improving outcome in peritoneal dialysis

IMPROVING OUTCOME IN PERITONEAL DIALYSIS

DR.M.B.M GHALIBMBBS,ABIM,MD,FISN,MRCP (UK),FRCP(Edin)

CONSULTANT PHYSICIAN & NEPHROLOGIST

ASSOCIATE PROFESSOR OF MEDICINEHEAD DEPARTMENT OF MEDICINE

KARARY UNIVERSITY

Improving Outcome in PD Patients

•Introduction.•Staff selection.•Staff training.•PD center facilities.•Patients selection.•Patient training.•Catheter insertion techniques.•New connectology techniques.•Peritonitis.•Conclusion.

INTRODUCTION

Incidence of ESRD in EDTA/ERA Registry from 1991-2001

Incidence of RRT 1997-2002by country code EDTA/ERA

Percent distribution per age category of incident Flemish ESRD patients

Age distribution of prevalent ESRD patients in relation with population

Flemish population

Classification of Renal Function

Stage I

Mild Kidney

Function

Moderate Kidney

Function

Kidney FunctionGFR (mL/min/1.73m2) ≈ CrCl (mL/min)

Stage II Stage III Stage IV Stage V

Severe Kidney

Function

Kidney Failure ESRD

130 120 110 100 90 80 70 60 50 40 30 20 15 10 0

CKD Risk Factors/Damage with Preserved

GFR

“Chronic Kidney Disease” (CKD)

Chronic Kidney DiseaseESRD, end stage renal disease

National Kidney Foundation. Am J Kid Dis. 2004;43(Suppl 1):S16-S41.

ESRD – The Tip of the Iceberg1988-1994 1999-2000 Prevalence

n=300,0000.1%0.2% Stage 4 – GFR 15–29

n=7,400,0003.7%4.2% Stage 3 – GFR 30–59

n=5,700,0002.8%2.2%Stage 2 – Kidney damage

& GFR 60–89

n=5,600,0002.8%2.2% Stage 1 – Kidney damage& GFR >90

Total: 19 M adults with CKD

8 M adults with GFR<60

Stage 5 – Kidney Failure (GFR <15) n=400,000

Coresh et al. Am J Kidney Dis, 41:1-12, 2003

Percentage of subjects with de novo CKD (eGFR< 60 ml/min) after a mean of 4.2

years of follow-up in the PREVEND study

Verhave et al Kidney Int 66 (suppl 92) : S18-S21, 2004

• In the baseline screening of the albuminuria-enriched cohort312 out of the 8592 (3.6% ) had a GFR < 60 ml/min/1.73m²

• In a FU study, eGFR was evaluated after a mean of 4.2 years in subjects with previously normal renal function but albuminuria. Out of the 6022 subjects 253 (4.2%) developed an eGFR of < 60 ml/min/1.73 m²

Prevalence of eGFR < 60 ml/min in selected European studies

8

11

5.7

13

17.8

0

2

4

6

8

10

12

14

16

18

Cirillo2004

Kissmeyer1999

Verhave2004

Otero Giz2005

Lameire2005

Percentage

Distribution of CKD stages in Belgian population at screening

82.2 84.3

17.5 15.5

0.24 0.25 0.02 00

10

20

30

40

50

60

70

80

90

>60 30-60 15-30 < 15 ml/min

MDRD CG

Prevalence of CKD (eGFR < 60 ml/min/1.73 m²)

19.3

12.9

15.8

21.5

27.5

0

5

10

15

20

25

30

35

Reported Coresh Hallan Froissart Toffaletti%

Van Biesen et al, NDT,2006

Mortality in different stages of CKD, based on MDRD (10 year FU)

4.8

7

12.2

25

0.4

2.3

4.8

7.7

0.5 1.2

3.3

7.7

0

5

10

15

20

25

30

Total CVD CHD

>90

60-89

30-59

15-30

Percentage

New cases

Age-standardized rates of death from any cause (A) or cardiovascular events (B)

Go et al New Engl J Med 2004, 351:1296-1305.

Kaplan-Meier of survival from CVD according to proteinuria-the Framingham cohort

Arnlov et al, Circulation 112: 969-975,2005

I have found a weapon of mass

destruction...

