PD SOLUTE CLEARANCE

Ma. Nisan T. Manauis, RN, MAN, CRNC

Board Member, RENAP

The Peritoneum
KEY POINTS
Serosal membrane with area equivalent to body surface area, I.e. 1 to 2 metres2 80% is visceral peritoneum and gets its vascular supply via the mesenteric arteries and portal veins 20% is parietal peritoneum and gets its vascular supply via arteries and veins of abdominal wall and has more important than visceral peritoneum Lymphatic drainage of peritoneal cavity is mainly via diaphragmatic stomata

The Peritoneum
KEY POINTS
Peritoneal cavity is lined by a mesothelial monolayer which produces a lubricating fluid Under the mesothelium is a gellike interstitium containing connective tissue fibres, capillaries and lymphatics
The effective surface area is critical for dialysis and depends on the vascularity of the peritoneum.

The Normal Peritoneum

Mesothelial cell monolayer

Interstitium

Peritoneal vasculature

The Normal Peritoneal Membrane

Diffusion

Transfer by diffusion is the passive transfer of solutes across the membrane, without the passage of solvent (water).

1
Sodium

Blood

Potassium
Chloride

Membrane

Dialysate
2

1 - Red blood cell 2 - Bacteria

Bicarbonate

Urea

Beta 2-m (Solute PM>5000)

Creatinine
Uric acid

Factors effecting Diffusion

u Membrane s Surface area, type, thickness u Blood film thickness u Dialysate flow configuration

u Concentration gradient u Size of solute

u u u u u Ultrafiltration Temperature of dialysate Qb - Blood flow rate Qd - Dialysate flow rate Time

Factors relevant to PD
u Membrane s Surface area, type, thickness u Blood film thickness u Dialysate flow configuration

u Concentration gradient u Size of solute

u u u u u Ultrafiltration Temperature of dialysate Qb - Blood flow rate Qd - Dialysate flow rate Time

Substance
Urea (mol wt 60) Creatinine (mo wt 113 Vit B12 (mol wt 1352)

CAPD
57

CCPD
57

NIPD
58

HD
126

47

47

36

100

34

30

17

30+

Weekly plasma clearances L/week

3 Pore Model
1 - Large pores or clefts (20-40 nm ) for transport of large molecules such as proteins. 2 - Small pores (4-6 nm ): more than others and responsible for transport of small solutes such as urea, creatinin, Na and K 3 - Transcellular (ultra pores ) with diameter less than 0.8 nm that responsible for water transport and are similar to aquaporins
*Sieving is induced by ultrapores

3 Pore Model
~250 ~40

< 5
cell junctions = large pores

water molecules via ultrapore

Solute Clearance in PD
Factors that deliver clearance Total volume v Volume per exchange v Number of exchanges Dwell time Factors driving clearance requirements Urea generation(diet, weight, metabolic rate) Residual renal clearance(kidney function) U.F. rate (solution tonicity, fluid intake) Peritoneal membrane (permeability)

Osmosis
Movement of water from an area of low solute concentration to an area of high solute concentration. Blood Dialysis solution 280 - 295mOsm/L 347- 486mOsm/L

Water

Solute Water Solute

Pathways for Peritoneal Transport

Capillaries
Endothelium Small solutes Macro molecules Water

Glucose Interstitium

Crystalloid osmosis

Colloid osmosis

Mesothelium
Peritoneal tissue layer

Dialysate

Peritoneal Transport 2 Clinical Endpoints

Clearance of solutes (by diffusion and convection) Fluid removal (transcapillary UF fluid absorption)

Peritoneal Transport 3 Distinct Processes

Diffusion Ultrafiltration Fluid Absorption

What Happens with Solute Removal During a CAPD Dwell?

Diffusion is at a maximum, and urea and creatinine equilibration are fastest, in the first hour but become slower as the gradient lessons with time
By 4 hours, urea is >90% and creatine > 65% equilibrated in most patients Dialysate to plasma (D/P) ratios measure degree of equilibration at a given dwell time (e.g. D/P Urea, D/P Creatine)

 Diffusion is not dependent to peritoneal blood flow.

