Associated Professor of Internal Medicine and Nephrology Fluid Management in PD Dr Abdullah Alhwiesh Associated Professor of Internal Medicine and Nephrology

Introduction Ultrafiltration Process Ultrafiltration Failure Definition Incidence Approach Types Management General Specific

Peritoneal Membrane (PM) Lines the peritoneal cavity PM surface area 1-2 m2 PM/Body SA 0.6-0.8 Two Portions 1. Visceral a. Lines the gut and other viscera b. 80-90% of total SA c. 25-30% participate in PD 2. Parietal a. Lines the abdominal cavity wall b. 10-20% of total SA c. 70-75% participate in PD

Transport Process High concentrated area to the low concentrated area Diffusion High concentrated area to the low concentrated area Ultrafiltatration (convection) Osmotic gradient Water move from low osmotic area to high area Absorption Lymphatic system

Barriers Between the Dialysate and Capillary Blood

Three-Pore Capillary Membrane

Ultrafiltration (UF) 40% of UF by aquaporin system 60% of UF by paracellular route UF depends on osmotic gradient Maximum at the beginning of dwell but decline with time due to: 1. Glucose absorption 2. Dilution of the dialysate

Dialysate Glucose Level Dialysate glucose (mg/dL) Dwell time (hours)

UF (cont.) 1. Lymphatic, varies directly with intraperitoneal pressure UF is counterbalanced by peritoneal reabsorption: 1. Lymphatic, varies directly with intraperitoneal pressure 2. Backfiltration Net fluid removal depends on the balance: UF and absorption Usually there is inverse relationship between UF volume and solute clearance.

Net UF Volume

Peritoneal Equilibration Test (PET) Dialysate Glucose (mg/dL) Transport Classification D/P Creatinine Dialysate Glucose (mg/dL) Net UF (mL) High High Average Mean Low Average Low 0.82-1.03 0.66-0.81 0.65 0.50-0.64 0.34-0.49 230-501 502-722 723 724-944 945-1,214 -470-35 35-320 320 320-600 600-1,276

Baseline PET 60 53% 50 40 30.9% 30 20 10.4% 5.6% 10 High High Average High High Average Low Average Low PD n=806 Blake, P, et al. PD I 1996;16:448-456

Transport Status Changes 8% convert to low transporter at two years Blake PG, et al. Adv Perit Dial 1989;5:3

UF Volume and Solute Clearance Twardowski ZJ, ASAIO Trans 90;36:8

UF (cont.) The mean TCUF for 4 hours dwell: 1. 1.5% Dextrose (1.36% glucose) 346 mosmol/kg (MW 182 dalton) 1.0 – 1.2 mL/min (240 mL/4 hr) 2.5% dextrose (2.27% glucose) 396 mosmol/kg 1.7 mL/min (400mL/4hr) 3. 4.25% Dextrose (3.86% glucose) 484 mosmol/kg 3.4 ml/min (816 mL/4 hr) 7.5% icodextrin (glucose polymer) 282 mosmol/kg (MW 20,000 dalton) UF maintained over at least 12 hours UF 1.4-2.3 mL/min

UF Volume 4.25 % dextrose Ultrafiltration (mL) 1.5% dextrose Time (h)

Icodextrin vs 1.5% and 4.25% Dextrose 100 200 300 400 500 600 527 150 510 448 561 101 552 414 Mean Net UF Volume (mL) n=46n=53 n=29 n=45 n=45 n=54 n=30 n=35 P<0.0001 P=0.44 P<0.0001 P=0.06 Dwell time 8 hours 12 hours RCT, MC CAPD FU 6 months (MIDAS Study Group) Mistry CD, et al. KI 94:46;496-503

Icodextrin vs 4.25% Dextrose 600 540 P<0.001 500 400 Net UF ML 300 195 200 100 Icodextrin n = 47 4.25 % Dextrose n = 45 RCT, DB, MC APD FU 2/52 dwell time 14 hrs mean D/P Cr 0.84 Finkelstein, F, et al JASN 2005;16:546-554

