

of

tiss

ues)

Percentage body fat

Predictors of discrepancy between measured and

estimated TBW- PDCovariate Standardised

βt Significanc

e

Constant 1.76 0.089

Plasma albumin -0.56 -3.04 0.005

CRP -0.31 -1.65 0.109

Solute transport 0.09 0.50 0.62

Comorbid Score 0.096 0.60 0.55

Use of Icodextrin 0.225 1.21 0.24

Plasma sodium -0.211 -1.32 0.197

Dialysate sodium loss 0.125 0.79 0.43

Urine sodium loss 0.049 0.29 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 20 26Gender split (M:F) 8:12 18:8 0.049Difference between measured TBWD and

estimated TBWBIA (L)

3.55 0.94 0.61 to 4.6 0.012

ECW:TBW ratio 0.495 0.472 -0.001 to -0.05

0.036

Plasma Volume (ml) 2551 2820 -124 to 661 NSCorrected plasma volume (ml/m2)

1463 1482 -135 to 173 NS

Plasma Volume (% different from predicted)

-0.94 -3.4 -12.2 to 7.2 NS

Baseline Results

PD Pat Symptomatic

HT non-renal

Controls

p-value

*

LV EF (%) 58±6 61±6 62±8 0.114

LVMI (g/m2) 113.0±29.6# 89.5±31.5 75.7±21.9 <0.001

LAVI (ml/m2) 31.6±12.8 29.9±10.5 23.6±8.0 0.024

Left atrial pressure (E/e’)

10.2±3.3 11.7±4.1 7.9±2.0 0.001

# post-hoc Tukey comparing PD and HFNEF patients* p<0.05 One-Way-Anova comparing patients and healthy controlsLV 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 PD Pat Symptomatic

HT non-renal

Controls

p-value

*

Apical Rotation (º)

9.6±3.7 8.7±3.4 13.5±3.4 <0.001

Basal Rotation (º)

-6.3±2.7# -8.6±3.0 -8.0±3.1 0.024

Longitudinal Function (%)

-18.8±2.2 -18.9±3.4 -21.0±2.9 0.012

Chamber Stiffness (1/ms2)

1.9±1.6 1.5±0.7 1.4±0.6* 0.205

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

Comparing the heart of PD patients with normal and

symptomatic HT

Fluid status measures according to HFNEF Status

Normal (n= 16)

HFNEF (n=12)

P

ECF:TBW ratio 0.47 0.47 NS

Corrected Plasma Volume (ml) 1372 1565 0.035

Plasma albumin (g/l) 31.3 32.7 NS

Measured OH index (L) 2.38 3.0 NS

ECF/height (L/m) 9.84 10.45 NS

Log CRP (mg/ml) 0.81 0.56 NS

Age (years) 58.8 60.6 NS

Gender Ratio (M:F) 50:50 50:50 NS

BMI (kg/m2) 26 26 NS

Systolic BP (mmHg) 140.7 142.2 NS

Diastolic BP (mmHg) 81.8 79.9 NS

1-Specificity1.00.80.60.40.20.0

Sen

sit

ivit

y

1.0

0.8

0.6

0.4

0.2

0.0

E/e'LAVILVMI

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

Dissociation of solute transport and

osmotic conductance

Ultrafiltration failure

EPS

Variability in membrane function

•Effective contact area

•Osmotic conductanceIncreasing vascularity

Increase in blood flow

Progressive fibrosis

Additional trigger

Stop PD

Peritonitis

Visceral involvement

IL-1/IL-6

VEGF

? TGF

EMT

?

Loss RRF

Glucose/GDP

Peritonitis

What are the mediators/potential biomarkers?

• Protein leak = fibrosis, = inflammation/EPS

• CA125 mesothelial cell health• IL-6 local production transport• VEGF local production

transport• TGF-β driver of EMT• MCP-1, CCL18 local production ?fibrosis• Hyaluronan ? Membrane health/healing• Fibrinolytic system • CRP systemic inflammationEPS

IL-6, inflammation and membrane function

• 32 incident patients• retrospectively

selected• Systemic v. local IL-6

correlate at baseline and 12 months

• Both at one year with solute transport

• ?comorbidity• ?RRF

Pecoits-Filho, PDI, 2006

IL-6 Genotype

Dialysate IL-6 Levels

Solute Transpor

t

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 effectIncident Prevalent

p valuepartial eta-

squaredp value partial eta-squared

Centre <0.001 0.176 <0.001 0.166

Gender 0.020 0.016 0.021 0.026

Albumin <0.001 0.053 0.048 0.019

Dialysate IL6 <0.001 0.103 <0.001 0.120

Day of test 0.015 0.017

Urine volume <0.001 0.030

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

Multivariate modelling

• Dialysate IL-6 with centre effectIncident Prevalent

p valuepartial eta-

squaredp value

partial eta-squared

Centre <0.001 0.179 <0.001 0.151

DP Cr <0.001 0.076 <0.001 0.102

Plasma IL-6 <0.001 0.052 0.022 0.017

Plasma TNF

Plasma IFN

Dialysate TNF 0.002 0.020 0.001 0.048

Dialysate IFN 0.009 0.022

Dialysate IL1 0.001 0.037

Urine volume 0.020 0.023

Type of PD (APD higher) 0.029 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 StudyInitial 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

AcknowledgementsCian ChanBarbara EngelRamzana AsgharBiju JohnKay TanFrauke WenzelburgerDavid Smith FRS

Patrik SpanelChris McIntyreJohn Sanderson

Renal Discoveries Extramural Grant Programme

AcknowledgementsCollaborators and

colleaguesEAPOS GroupBengt RippeDaniele VenturoliRay KredietDenise SampimonRamzana Asghar Lily MushaharKit HuckvaleBiju JohnJeff PerlPD staff and patients

Titus AugustinePaul Brenchley

Biopsy RegistryJohn Williams

Nick Topley

Kate Craig

GLOBAL Fluid Study

Nick Topley James Chess Mark Lambie Charlotte James

Study Investigators