Strategies to Preserve the Peritoneal Membrane. Reusz GS Ist Dept of Pediatrics Semmelweis University, Budapest

Strategies to Preserve the Peritoneal Membrane Reusz GS Ist Dept of Pediatrics Semmelweis University, Budapest

Outline 1. Structure of the peritoneal membrane 2. Mechanisms of peritoneal injury 3. Signs and main types of membrane dysfunction 4. Measures to preserve membrane integrity a) Biocompatible PD solutions b) Replace glucose (icodextrin, amino-acid) c) Prevent peritoneal fibrosis by RAAS blockade 5. Encapsulating peritonitis

Structure of the Peritoneal Membrane Saxena R: Pediatr Nephrol (2008) 23:695 703

Factors leading to injury Evident injury to the peritoneum Peritonitis recurrent inflammation, fibrosis Hemoperitoneum Mechanical injury Other slowly-acting factors Glucose GDPs/AGEs Low ph Inflammation: (TGF-β, IL-1, FGF2, TNF-α) Angiotensin II

Mechanisms leading to the loss of peritoneal function Fuesshoeller A. Ped Nephrol 23:19, 2008

J Am Soc Nephrol 18: 2004 2013, 2007

Time course of events responsible for alterations of the peritoneal membrane J Am Soc Nephrol 18: 2004 2013, 2007

Modifications of the peritoneal membrane exposed to PD Structure at the beginning of therapy Stucture after 5 years of PD treatment J Am Soc Nephrol 21: 1077 1085, 2010

The peritoneal membrane b) a) 2016.11.11. 11 a) Normal b) after 10y PD

Low effective peritoneal surface area Signs of membrane dysfuncion Ultrafiltration failure Signs of ultrafiltration failure In the absence of patient non-adherence Stable residual renal function No mechanical disruption of the peritoneal membrane Inadequate dialysis dose Background Large effective peritoneal surface area Increased absorption of glucose Increased lymphatic reabsorption rate

Large Effective Peritoneal Surface Area Increased number of capillaries and lymphatic vessels Increased surface area and/ or permeability lead to increased glucose absorption and More rapid dissipation of the osmolar gradient Diagnosis Drain volume Low < 400 ml net UF over 4 hr with 4.25% dextrose (3.86% glucose) Clearence High: D/P creatinine > 0.81

Measures to slow down deterioration and to reconcstitute peritoneal integrity Evident injury to the peritoneum Peritonitis recurrent inflammation, fibrosis Hemoperitoneum Mechanical injury Other slowly-acting factors Glucose AGEs/GDPs Low ph Inflammation: (TGF-β, IL-1, FGF2, TNF-α) Angiotensin II Avoid direct injury Exit site, tunnel infection Peritonitis Avoid chronic aphysiologic insults and fibrosis Lower glucose concentration Lower GDP and AGE-s Avoid or reduce lactate burden Replace glucose by other osmotic agents ICODEXTRIN, Aminoacids RAAS blockade

Neutral ph, Low GDP Bicarbonate PD Solutions Conventional glucose-based PD fluid High concentration glucose degradation products (GDPs) - Secondary to heat sterilization - Buffered by lactate at low ph 5-6 Bioincompatible 2 compartment system more neutral ph Low ph compartment contains glucose - Reduces GDPs during sterilization Bicarbonate or lactate/bicarbonate compartment Avoids calcium precipitation No convincing evidence of beneficial effect on the peritoneal membrane Perl et al. Kid Int 79:814, 2011

Some commercially available biocompatible solutions Chaudhary K et al: Clin J Am Soc Nephrol 5: 723 732, 2010

Perl J et al: Kidney International (2011) 79, 814 824 GDP content of biocompatible and traditional PD solutions 3-deoxyglucosone 3,4-dideoxyglucosone-3-ene 5-hydroxymethyl furaldehyde Formaldehyde Acetaldehyde

Patient and technique survival curves of patients on convential (CS and biocompatible (BCS) PD solutions n = 187 (BCS, n = 81; CS, n = 106) Cho HJU et al: Nephrol Dial Transplant (2010) 25: 1964 1973

Biocompatible dialysis fluids for peritoneal dialysis (Review) Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD007554. DOI: 10.1002/14651858.CD007554.pub2.

Structure of icodextrin

Icodextrin Reduces Glucose Toxicity Hyperosmolar Stress Glucose degradation products (GDPs) Advanced glycation end-products (AGEs) Cooker et al. Kidney Int Suppl 81:S34, 2002

Serum and urine levels of icodextrin metabolites Rodriguez-Carmona a et al: Perit Dial Int 2007; 27: 260 266.