Diabetic Nephropathy

• fructose 3 kg• acetaldehyde

100 ml• formaldehyde 6 ml• 3-DG 100 g• 3,4-DGE 10 g

• 3000-7000 litres of fluid• 50-175 kilo pure glucose

A patient on PD is exposed to

Clinical relevance

roughly

Long-term PD: Structural Changes

Mateijsen et al, PDI, 19, 517-525, 1999

AT START PD AFTER 25 MONTHS PD

0.5 1.0 2.0 3.0 4.0 5.0 6.0 7.0Years on Treatment

0.625

0.650

0.675

0.700

0.725

0.750

n= 580

n= 560

n= 370

n= 229

n= 167

n= 118

n= 73

n= 58

Longitudinal changes in Solute Transport

0.5 1.0 2.0 3.0 4.0 5.0 6.0 7.0Years on Treatment

300

350

400

450

500

n= 574

n= 554

n= 363

n= 223

n= 163

n= 117

n= 68

n= 57

Davies S, ASN 2002

Solute transport Ultrafiltration

Brownlee et al, NEJM, 318, 1315-1321, 1998

Glucose

Matrix proteinamino groups

Amadoriproducts

Extravasatedlipoproteins

AGEs

Covalent AGEcrosslinks

AGEs

AGE - RAGE Interaction

AGE

RAGE

VEGF

PDGF

TGF IL-1

Adhesion moleculesProcoagulant factors

AGE Accumulation in the Peritoneal Membrane

Honda et al, NDT, 14, 1541-1549, 1999

Bioincompatibility of current PD fluids

• Unphysiological composition:– acidic pH – [high lactate concentration]– high glucose concentration– hyperosmolality

• Heat sterilisation of glucose gives rise to glucose degradation products which may increase AGE formation

Acute toxicity

Chronic toxicity

• Inflow pain during initial peritoneal contact

• Inhibition of growth, viability and function of different peritoneal cell types including mesothelial cells

• GDP’s are a major catalyst of AGE formation

• Peritoneal AGE formation (associated with loss of ultrafiltration) over time

What is the clinical importance of

GDPs?

What is the clinical importance of

GDPs?

Wieslander et al, Adv Perit Dial 1996, 12: 57- 60

• Gambrosol Trio, Gambro

– Lactate-buffered (40 mM), pH~ 6.4

• Balance, Fresenius

– Lactate-buffered (35 mM), pH~7.4

• Bicavera, Fresenius– Bicarbonate-buffered (34 or 38 mM), pH~7.4

• Physioneal, Baxter– Bicarbonate/lactate-buffered (15/25 mM), pH~7.4

Peritoneal dialysis solutions (glucose-based) with reduced GDP content

pH8.0-8.6

Solution A Solution B

ElectrolytesGlucose

pH2.6-3.1

Lactate

Mixed Solution

LactateElectrolytes

Glucose

pH 6.8-7.4

PDF with Reduced GDP Content

CAPD Balance, Fresenius Medical Care

Biocompatibility of new peritoneal dialysis solutions.What is the clinical evidence?

• Less infusion pain• Better preservation of mesothelial cell mass• Less peritoneal neovascularisation• Preservation or restoration of peritoneal

ultrafiltration• Reduced intraperitoneal AGE/ALE

formation• Less beta-2 microglobulin amyloidosis?• Reduced incidence of peritonitis?

Frequency of peak infusion painseverity using the verbal rating scale.

Mactier et al, KI, 53, 1061-1067, 1998.

Very severe pain

Severe pain

Moderate pain

Mild pain

No pain

0 2 4 6 8 10 12 14 16 18 20 22

Frequency

Bicarbonate/lactate

Bicarbonate

Lactate

Plasma fluorescence during the low GDP and conventional PD fluid periods.

Zeier et al Kidney Int 63: 298-305, 2003

CA 125 in spent dialysate afterlong-term treatment with PD-Bio

U/m

l

Conventional glucose PD-Bio0

25

50

75

1001 month

6 months

12 months

(27)

(16) (9)

(23) (22) (7)

Peritonitis incidence in patients prescribed PhysionealEuropean PD Solutions Registry

Dianeal Physioneal

Adjusted peritonitis rateepisodes/pt.months

1 in 34(30-38)

1 in 74*(51-107)

Duration of peritonitisdays

19(16-22)

12*(9-16)

