Peritoneal Dialysis Solutions. Cristina Lage Medical Affairs and Information

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1 Peritoneal Dialysis Solutions Cristina Lage Medical Affairs and Information 1

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3 Standard, single-chambered FME PD solutions - composition * Electrolytes to maintain balance Sodium mmol/l Potassium mmol/l Calcium mmol/l Magnesium 0.50 mmol/l Chloride mmol/l * An osmotic agent to facilitate ultrafiltration Glucose g/l (osmolarity ~ mosm/l) * A buffer to correct metabolic acidosis Lactate mmol/l (ph ~ 5.5) 3

4 Components of PD fluids E l e c t r o l y t e s O s m o t i c a g e n t s B u f f e r s 4

5 Sodium concentration Typical concentration: 134 meq/l Solutions with very low sodium concentrations are recommended when UFR is very high (104 to 125 meq/l) The low sodium solutions Increase sodium removal Maintain normal blood sodium concentration Reduce thirst Improve blood pressure 5

6 Sodium concentration Depends on the hypertonicity of the fluid and the ultrafiltration rate Hypertonic solutions cause hypernatremia due to sodium sieving or excessive water removal relative to sodium through the ultrasmall pores Na+ H 2 O Na + Na+ H 2 O Na+ Blood Na+ Dialysate 6

7 Electrolyte potassium (K+) Main cation of the intracellular fluid responsible for membrane potential Hyperkalemia most harmful complication in ESRD arrhythmia & finally cardiac arrest Standard PD fluids contain no potassium efficient diffusive removal! 7

8 Electrolyte calcium (Ca 2+ ) Calcium triggers muscle contraction Responsible for mineralisation of bone regulatory role of PTH & vitamin D Hypocalcemia risk of osteodystrophy Hypercalcemia risk of tissue calcification! 8

9 Calcium concentration Typical calcium concentrations: 1.25 to 1.75 mmol/l Optimal calcium concentration also influenced by dose of oral calcium salts used for phosphate binding and supplemental vitamin D 9

10 Components of PD fluids E l e c t r o l y t e s O s m o t i c a g e n t s B u f f e r s 10

11 Osmotic agents facilitate ultrafiltration removal of excess water (H 2 O) - driven by the osmotic gradient = difference in osmotic pressure between blood & dialysate H 2 O H 2 O H 2 O Blood H 2 O H2O H 2 O H 2 O Dialysate H2O H 2 O 11

12 Osmotic agents - classification Low molecular weight compounds Glucose Fructose Glycerol Xylitol Sorbitol Amino acids High molecular weight compounds Albumin Peptides Gelatins Synthetic polymers Glucose polymers Icodextrin, Starch, Dextrans 12

13 Osmotic agents - LMW Glucose The common osmotic agent Advantages: efficient safe readily metabolised source of energy cheap 13

14 Glucose cont. Glucose content in FMC bags is expressed as: Glucose anhydrous 15,0 g/l (1.5%) 22,73 g/l (2.3%) 42,5 g/l (4.25%) Glucose monohydrate 16,5 g/l 25,0 g/l 46,75 g/l 14

15 Glucose cont. Fluid removal is dependent on: dwell time / peritoneum characteristics / glucose concentration 15 DeSanto NG et a; Int J Artif Organs, 2:119, 1978)

16 UF depends on peritoneal transport type Total dialysate volume L Low transporter High transporter Dwell time (h) Twardowski, Adv Perit Dial 1990:

17 Glucose cont. Disadvantages: Obesity, Malnutrition High calorie uptake Metabolic derangements Impaired peritoneal host defence Impairment of the peritoneal membrane Formation of GDPSs (glucose degradation products) Ultrafiltration failure Formation of AGEs (advanced glycosylation end products) 17

18 Polyglucose: Basics A glucose polymer based on starch Mixture of glucose polymers in different chain lengths (4 to 250) Mean MW: 16,200 Dalton (glucose MW 180 Dalton) Function Colloid osmosis Iso-osmolar Slow/low absorption Sustained UF UF during long dwells only 18

19 How is polyglucose UF different from dextrose? UF rate is lower Minimal or no UF during short dwells 19

20 Potential hazards of icodextrin Ultrafiltration failure Increased metabolites (maltose) in serum Hyponatriemia Bioincompatibility Glucose degradation products and AGEs Allergic reactions Sterile peritonitis Disturbed laboratory measurements 20

21 Components of PD fluids E l e c t r o l y t e s O s m o t i c a g e n t s B u f f e r s 21

22 Buffer compounds in PD Acetate not used anymore in PD Lactate still the common buffer Bicarbonate the physiological buffer 22

23 Standard FME PD solution buffers 35 mmol/l Lactate 34 mmol/l Bicarbonate (39 mmol/l Bicarbonate) Correction of metabolic acidosis 23