Am J Nephrol 2014;39:515 527

Icodextrin decreases mortality and technique failure 2163 Korean PD patients on PD using: - 641 icodextrin 50% of time on PD - 1522 non-icodextrin Mortality 14.4% (icodextrin) vs. 20.0% (non-icodextrin) HR 0.69 (95% CI, 0.52-0.90; p=0.004) Technique Failure 5.6% (icodextrin) vs. 8.8% (non-icodextrin) HR 0.60 (95% CI, 0.40-0.92; p= 0.018) Han et al. Nephrol Dial Transpl 27:2044, 2012

The role of the local RAAS system Peritoneal mesothelial cells: Local renin-angiotensin-aldosterone system Contributes to interstitial fibrosis Increases TGF-β Increases fibronectin Increases VEGF The peritoneal mesothelial RAAS is up-regulated by: Glucose Low ph Peritonitis Nessim et al. Kid Int 78:23, 2010

Peritoneal Membrane Small Solute Permeability Over Time Kolesnyk I et al. Nephrol Dial Transpl 24:272, 2009

Causes of Membrane Failure Large effective peritoneal surface area Increased absorption of glucose Low effective peritoneal surface area Simpe fibrosis Encapsulating peritonitis Severe decrease in surface area and/or permeability leads to restricted transport of fluid and solutes

Encapsulating peritoneal sclerosis (EPS) Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome characterized by bowel obstruction (intermittent, recurrent, or persistent) caused by a wide range of adhesions of a diffusely hypertrophied peritoneum. Kawaguchi Y et al. Perit Dial Int 20:Suppl 4; 3, 2000

Factors Implicated in the Pathogenesis Factors Related to PD Duration of PD Prior peritonitis High transport status Bioincompatibility (glucose, hypertonicity, low ph) Acetate- based dialysate Plasticizers Chlorhexidine Withdrawal of PD

Summary of the literature on pediatric encapsulating peritoneal sclerosis Stefanidis et al: Pediatr Nephrol (2014) 29:2093 2103

Encapsulatingperitonitis: The two-hit hypothesis. Pediatr Nephrol (2014) 29:2093 2103

Serafimidis et al:bmc Surgery 2006 10.1186/1471-2482-6-3

Computed tomography scan of encapsulating peritoneal sclerosis Vlijm A et al. NDT Plus 2011;4:281 284

Treatment Stop PD Nutritional support Surgery enterolysis 96% restoration of bowel function but high rate of recurrence and often need post- op immunosuppression Immunosuppression (case reports and series) Corticosteroids Azathioprine Mycophenolate mofetil Sirolimus Tamoxiphen Korte et al. Nat Rev Nephrol 7:528, 2011 Balasubramaniam et al. Nephrol Dial Transplant 24:3209, 2009

Summary The peritoneal membrane is a dynamically changing organic structure PD is a non-physiological procedure, however, damage inflicted to the peritoneum can be minimized by Preventing bacterial inflammation Minimizing the effect of bioincompatible fluids GDP, AGE, lactate Slowing or halting the fibrotic procedures by the use of RAAS inhibition

Case 2 10 years old girl Medical history (from an other institute) Tubulopathy of unknown origin, discovered at the age of 2 months, metabolic crisis wasting of Na, K, NaHCO3, secondary hypophosphatemic rickets Supportive treatment CRF at the age of 4

Case 2 Poor familial background RRT by CVL Left jugular vein occluded after ~1 year Right jugular vein occluded after ~1 year Left femoral vein occluded after 0.5 year Transplanted Graft failure after ~ 3 years

Case 2 What to do next? a) Try to make a cimino fistula b) Try to insert a new central line c) Peritoneal dialysis CAPD was initiated Average fast transporter Still some RRF (ultrafiltration, without effective solute removal) Repeated peritonitis episodes Decreasing solute removal Decreasing ultrafiltration Episodes of overhydration

Case 2 What next? PET test Fast transporter P/D urea 0.97 How to change PD prescription Actually: CAPD, 4 exchanges/day (3 daytime, 1 nighttime) APD 8 rapid changes during the night + 1 daytime dwell then 2 daytime dwells What next? Re-transplantation?

Therapeutic strategies

Evidence Cochrane database analysis 36 Studies - Adult and kids - RCT or quasi RCT - 2719 Pts - Poor design - Allocation bias - Lost to Follow up 0-85% - Based on the best available evidence, the use of these 'biocompatible' PD solutions resulted in clinically relevant benefits without added risks of harm.