Van Bree et al, JASN,2002; 13:43A abstract ASN 2002

13,89 13,01

52,03

0

20

40

60

80

12,72

42,12

15,36

0

20

40

60

80

Month0 3 6

Month 0 3 6

Euro Balance Trial: Effluent CA125Euro Balance Trial: Effluent CA125

conventional PDFCAPD balance

Patient group I, n = 24 Patient group II, n = 23

p < 0.01 p < 0.01p < 0.01

CA125 measured with electrochemi-luminescence immuno assay (ECLIA)

mean ± SD

U/ml U/ml

Euro Balance Trial: Serum Imidazolone

Euro Balance Trial: Serum Imidazolone

58,1868,22

43,99

0,00

20,00

40,00

60,00

80,00

100,00

mean ± SD

n = 11

Baseline 3 months convention

al PDF

3 months CAPD

balance

Imidazolone measured with ELISA

Imid

azo

lon

e (

ng

/ml)

ns p<0.01

The Korean outcome study-patient survival

Lee HY, PDI 25:248-255, 2005

The Korean outcome study-peritonitis incidence

Lee HY, PDI 25:248-255, 2005

Benefits of Residual Renal Function

Reduces Mortality

Contributes to total solute clearance (1 ml/min CrCl = 10 liter

CrCl/week)

Facilitates volume control

Allows for more liberal

diet and fluid intake

Provides endocrine functions• Erythropoietin production• Ca++, phosphorus and vitamin D

homeostasis

Improves 2-

microglobulin and middle molecule

clearance

Increases nutritional

status

Improves QOL

Essentials of Peritoneal Dialysis

PERITONITIS

• One of the major problems of PD• Decreasing incidence: most centers less than

1episode/24 ptms.• Most common cause of technique failure (up to

50%)• 23% of hospital admissions in PD patients are

related to infection.• Mortality risk: presence of peritonitis related to later

mortality (Piraino et al, JASN, 9, 1958-1964, 1998)


Peritoneal defense mechanisms (1)

• Cellular defense :– Peritoneal PMN in PD-patients are

in a “chronically elicited” state, with a decreased response upon stimulation, possibly due to low pH, glucose, GDP’s, osmolarity and the presence of uremic toxins in the dialysate

Topley et al, oa Kidney Int, 34, 404-411, 1988Jörres et al, Perit Dial Int, 13, suppl 2, S291-S294Vanholder et al, Kidney Int, 50, 643-652, 1996


GDP : Effects on Host Defense

Wieslander et al, PDI, 15, S52-59, 1995.

3000

2000

1000

0

IL-1

(p

g/m

L)

culturemedium

heat-sterilized

PDF

heat-sterilized

PDF

filter-sterilized

PDF

filter-sterilized

PDF

1.5% glucose 4.0% glucose

*


Phagocytosis and TNF- release in monocytes are dependent on intracellular pH

Douvdevani et al, J Am Soc Nephrol 1995, 6: 207-213

TNF- (ng/ml/106 cells)

Intracellular pH

con 6.0 6.3 6.5 7.1

0

1

2

3

4

5

* *

* p < 0.05 vs. control

% Phagocytosis

con 6.0 6.3 6.5 7.1

10

20

30

40

50

0

**

Intracellular pH


Effect of pH on respiratory burst activation of PMN

Chemiluminescence response

Liberek, Topley, Jörres et al, Nephron 1993; 65: 260-265

pH 7.3

pH 5.2

010 20 30 400

25

50

75

100

125

150

175

Lactate concentration (mM)

CL

res

pons

e (%

)

*

*

* *



• Cellular defense :

– Peritoneal PMN in PD-patients are in a “chronically elicited” state, with a decreased response upon stimulation, possibly due to pH, glucose, osmolarity and the presence of uremic toxins in the dialysate

– Interaction of bacteria and PMN initiates release of chemotactic factors, interaction of the peritoneal macrophage with the mesothelial cell and the subsequent release of pro-and anti-inflammatory cytokines.

Topley et al, oa Kidney Int, 34, 404-411, 1988Jörres et al, Perit Dial Int, 13, suppl 2, S291-S294Vanholder et al, Kidney Int, 50, 643-652, 1996



• Humoral factors:– Fast influx of immunoglobins and complement factors,

probably induced by increased levels of PGE2 and PGI2(vasodilators)

– Secretion of cytokines by mesothelial cells: IL6, IL8, IL1-alfa and IL1-beta

– Expression and release of ICAM -1 and VCAM-1 by mesothelial cells

– Secretion of IL-1 and TNF-alfa by PMN resulting in a fast upregulation of inflammatory response


Impact of peritonitis (1)

• On survival:– Direct cause of death in 1-6% of PD patients– Peritonitis rate itself is an independent risk factor for

death, especially in whites, non-diabetics, and patients >60 years old (Fried, Piraino;: JASN 7, 2176-2182, 1996)