24 Lactate must be metabolised in order to function as a buffer Lactate Pro-drug : buffers only after complete metabolisation ph Bicarbonate Direct action as buffer 24

25 Pure bicarbonate is obligatory in case of disturbed lactate metabolism Lactate is metabolised in the liver. ESRD patients with hepatic dysfunction (e.g. liver cirrhosis, congestive heart failure, newborns) suffer from hyperlactaemia when treated with lactate containing solutions. In addition, patients, in particular children with ESRD, who may not be able to metabolise lactate may not have sufficient buffer available. 25

26 bicavera _ no precipitation The Problem The Solution NaHCO 3 + CaCl 2 Solution ASolution B NaCl + HCl + CaCO 3 Bicarbonate 34 mm 39 mm ph < 8,0 Electrolytes Glucose ph No precipitation of calcium and magnesium carbonate when produced in a gas-tight, double- chamber system ph

27 Whole study population: No difference in blood HCO 3- between bicavera andlac-buffered solutions (mmol/l) weeks Weeks venous arterial Bic Lac Bic Lac Feriani M et al, Kidney Int 1998;54:

28 Subgroup analysis: 34 mm BIC-PDF (bicavera ) especially effective in acidotic patients 5.0 HCO 3 - differences from baseline (mmol/l) * * weeks -5.0 * p < mm lactate 34 mm bicarbonate (bicavera) Feriani M et al, Kidney Int 1998;54:

29 Pure bicarbonate solutions - especially indicated in patients as follows: Patients with insufficient acidosis compensation while on lactate-buffered PD solutions and malnutrition bone disease Patients with impaired lactate metabolism immature metabolic pathways (e.g.newborns) severe hepatic insufficiency global or right heart insufficiency 29

30 Contact between peritoneal dialysis solution and peritoneal membrane During CAPD treatment an annual PD fluid volume of 2000 ml/ dwell 4 dwells/ day 365 days/ year x x = ~3000 Liter PDF is applied to the peritoneal cavity.

31 Morphological changes in the peritoneal membrane during long-term peritoneal dialysis 100µm 100µm Normal parietal peritoneum Parietal peritoneum >5 years PD The Peritoneal Biopsy Registry Williams JD, J Am Soc Nephrol 2002; 13:

32 New Solutions: stay safe balance and bicavera 32

33 Bioincompatibility of current PD fluids Unphysiological composition: acidic ph (ph ) high glucose concentration ( g/l) Acute toxicity hyperosmolality (~ mos/kg) Heat sterilisation of glucose gives rise to glucose degradation products (GDP) which in turn may increase AGE formation Chronic toxicity 33

34 The ph/gdp dilemma Low ph bioincompatible for the peritoneal membrane and provokes inflow pain Low ph important for prevention of caramelization and GDP formation during heat sterilization 34

35 Solution to the ph/gdp dilemma......allows only a neutral solution entering the peritoneal cavity balance bicavera Solution B Solution A Solution B Solution A Lactate Electrolytes Bicarbonate Electrolytes Glucose 34 mm 39 mm Glucose ph 8,0-8,6 ph ph < 8,0 ph Mixed solution ph

36 BicaVera, double-chambered FME PD solutions - composition * Electrolytes to maintain balance Sodium 134 mmol/l Potassium 0.00 mmol/l Calcium mmol/l Magnesium 0.50 mmol/l Chloride mmol/l * An osmotic agent to facilitate ultrafiltration Glucose g/l (osmolarity ~ mosm/l) * A buffer to correct metabolic acidosis Bicarbonate 34 mmol/l (ph ~7.4) 36

37 Balance, single-chambered FME PD solutions - composition * Electrolytes to maintain balance Sodium 134 mmol/l Potassium 0.00 mmol/l Calcium mmol/l Magnesium 0.50 mmol/l Chloride mmol/l * An osmotic agent to facilitate ultrafiltration Glucose g/l (osmolarity ~ mosm/l) * A buffer to correct metabolic acidosis Lactate 35 mmol/l (ph ~7.0) 37

38 3-deoxyglucosone [µmol/l] Low ph is an option to reduce GDP formation during heat-sterilisation ph dependent formation of 3- DG (3-deoxyglucosone) PH 36

39 Glucose degradation products... Provoke infusion pain are cytotoxic Promote the formation of AGEs 39

40 Fischbach Michel A NEW NEUTRAL-pH LOW-GDP PERITONEAL DIALYSIS FLUID Rainer Himmele, Lynn Jensen, Dominik Fenn, Chih-Hu Ho, Dixie-Ann Sawin, and Jose A. DiazBuxo Peritoneal Dialysis International 32, : 2012 Conventional PDF s less GDP s in hyper than in ico 263 Balance 54 Bicavera 4.25% Extraneal icodextrin ph 5.8 Physioneal 3.86% Delflex Neutral ph, Balance (Fresenius Medical Care, Bad Homburg, Germany), BicaVera (Fresenius Medical Care), and Gambrosol Trio (Gambro Lundia AB, Lund, Sweden) exhibited similar low total GDP concentrations, with maximums in the 4.25% solutions of 88 μmol/l, 74 μmol/l, 74 μmol/l, and 79 μmol/l respectively; the concentration in Physioneal (Baxter Healthcare Corporation, Deerfield, IL, USA) was considerably higher at μmol/l. The total GDP concentration in Extraneal (Baxter Healthcare Corporation) was 63 μmol/l, being thus slightly lower than the concentrations in the 4.25% glucose solutions, but higher than the concentrations in the 1.5% and 2.5% glucose solutions