Icodextrin vs 2.5% Dextrose 600 587.2 500 P< 0.001 400 346.2 Mean Net UF Volume (mL) 300 200 100 7.5 Icodextrin 2.5 % Dextrose n=90 n=85 RCT, DB, MC CAPD FU 4/52 dwell time 10.5 h (Icodextrin Study Group) Wolfson M, et al. AJKD 2002;40:1055-65

Theoretical Concern 7.5% Icodextrin 20% absorbed Maltose Metabolized Maltose Cannot be Metabolized Accumulate in the Body No Toxic Effects Mistry CD, et al KI 94;46:496-503 Wolfson M, et al AJKD 2002; 40:1055-65

Ultrafiltration TFR > 2035 mL/24h TFR 1570-2035 mL/24h TFR 1265-1570 mL/24h TFR < 1265 mL/24h Each 100 mL/24h of TFR, RR 0.90 (95% CI, 0.84 to 0.96)P < 0.01 Prospective, observational study CAPD 93% n=125 FU 3 years Mean UV 364 mL/24h UV 21.8% Ates, et al. KI 2001;60:767-776

Ultrafiltration 90 82% RR 0.45 P=0.047 80 70 56% 60 50 40 30 20 10 Patient Survival % 40 30 20 10 UF mL/day >750 <750 n =131 n = 43 Prospective, observational, MC anuric APD median Ico 50% FU 2 yrs (EAPOS) Brown, EA, et al. JASN 2003; 14: 2948-2957

UF Failure Definition: UF Volume < 400 mL after 4 hours dwell with 2L of 4.25% dextrose (3.86% glucose) Fluid overload is risk factor for CV morbidity and mortality UF failure is important cause of PD technique failure 1-6% Incidence: 10-40% Heimburger O, et al KI 90;38:495 - 506 2.6% after 1 year 30.9% after 6 years

Causes of Fluid Overload Fluid overload is not always due to UF failure Causes of fluid overload: A) Non-membrane related e.g. excess salt and water intake severe hyperglycemia non-compliance with exchanges inappropriate hypertonic solutions loss of residual renal functions mechanical causes I.e leaks, catheter obstruction or malposition

Causes of Fluid Overload A) Membrane related (UF Failure) 3 types (1,2, and 3) based on modified peritoneal equilibration test (PET) to evaluate UF response and small MW solute transport

UF Failure Peritoneal membrane function Ultrafiltration Response Modified PET 4.25 % 2L Drain Volume < 2400 ml/4hrs Drain Volume > 2400 ml/4hrs Re-evaluate clinically Small Solute Profile

UF Failure Type 2 Type 1 Type 3 Small Solute Profile Low Transport D/PCr < 0.5 High Transport D/PCr > 0.81 HA or LA D/PCr 0.5-0.81 Inherent high/ Recent peritonitis/ Longterm PD Mechanical/ Enhanced Reabsorption/ Aquaporin Deficiency Disruption of Peritoneal Space Type 2 Type 1 Type 3

Type 1 UF Failure Low UF volume (< 400 ml/4h with 4.25% dextrose modified PET) and high small MW solute transport status (D/P Cr > 0.81) Most common Three Groups: 1. Patient with inherent high transporter, 10% of starting PD 2. Patients with peritonitis 3. Patients who converted to high transporter with time. Risk of high protein loss Higher mortality

Pathophysiology of Type 1 UF Failure  Vascular permeability /  Vascularity  Effective PM surface area Rapid Dialysate Glucose Absorption Loss of Osmotic Gradient (Low UF Volume & High Small MW Solute Clearance) Type 1 UF Failure Peritoneal Neoangiogenesis Constant Glucose Exposure

Type 2 UF Failure Low UF volume ( < 400 ml/4 h with 4.25% dextrose modified PET) and low small MW solute transport status (D/P Cr < 0.5) Very rare Causes: 1. Peritoneal fibrosis/sclerosis 2. Intraabdominal adhesions 3. Scleresing encapsulating peritonitis Low transporter and leaks or mechanical problems or high lymphatic reabsorption can mimic type 2 UF failure.