Diffusion is not dependent to peritoneal surface area but to vascularity.

Diffusion is also dependent to osmotic gradient and size of solutes. The most important factor which is modifiable is dialysate fluid volume and osmolality.

Peritoneal Equilibrium Test

2 liters of 2.5% dextrose and measurement of dialysate glucose and urea at the times: 0, 2, 4 and plasma glucose and urea at the times:0, 2, 4
Every patient may be: 1- high transporter 2- high average transporter 3- low average transporter 4- low transporter

% Pts. Membrane 4-Hr D/P type Creatinine 10% High

Characteristics

Very efficient membrane Transports solute quickly Increased glucose absorption May have difficulty achieving ultrafiltration At risk for low serum albumin

53%

High Average Low Average Low

0.65 - .81

Efficient membrane Transports solute well Ultrafilters well Less efficient membrane Transports solutes somewhat slowly Ultrafilters well Inefficient membrane Transports solutes slowly Difficult to obtain Cr Cl when no residual renal function Ultrafilters very well

31%

0.50 - .64

6%

0.34 -.49

Peritoneal Equilibrium Test

Glucose
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 Hours 3

Low Low ave Ave High ave High

Creatinine
1 0.8

D/DO

D/P

0.6 0.4 0.2 0 0 1

2 Hours

Diffusion How to increase it?

Maximize concentration gradient - More frequent exchanges (e.g., APD) - Larger dwell volumes Increase effective peritoneal surface area - Larger dwell volumes

Diffusion
How to Increase It
Maximize concentration gradient - More frequent exchanges (e.g., APD) - Larger dwell volumes Increase effective peritoneal surface area

- Larger dwell volumes

Peritoneal Fluid Absorption

Occurs directly via lymphatics

Also absorption into tissues with subsequent removal via lymphatics and capillaries Difficult to measure but is about 1 to 2 mls per minute (250-500 mls in 4 hours)

Net Ultrafiltration
Net UF is actual UF minus fluid absorption e.g. 1000mls 200mls = 800 mls Net UF
Clinically we can only influence Net UF by: altering the osmotic gradient (e.g. from1.36% to 2.27%), changing the osmotic agent (e.g. from glucose to icodextrin)

Pathways of Glucose Flow

Capillary

Glucose

Glucose transporter mediated: minimal Intercellular: >90%

Peritoneal Space

Membrane Model
Membrane

BLOOD

PERITONEAL DIALYSATE

What Happens to Fluid Removal with a 2L 4.25% PD Dwell?

Note: I/P = Intraperitoneal or inside peritoneal cavity
UF is maximal at the start of the dwell, approx. 15 ml/min It quickly lessons as glucose diffuses out of the dialysate into the blood and as the UF dilutes the glucose I/P volume increases until about 3 hours when UF rate falls to equal the constant fluid absorption rate of 1-2 ml/min After this, the I/P volume reduces until it is less than 2L after 8-10 hours, leading to net fluid retention

Small Solute Clearance in PD Patients

Clearance is the quantity of plasma from which solute is cleared per unit time In PD: > total clearance = peritoneal + residual renal
Peritoneal clearance depends on: > diffusion + UF fluid absorption and so varies during the course of the dwell period Daily peritoneal clearance = > daily dialysate drain volume x D/P ratio (for the solute concerned over that day)

Determinants of Clearance Achieved on PD

Residual renal function Body size (Volume or Body Surface Area)
Peritoneal solute transport rate The prescription

What About Protein?