41 AGEs Reactive carbonyl compounds derive from uremic plasma and heatsterilised PDF and lead to protein modifications Advanced Glycation End Products accumulate in the peritoneal membrane and induce functional and structural alterations Clinical Implication Peritoneal membrane alterations associated with UF reduction Miyata et al, Kidney Int 2000, 58: Nakayama et al, Kidney Int 1997, 51: Honda et al, Nephrol Dial Transplant 1999, 14:

42 Cellular toxicity and bioincompability: importance of the ph and the GDP s Wislander et al. (PDI 2001) Degree of cellular cytotoxicity (macrophages, polynuclears, fibroblasts, mesothelial cells) Low ph GPD's Osmolality Lactate

43 Overall importance of AGEs in chronic end stage renal disease involved in aging process In diabetics In uraemia Activation of monocytes, macrophages, endothelial cells via NFκB cytokine release Inflammation release of growth factors cell proliferation Correlation with AOPPs (Advanced Oxidation Protein Endproducts) Correlation with ALEs (Advanced Lipoxidation Endproducts) AGEs and ALEs in atherosclerotic vessel walls Hörl WH, Wien Klin Wochenschr 2003;115/7-8:

44 GDP concentrations in different PDF Concentration (µmol/l) Conv. PDF 1.5% gluc Conv. PDF 4.25% gluc 3- Deoxyglucosone Acetaldehyde Formaldehyde Methylglyoxal balance 1.5% gluc Tauer et al, Biochem Biophys Res Commun 2001, 280(5): & & & & & balance 4.25% gluc bicavera bicavera 1.5% gluc 4.25% gluc sterile filtered 4.25% gluc 41

45 More CA125 (mesothelial cells) with improved biocompatibility, most consistent effect In clinical studies, use of new glucose-based solutions with low GDPs and a neutral ph is associated with increased effluent levels of cancer antigen 125 (CA125) (1-3), which is used as indicator for MC mass (4). Higher CA125 levels suggest regeneration of the MC layer (5), and surfactant availability?. Extremely low CA125 concentrations have been found in effluent of patients preceding the diagnosis of peritoneal sclerosis (6). 1. Rippe B, et al. Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products. Kidney Int 2001; 59: Williams JD, et al. The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (Balance) on the peritoneal membrane. Kidney Int 2004; 66: Jones S, et al. Bicarbonate/lactate-based peritoneal dialysis solution increases cancer antigen 125 and decreases hyaluronic acid levels. Kidney Int 2001; 59: Visser CE, et al. Cancer antigen 125: a bulk marker for the mesothelial mass in stable peritoneal dialysis patients. Nephrol Dial Transplant 1995; 10: Szeto CC, et al. Clinical biocompatibility of a neutral peritoneal dialysis solution with minimal glucose-degradation products a 1-year randomized control trial. Nephrol Dial Transplant 2007; 22: Ho-dac-Pannekeet MM, Hiralall JK, Struijk DG et al. Markers ofperitoneal mesothelial cells during treatment with peritoneal dialysis.adv Perit Dial 1997; 13: 17 22

46 Euro Balance Trial: Effluent CA125 was significantly increased in patients treated with balance in both 42 Williams JD et al, Kidney Int 2004;66: arms of the study p< p< U/ml Conv. PDF Conv. PDF Group 1 36 Balance Conv. PDF Balance Conv. PDF Group 2

47 Importance of RRF in CAPD patients Maintenance of endocrine functions of the kidney Erythropoietin synthesis Conversion of vitamin D in its active form Elimination of β 2 -microglobulin Preservation of adequate hydro-electrolyte equilibrium Each 1 ml/min GFR adds 10 L/week of CCr 47

48 Advantages balance and bicavera ph neutral Reduction of inflow pain Reduced GDP formation Reduced AGE formation Improved biocompatibility Improved membrane preservation with bicaverabetter correction of metabolic 48 acidosis

49 Conclusions on new PD solutions ph-neutral, dual-chambered solutions with reduced GDP content will become the gold standard for chronic PD Neutral ph and reduction of GDP content will contribute to preserve long-term peritoneal membrane function! Reduction of GDP lead also to benefial systemic effects (reduction of systemic AGEs and preservation of RRF) improved patient outcome 45

50 Thank you 45