Fischbach Michel. Pediatric Dialysis Unit University hospital Strasbourg France

Transcription

1 Importance of varying dwell time and fill volume to optimize volume control in children on PD UF «water» : free water (AQ1) and coupled water (small pores) sodium removal (small pores) Pediatr Nephrol (2014), 29: Fischbach Michel Pediatric Dialysis Unit University hospital Strasbourg France

2 Muscle wasting in chronic kidney disease : the role of the ubiquitine proteasome system and its clinical impact VR Royan, WE Mitch. Pediatr Nephrol 2008; 23: Malnutrition Volume overload Metabolic acidosis Inflammation Insuline resistance (PTH) GH-IGF1 axis anomalies Cachexia in uremic patients : loss of protein stores, muscle wasting, growth impairment : ATP-dependent, ubiquitin-proteasome system

3 The impact of strict volume control strategy on patient survival and technique failure in peritoneal dialysis patients. Kircelli F et al. Blood Purif. 2011; 32: 30-7 Strict volume control by dietary salt restriction and ultrafiltration was applied over a 10-year period. Mean BP decreased from 138/86 to 114/74 mm Hg. Overall and cardiovascular mortality rates were 48.4 and 29.6 per 1,000 patient-year Strict volume control (lowered BP) leads to a decrease in mortality of nearly 40% Euvolemia is probably a more important adequacy parameter than small solute clearance (urea) as fluid status, but not small solute clearance predicts outcome

4 Fluid status in PD patients: the European body composition monitoring (EuroBCM) study cohort W. Van Biesen et al PLOS ONE 2011; 6(2): E17148; PD patients from 28 centers, 6 countries Only 40 % normovolemia!!! 60 % 7 % underhydrated 53 % overhydrated (25%>15% OH; severe OH) BP and OH were not directly related : importance of both dry weight/uf («water prescription») and sodium balance/dialytic removal versus diet

5 Blood Pressure versus hydration in patients on dialysis : «box plot», importance of the BCM evaluation Volume dependent high BP (natural relation) needs an UF prescription in ml (water and/or water and sodium) Volume non dependent BP vascular reactivity?, complex situation: needs more than a «weight loss/water» prescription, importance of sodium balance, nutrition, non osmotic sodium (Tietze)

6 Mortality, % Mortality % Ultrafiltration et survie en DP impact of both: the UF amount (ml) and the Na dialytic removal for patients outcome From Brown EA et al. J Am Soc Nephrol 2003 and Ates et al. Kidney Int UF amount in anuric patients 1.0 Dialytic sodium removal high Moyenne haute medium low UF > 750 ml/day UF < 750 ml/day Time, months Time, months Sodium and fluid: the «assassins» Importance of the UF «quality»: not only free water (AQ1) but also coupled (small pores) sodium and water

7 Volume control in PD patients, ultrafiltration and sodium removal Optimizing PD prescription for volume control: the importance of varying dwell time and dwell volume. M Fischbach et al. Pediatr Nephrol 2014 Ultrafiltration (ml; AQ1+Small pores) 1) AQ1, solute free water 2) Small pores, solute coupled water Pressure gradients Convective process Sodium removal (Small pores) Coupled water (convective; drag+lag) Diffusion gradient Diffusion distance (ratio area/fill)

8 Transport across the Peritoneum Rippe B et al. Kidney Int 40, Ultrasmall pores, aquaporins : radius < 3 Å (water selectivity, free water) - the most numerous, transcellular pathway : endothelial cell - 50 % UF : effectiveness of glucose as an osmotic agent despite its small size (crystalloid osmosis) - explains sodium sieving (dip in NaD) 2. Small pores : radius Å (water + solutes: coupled water) - 1/10000 AQ1, paracellular pathway (interendothelial clefts) - 50 % UF : hydrostatic + colloid/oncotic osmotic forces 3. Large pores : very rares pores, usually restricted amount of UF, large solutes (number impacted by inflammation status)

9 UF : AQ1 (40/50%) + small pores (60/50%) large pores (negligible) Rippe B et al. Kidney Int 40, 1991 from Coester AM et al. NDT plus 2, 2009

10 Pressure gradients across the peritoneal membrane during dialysis Capillary hydrostatic perfusion pressure Colloïd oncotic pressure (albumine) Back filtration UF Filtration Peritoneal Cavity UF, BP/vaso activity UF, Crystalloid osmotic pressure (glucose) Intraperitoneal pressure (IPP)

11 UF : pressure gradients across the peritoneal membrane during a dialysis exchange from Coester AM et al. NDT plus 2, 2009 Hydrostratic capillary pressure (vascular tonus) : inter/intraindividual variability; «pressure wave/vasodilatation» and PDF bio (in)compatibility Pro Hydrostratic capillary pressure (+17 mmhg) Transcapillary osmotic gradient (cristalloid peritoneal osmotic pressure minus plasma osmotic pressure) + 24 mmhg (1.36 %) +42 mm Hg (3.86 %) disappearance over time Contra Capillary osmotic colloid pressure (-21 mmhg) Intraperitoneal pressure (IPP (- 9/8 mmhg) Total (maximum) pro + 41 to to +29 contra - 30

12 Quantification of free water transport during the peritoneal equilibration test Cnossen TT, Smit W, Konings CJAM, Kooman JP, Leunissen KM and Krediet R. Perit Dial Int 2009; 29: Osmotically induced water transport (osmotic and oncotic «forces») occurs : through small pores (coupled water) and through AQ1 (free water) and is especially marked during the first hour of a dwell (hypertonic) and correlates well with the D/P sodium UF = (free water) + (coupled Na water) with the assumption that lymphatic/tissular absorption and diffusion of sodium are small over the exchange (short dwell), and that coupled Na water = amount of Na transported / plasma Na concentration