Protein losses occur via large pores, are greatest in high transporters and average 6 to 10 g/day
About 50% of losses are albumin and there is an inverse relationship to serum albumin Fluid absorption during a dwell prevents losses being greater Losses are not much affected by PD prescription, but increase during peritonitis

Total Removal of Protein in Different Transport Groups

Total removal of protein, mg
3000 2500 2000 H H-A 1000

1500

500
0

L-A L

60

120 180 240 300 360

Time, min
Wang et al. Nephrol Dial Transplant 13: 1242-49, 1998

Georgi Abraham MD, FRCP Sri Ramachandra Medical College & Research Institute

PRESCRIPTION OF PD ACCORDING TO NEW GUIDELINES

Clinical Context
50/M Chronic Kidney Disease Diabetes Hypertension IHD, Nonsmoker 50 Kg, 160 cm (BMI: 20.5 BSA: 1.49m2) UO: 600 ML, r Ktv: 0.3, pKtV: 1.5 Echo: Normal ejection fraction Initiated on CAPD 2L exchanges, 3 times/day PET: High Average

Clinical Management
How does Adequacy needs to be assessed? What adequacy targets are optimal? How many exchanges does he need? How to achieve euvolemia? Is it important to preserve residual renal function? Strategies?

Adequate Peritoneal Dialysis

Clinical Emphasis + Absence of uremic symptoms + Avoidance of fluid overload + Blood pressure control + Preservation of residual renal function + Well nourished + Phosphorus control + Acid-base balance + Correction of anemia
ISPD Guidelines 2007: PDI 2007; 26: 520 -522

Adequacy Assessment and Interventions

Adequacy Assessment and Prescription adjustment
Nutrition Assessment

Clinical Assessment

Clearance Assessment

Continue without Adjustment

YES

Target met
NO

Prescription Adjustment

Routine follow-up with adequacy assessment at 4 month visit

Global assessment of treatment Check PET & Kt/V Consider adjusting prescription

Interventions may be required if targets are not met

Initial Consensus

NKF-DOQI Guidelines: 1997 Weekly Total Solute Clearance Goals KT/V CrCl (minimum) (minimum) CAPD (evidence) 2.0 60L/1.73m2 CCPD(opinion) 2.1 63L/1.73m2 NIPD(opinion) 2.2 66L/1.73m2
WHAT WAS THE LEVEL OF EVIDENCE FOR THESE RECOMMENDATIONS ?

Patient Outcome: Adequacy parameters

Blake (Adv PD 1989)
Increased risk with Kt/V <1.5

DeAlvaro (Adv PD 1992)

Less risk with Kt/V of 2.0 than with <1.7

Teehan (Sem Dia 1992)

Less risk with mean Kt/V > 1.89

Genestier (NDT 1995)

Less risk with higher initial Kt/V or Cr Cl

Maiorca (NDT 1995)

Best survival with Kt/V > 1.96

CANUSA: The evidence N = 680 Prospective Cohort of CAPD, 1990 - 1992 14 centers in USA & Canada RR = DM, Age, CVD, Low S. Alb, SGA
Kt/V 0.1 = in 5% of RR death Cr Cl 5L/Wk/1.73 M2 = 7% RR death
Kt/V: 2.1, WCC 70L/1.73 M2 = 2 YR survival 78 %(pt),75%(tq)

J Am Soc Neph 1996: 7 (2) 198 - 207

Challenging Evidence
Continental divide

From Asia
First contradiction

Are 3 exchanges a day adequate for Asian patients?

YES NO

Is Dialysis target realistic? Are Asians Different? Is Adequacy important for Asians? What is the magnitude of benefit and optimal dose of Dialysis?

Economic determinant of PD
In Asian countries PD treatment rate: shows a definite relationship with the wealth of the nation
Per capita GNI(World Bank criteria)
Low income US$<755 Middle income -lower US$ 762-2995 upper US$ 2996-9265 High income US$ 9266 >

Cost of PD

Li and Chow,PDI, 2001

Utilization of PD

Li and Chow,PDI, 2001

HongKong: Initial evidence

2 year and 5 years survival: 82%, 58.4%
A survival rate comparable to centers with standard 4 x 2L/day, or even better

Cross-sectional cohort:
Only 11 (5%) used more than 6 L/day Mean Kt/V 1.76, CCr 58 L/week
LO WK PDI 1996

Korea (n=128)
2 year survival 5 year survival Technique surv

< 2.1 97.9 66.8% 57.2%

>2.1 95.6 97.9% 77.7%

p value n.s. 0.0534 n.s.