Pathophysiology of Type 2 UF Failure Irritants e.g peritonitis Abdominal Operation/intra-abdominal inflammation Stimulate PM macropahages Extensive Adhesion Formation Secreate lymphokines Activate fibroblast  Effective PM Surface Area PM fibrosis  PM permeability Type 2 UF Failure Type 2 UF Failure (Low UF Volume and Low Small MW Solute Clearance) (Low UF Volume & Low Small MW Solute Clearance)

Type 3 UF Failure modified PET) and low average or high average small Low UF volume (< 400ml/4 h with 4.25% dextrose modified PET) and low average or high average small MW solute transport status (D/P Cr 0.5-0.81) Causes: 1.  lymphatic absorption 2. Aquaporins loss or dysfunction

Lymphatic Absorption Absorption process is independent of osmotic pressure Absorption process is dependent on intraperitoneal pressure Net UF 16% higher in supine position Imholz AL, et al. NDT 98;13:146 Absorption rate 1-1.5 ml/min Associated with large PM surface area Increased PD duration does not enhance lymphatic absorption Michels WM, et al. PDI 2004;24:347 Measurement of lymphatic absorption is uncommon in clinical practice due to complexity of the procedure.

Pathophysiology of Aquaporins Dysfunction Type 3 UF Failure Constant Glucose Exposure Peritoneal Neoangiogenesis Transcellular glycosylation of aquaporin-1 Impaired aquaporin-1 function Type 3 UF Failure (Low UF Volume & Low Average or High Average Small MW Solute Clearance)

Aquaporins Loss or Dysfunction Rare Condition Various indirect methods to estimate aquaporin function: Sodium Sieving Difference in net UF between 4.25 % and 1.5 % dextrose UF after 2-4h dwell with 4.25% dextrose  UF after 4h dwell with 1.5% dextrose

Sodium Sieving

General Guidelines for Prevention of Volume Overload 1. Routine Monitoring Dry Weight, Residual Renal Function, blood pressure, PET 2. Dietary Counselling Appropriate salt and water intake 3. Protection of Residual Renal Function (RRF) Avoidance of nephrotoxic agents e.g. NSAIDs aminoglycosides, contrast 4. Diuretics Use  Urine Output Furosemide (500 mg x 3wk or 500 mg PO OD or 200 mg PO BID) with or without metolazone (5-10 mg) 30 min prior to furosemide Do not preserve RRF

Diuretics and RRF Variable Control n=30 Diuretics n=31 P Value  Urine Vol. mL/month CrCl mL/min/month Urinary Kt/v per month -23.3  11.2 -0.071  0.04 -0.019  0.01 +6.47  9.52 -0.12 0.05 0.020 0.01 0.047 0.45 0.92 RCT CAPD FU 1 year Furosemide 250 mg PO OD  Metolazone 5 mg PO OD Medcalf JF, et al KI 2001;59:1128-33

General Guidelines for Prevention of Volume Overload Education to enhance compliance Appropriate prescription Hyperglycemia control Preservation of PM function Decrease the peritonitis rate Use more bicompatible solutions Reductions of PM glucose exposure

What is the ideal solution ?

1 - Have a sustained and a predictable solute clearance with minimal absorption of the osmotic agents . 2 - Provide deficient electrolytes and nutrients, if required . 3 - Correct acid base problems without interacting with other solutes in the peritoneal dialysis fluid . 4 - Be free of and inhibit the growth of pyrogens and micro-organisms . 5 - Be free of toxic metals . 6 - Be inert to the peritoneum .