• peritonitis indirectly related to 15.8% of deaths; Gram- peritonitis indirectly related to 8.8%

• use of Y-set made no difference for death risk• for every 0.5/year increase in peritonitis rate, death

risk increased 10-11%


Impact of peritonitis (2)

• On technique failure : 50% of transfers to HD related to peritonitis (Van

Biesen et al, Advances in Peritoneal Dialysis, 14, 90-94, 1998)36% of transfers to HD related to peritonitis (Maiorca et al, Perit Dial Int, 16, 276-287, 1996)78% of transfers to HD related to peritonitis (Woodrow et al, Perit Dial Int, 17, 360-364, 1997)

Use of Y-system did not influence technique survival, despite better peritonitis rate

High mortality up to 1 year in period following technique failure due to peritonitis.


Impact of peritonitisCauses of hospitalization

Peritonitis18%

Catheter Infection

1%

Other infection14%

CV Disease32%

Catheter malfunction

1%

Other34%

Fried et al, AJKD, 33, 927-933, 1997


Infection routes (1)• Intra (trans) luminal infection=

– Infection occurs through the endoluminal site of the catheter

– Mostly (not always) related to manipulation: touch contamination

– Mostly organisms from the skin: Gram+; Staph • Periluminal infection=

– Infection occurs through the space between catheter and skin.

– Most frequently related to exit site infection or tunnel infection


Infection routes (2)

• Impact of double-bag Y-set (flush before fill)

Factor Rel. risk P-value

Age 1.001 NS

Diabetes 1.000 NS

Sex 0.975 NS

CAPD-system 0.620 P<0.0001

Woodrow et al (Perit Dial Int, 17, 360-364, 1997)


Peritonitis incidence in a single centre

0

10

20

30

40

50

60

92 94 96 98 2000

Gram+

Gram-

Kim et al, Seoul, unpublished data

Episodes/pt year


Infection routes (3)

• Impact of APD vs CAPD:– a lower peritonitis incidence in APD was reported by

several groups:• French multicenter study: CAPD 1/24 ptm vs APD

1/29.2ptm (p<0.01) (Perit Dial Int, 19, S32, 1999)• Locatelli et al: CAPD 1/8.3ptm vs APD 1/18.9ptm

(Perit Dial Int, 19, S33, 1999)• Perez-Fontan et al CAPD 1/16ptm vs APD 1/35ptm

(Perit Dial Int, 19, S35, 1999)– Italian study group: CAPD 1/27ptm vs APD 1/22 ptm

(Perit Dial Int, 19, S38, 1999)


Consensus is what elderly statesmen agree upon in public, but never believe in private.

Aba Eban


Treatment (1)• Antibiotics: no consensus on

– empiric antibiotic treatment of choice– route of administration (oral, intravenously, intraperitoneally)– duration of therapy

• Peritoneal lavage:– premise: wash out bacteria– however: also wash out of PMN and defense mechanisms

• Heparin:– inhibits fibrin formation– potential reduction of number of adhesions, and potential

protective effect on peritoneal membrane


Empiric Treatment

Consider the following:• epidemiology of organisms causing

peritonitis• clinical efficacy• pharmacokinetics/dynamics of antibiotics• safety of antibiotics• convenience• cost


Staph Aureus Prophylaxis

• Staph A. leading cause of exit-site and tunnel infections

• Staph A. carriage on exit-site is associated with more infection than nasal carriage

• Screening for carriage: use swab humified with saline


Staphylococcus peritonitisRelation with carriers

0

10

20

30

40

50

60

70

Exit site Nose Nails Partner

% cu

ltures sam

e organism

as in d

ialysate

Amato et al, AJKD, 37, 43-48, 2001


Nasal Prophylaxis(Mupirocin study group)

• Nasal swabs: 2 out of 3 positive = carrier• 1144 patients screened; 23.3% carriers• nasal ointment, 5 days every month: mupirocin vs

placebo• nasal carriage after treatment: 10% in mupirocin vs

48% in placebo group• no direct evidence for resistance; however: Perez-

Fontan et al: increase of mupirocine resistance over a two year application period (AJKD 1993)


Nasal Prophylaxis(Mupirocin study group)

00.5

11.5

22.5

33.5

44.5

Exitsiteinfection (all)

Exit siteinfection

(Staph A.)