Survival separates after 2 years Cox Model: Age, DM, Kt/V

Kt/V 0.1 increase associated with reduced R.R.39%

Survival not different significantly with:

Kt/V < 1.7 (n=14) and 1.7-2.0 (n=50) CCR > and < 60 L/week
Noh HJ PDI 2000

Korea
Excellent 5 years survival in high Kt/V group: 98% Kt/V determined largely by body size: 62 vs 54 kg rather than prescription More females in higher Kt/V group: 26% vs 79% (P<0.05) Lower peritoneal and higher renal clearance in high Kt/V group:
Peritoneal 1.7 vs 1.9 (P<0.05) Renal 0.08 vs 0.29 (P<0.05)

Survival benefit not related to peritoneal Kt/V

Noh HJ PDI 2000

Turkey (n=334
Mean age 42.2, DM 12.9%
Kt/V 2 year pt survival ----------------------------------------1.5-1.6 89% 1.7-1.8 97% 1.9-2.1 100% >2.1 93% Comments: Averaged Kt/v is measured. Patients living longer might have lower averaged Kt/V because of more readings with lower kt/V
Utas C PDI 2001

 Assigned into 3 groups

Kt/V <1.7, 1.7-2.0 and >2.0
(according to their baseline Kt/V - non-randomized)

China n = 146

Subsequent PD prescriptions
Adjusted to keep the Kt/V in the assigned range

Overall 2 year: actuarial patient survival technique survival

90% 76%

Significant lower survival in Kt/V below 1.7 (p<0.05) but similar for 1.7-2.0 & >2.0 78%, 96%, 95% respectively
Yao Q, HK J Nephrol 2001

Yao Q, HK J Nephrol 2001

China
Overall 2 year actuarial patient survival 90%, patient and technique survival 76%
Significant lower survival in Kt/V below 1.7 (p<0.05), but very similar for 1.7-2.0 and >2.0 (78%, 96%, 95% respectively) No difference in peritonitis and hospitalization rate
Qao Y, HK J Nephrol, 2001

Asia: Mounting evidence

Is Dialysis target realistic?
Economic limitations; Customized solutions

Is Adequacy important for Asians?

Kt/V influence survival

What is the magnitude of benefit and optimal dose of Dialysis?

<1.7 increased mortality

Are Asians Different?

Appear to be

Evolving consensus

Adequate Peritoneal Dialysis

Clinical Emphasis + Absence of uremic symptoms + Avoidance of fluid overload + Blood pressure control + Preservation of residual renal function + Well nourished + Phosphorus control + Acid-base balance + Correction of anemia ISPD Guidelines 2007: PDI 2007; 26: 520 -522

Nomenclature shift
Kt/V & Cr Cl reccommendations
Guidelines for targets for solute and fluid removal in adult patients on CPD

Solute Clearance Target

Only urea clearance is recommended for Chronic Peritoneal Dialysis Focus shift from Optimum to Minimum
Evidence based

Equal or more than

Kt/V > 1.7

Cr Clearance
No recommendations for Cr Cl target for CAPD For APD
Cr Cl 45 L /wk/1.73 m2

RRF
For relevant patients
Monitoring
Not less than 4 6 months

Conclusion
A knowledge of peritoneal anatomy and physiology is important in the management of PD patients
In particular, it helps to solve problems with clearance and ultrafiltration It also improves understanding of the impact of new technologies such as cyclers, larger dwell volumes, new PD solutions, etc.

Conclusion
Initial Guidelines
Opinion based: Non randomized cohort studies Solute clearance ~ Adequacy Optimal target concept

Challenging evidence
Asia: Minimal Kt/V

Noh:>2.1, better long term survival Szeto & Wang: nutritional state better with total Kt/V >1.7 Szeto: reduced mortality risk in both anuric and non anuric patients, but no cut off level suggested Lo: cross sectional: trend towards better survival with higher total kt/V, no cut off level suggested Lo: randomized study suggest Kt/V <1.7 is associated with more problems Yao: non-randomized study: increased mortality for sustained Kt/V < 1.7

Asian adequacy targets

Consensus shift
Solute clearance alone ~ Adequacy: Clinical assessment approach Minimal target concept Residual renal function emphasis