Low molecular weight agents : 1- Glucose (Dextrose) - The most commonly used - 3 different dextrose monohydrate concentrations 15%, 2.5% , and 4.25% Advantages : Cheap Safe Easily available In market for long time. -Not ideal osmotic agent : ● easily absorbed so short UF ● Absorption→ Metabolic complications : Hyperglycemia Hyperinsulinemia Hyperlipidemia Obesity ● Hyperosmolarity , low PH , GDPs affect Peritoneal host defense mechanisms by inhibiting : Phagocytosis and bactericidal activity (Bio- incompatibility )

High molecular weight agents : Glucose polymers ( Icodextrin 7.5%) - Mixtures of oligopolysacchaides of variable chain lenghts . - Substitute for glucose solutions : - Diabetics . - If long dwell is required . - If Better UF is required .

Advantages : - Prolonged positive UF because of slow absorption ( large MW) . - Iso-Osmolar : (282) It induces transcapillary UF by a mechanism resembling colloid osmosis mainly through small pores . Almost no sieving of solutes→ increased convective transport and clearance of small solutes .

Sustained UF Potential Icodextrin vs Dextrose As shown on this slide, computer modeling using actual peritoneal transport data from patients with high-average transport profile on continuous ambulatory peritoneal dialysis1-3 confirms simulated ultrafiltration (UF) profiles across a variety of peritoneal dialysis (PD) solutions.4 As predicted, dextrose-based PD solutions are associated with maximal UF at the beginning of the dwell, when osmotic forces are greatest. As the dwell progresses, however, glucose is absorbed and the rate of UF declines as the osmotic gradient is diminished, ultimately leading to negative net UF. In contrast, icodextrin is able to maintain osmotic forces over extended periods of time. As a high molecular weight colloid osmotic agent, icodextrin does not readily diffuse across the peritoneal membrane but rather is slowly removed from the peritoneal cavity via lymphatic absorption. This results in sustained UF and solute clearance over longer dwell periods compared with dextrose-based solutions.1-3 Ho-Dac-Pannekeet et al. Kidney Int 1996;50:979-86; Douma et al. Kidney Int 1998;53:1014-1021; Mujais S et al. Kidney Int 2002; 62(Suppl 81): S17-S22 1Ho-Dac-Pannekeet MM, Schouten N, Langendijk MJ, et al. Peritoneal transport characteristics with glucose polymer based dialysate. Kidney Int. 1996;50:979-986. 2Douma CE, Hiralall JK, Waart DR, Struijk DG, Krediet RT. Icodextrin with nitroprusside increases ultrafiltration and peritoneal transport during long CAPD dwells. Kidney Int. 1998;53:1014-1021. 3Mujais S, Vonesh E, Moberly J. Clinical physiologic correlates of ultrafiltration in peritoneal dialysis. Kidney Int. In press. 4Rippe B, Levin L. Computer simulations of ultrafiltration profiles for an icodextrin-based peritoneal fluid in CAPD. Kidney Int. 2000;57:2546-2556.

2- Balance Bi-chamber bags. Neutral PH, low GDPS Aretrospective study : over 2000 Pts Conventional solutions vs Balance Comparing the outcome and survival : high with balance but it was a retrospective study therefore a randomized Prospective studies are required . Lee Hy etal Perit Dial Int 2005 ; 25:248

3- Amino acid solutions : - Malnutrition is common in PD patient : higher mortality higher hospitality - Multi-factorial etiology ? Protein loss (15 grams/day) - Early Experience with AA solutions not very successful ? not well designed for PD - Nutrineal 1.1% solution of combination of essential and nonessential AA is as effective as 1.36% Dx solutions and improve the nutritional status of dialysis Pts. A/e : • worsening of acidosis • ↑BUN • Expensive

Management of Type 1 and 3 UF Failure Use icodextrin in long dwell Avoid long dwell: 1. CAPD a. Use automated night-time exchange device b. Switch to APD ( lymphatic absorption) 2. APD a. Dry daytime b. Mid-day drainage c. Dwell 3-4 hours before APD d. One or more daytime exchanges Resting membrane temporary switch to HD (4/52) 23/33 (69%) respond (Type 1 UF failure) Switch to HD permanently Garosi G, at al. Adv PD 1999;15:185

Management of Type 2 UF Failure Use loop diuretics in patients with RRF Majority, transfer to HD permanently

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