Peritonitis(Staph A.)

placebo

Mupirocin

Infection

s per 100 p

atient years

JASN, 7, 2403-2408, 1996

P = 0,17 P < 0,01 P = NS


Exit-site prophylaxis

0

2

4

6

8

10

12

14

16

Bernardini Thodis

Historicalcontrol

Mupirocine

Bernardini et al, AJKD, 27, 695-700, 1996Thodis, PDI, 18, 261-270, 1998

Stap

h A

periton

itis rate/100 pty

N=188

P=0,05


Gram PositiveOrganism on

culture*

Enterococci S.aureusOther Gram

Positive Organisms

STOP CephalosporinAdd Ampicillin-125 mg/LContinue Aminoglycoside

DiscontinueAminoglycoside

Continue CephalosporinAdd Rifampin 600 mg/d PO


Continue Cephalosporin

If no improvementRe-culture and evaluate**

Peritonitis with Exitor Tunnel Infection

Consider Removal of catheter

Evaluate for Occult Tunnel Infection

21 days14 days 14 days

96 hours

24-48 hours

Durationof Therapy


Gram Negative Organisms on culture*

Single Gram Negative(Non-Xanthomonas)

Pseudomonas/Xanthomonas

Multiple Organismsand/or Anaerobes

Adjust Antibioticsto Sensitivity Patterns

Continue ContinousAminoglycoside Therapy, Discontinue Cephalosporin

Add agent with Activity Againstthis Pseudomonas/Xanthomonas


Continue Cephalosporin

If Clinical Improvement : Continue Above therapyIf No Clinical Improvement : Repeat Cell Count; Cultures and Gram Stain; If Culture Positive Remove CatheterIf No Clinical Improvement and Exit Site Infection Present - Remove Catheter

21 days14 days 14 days

96 hours

24-48 hours

Durationof Therapy

Agents with Anti-Pseudomonas or Anti-Xanthomonas Activity Agent Dosage 1. Ceftazidime 125 mg/L IP 2. Piperacillin 4 gm every 12 hours IV (adults)

150 mg/kg every 12 hours (children) 3. Ciprofloxacin 500 mg BID PO (avoid in children) 4. Aztreonam LOAD : 1000 mg/L MAINT : 250 mg/L IP 5. Imipenem LOAD : 500 mg/L MAINT : 200 mg/L IP 6. Sulfamethoxazole/Trimethoprim LOAD : 1600/320 PO Q 1-2d 7. Aminoglycosides Increase dose to 6-8 mg/L IP in each exchange**


Yeast on GramStain or Culture

Flucytosine** Load : 2000 mg POMaint : 1000 mg/d PO and

Fluconazole** 200 mg PO/IP daily

If Clinical Improvement : Therapy Duration

4-6 Weeks

If No Clinical ImprovementRepeat Cell Count, Gram

Stain, Culture and ConsiderCatheter Removal.

4 - 7 days

24-48 hours

*

*


Cloudy Fluid and/or Abdominal Painand/or Unexplained Fever

Cell count/differential Gram Stain Culture

Initiate Empiric*Therapy

Cefazolin or Cephalothinand Aminoglycoside

CultureNegative

Gram PositiveOrganismon Culture

24 hours

0 hours

Yeast onGram Stain or

Culture

Gram NegativeOrganism on

Culture

* Empiric Therapy

Agent Continuous Dose Intermittent Dose(in 1 exchange/day)

Residual urine output (mL/day)Anuria (<500) Non-anuria (>500)

cefazolin or 500 mg/L load then 500 mg/L increase dose cephalothin 125 mg/L in each exchange (or 15 mg/kg) by 25%

gentamycin 8 mg/L load, then 4 mg/L 0.6 mg/kg 1.5 mg/kg initial loading dosemetilmicin in each exchange body weight See footnote for maintenancetobramyxin dose recommendations

amikacin 25 mg/L load, then 12 mg/L 2 mg/kg 5 mg/kg initial loading dose.in each exchange body weight See footnote for maintenance

dose recommendations


Indications for catheter removal

• Simultaneous exit-site/ tunnel infection (role for ultrasound)

• Fungal peritonitis• Persisting or relapsing peritonitis,

especially Staph A., Pseudomonas, Acinetobacter, or other water-borne bacteria


CONCLUSION

• Better facilities & training(patients & staff).• Prevention, prophylaxis & treatment of

peritonitis.• Biocompatible PD fluids.• APD for high transporters.• Preservation of residual renal function.• Treat co-morbidities.

THANK YOU

improving outcome in peritoneal dialysis

Health & Medicine

peritoneal membranehonda

age accumulation

zeier et

frequency16182022mactier

longterm pd

pd patients introduction

kidney int

incidence of esrd