13 AQ1 small pores

14 Sodium sieving (NaD): early in dwell «small pores function impact on AQ1function» small solute transport rate, glucose conductance e a r l y An absent or decreased sodium dip can be due to 1) decreased Aquaporin (AQ1) function but can also be due to 2) a fast diffusive transport (through the small pores). Evaluation of peritoneal membrane characteristics: a clinical advice for prescription management by the ERBP working group Wim van Biesen et al Nephrol Dial Transplant (2010) 25:

15 Importance of the glucose conductance : fill volume/ dwell time, osmotic agent (type/concentration) and exchange permeability (PSA) «small pores function impact on AQ1function»

16 Threefold peritoneal test of osmotic conductance, ultrafiltration efficiency, and fluid absorption Waniewski J, Paniagua R et al. Perit Dial Int 2013; 4(vol 33): Osmotic conductance ml/min over mmol/l gradient UF Efficiency ml/glucose absorption glucose conductance or metabolic cost of UF

17 Peritoneal dialyis: from bench to bedside. Krediet R. Clin Kidney J 2013; 6: UF failure occurs in 43 % of patients (Davies S, Kidney Int 2004) caused by a less effective osmotic gradient, that is the osmotic conductance (AQ 1 ) to glucose (reflection coefficient=pores capacity, and UF coefficient=numbers of pores), ml/min UF for glucose in mmolml as mean concentration/absorption/gradient but is also glucose diffusion via the small pores (peritoneal small solute transport rate)

18 Dialytic (PD) sodium removal: small pores, convection and diffusion 1. Small pores : PSA recruited/available (fill volume) 2. Convective transport : coupled with water (drag/lag) 3. Diffusive gradient (sodium intake/nad) : Na plasma - NaD 4. Fill volume of dialysate (Cl=D/PxV), that is the volume of diffusion (and membrane recruitment, «full» dialyzer, more small pores) 5. Ratio PSA/volume, distance of diffusion: permeability of the exchange 6. Diffusion time: dwell time 7. More? Electrokinetic?

19 Determinants of sodium removal with tidal automated peritoneal dialysis. Domenci A et al. Adv Perit Dial. 2012; 28:16-20 Removal of sodium correlated weakly with UF in tidal APD and showed wide inter-patient variability Dialytic sodium removal should be measured rather than roughly estimated from UF (AQ1, only water and small pores, solute diffusion and convective solute coupled water)

20 Time-dependent associations between total sodium removal (TSR) and mortality in patients on peritoneal dialysis Dong J et all. Pert Dial Inter 2011, TSR, sodium removal is largely dependent from diet and nutrition parameters +++ (Napl) A high TSR remained predictive of low risk of death even after RRF and other covariates were included in the Cox regression model Notably, the high TSR observed is the result of higher peritoneal sodium removal: TSR was doubled in high TSR group that seen in low TSR group (0;96 versus 1;99 gramme per session), even though ultrafiltration was only 30% greater, dissociation+++

21 Designing a Low Sodium Dialysate: the impact of diffusion Napl-NaD Rippe et al, PDI 2004;24:10-27 Importance of the diffusive gradient Napl/NaD Small pores recruitment (fill volume optimization) Dwell time: not too short, 120/240min

22 How to achieve a low sodium dialysate Manufactured PDFs with low sodium (need for «more» osmotic agent : more glucose!) Dilution (with sodium free water/aq1) of the infused PDF : role of the intraperitoneal residual volume Ultrafiltration exchange Short/small cycle AQ1 water,hemoconcentration Not «fully drained», too low IPP Purification exchange Long/large cycle Small pores water, solute coupled water by diffusion gradient Napl/NaD

23 Optimizing PD prescription for volume control: the importance of varying dwell time and dwell volume. M Fischbach et al.pediatr Nephrol 2014 Hemodialysis Peritoneal Dialysis Ultrafiltration (ml) Sodium (Na) removal Water removal by filtration (iso-osmotic, isonatric, via a pressure gradient) 80 % by convection (UF) 20 % by diffusion (NaPl NaD gradient) 50 % via aquaporin 1 (osmotic gradient): sodiumfree UF, early in dwell 50 % via small pores, transport of water and solutes (concentration and pressure gradient), coupled UF, later in dwell Mainly via small pores, coupled and by diffusion (NaPl-NaD gradient) Body weight loss: 1kg 1L: 80% water and Na 1L : only 50% water and Na NaPl: plasma sodium concentration ; NaD: dialysate sodium concentration ; UF: ultrafiltration

24 Conflicting goals of a peritoneal dialysis prescription. Fischbach M et al, PDI 2000; 20:603-6 Which fill volume for which goal? clinical tolerance : «small» fill volume ultrafiltration capacity : «small» fill volume (low IPP) purification capacity : «large» fill volume (the «dialyzer») Which dwell time for which goal? - ultrafiltration (maintained osmotic gradient) : «short» dwells - purification (urea/phosphate/na) : «long» dwells Ultrafiltration and/or purification : «small or large», «short or long» not a unique prescription, importance of varying dwell time and fill volume

25 Effect of fill volumes on PSA recruitment : Ao/ x increased significantly, +21 %, from to , as the fill volume was raised from 800 to 1400 ml/m² BSA. A further increase to ml/m² did not result in any significant change of Ao/ x, (N=8) Fischbach M, Haraldsson B, JASN 2001; % «more dialyzer», PSA «fully» recruited only at 1400/1500 ml/m P< Fill volume (ml/m²)

26 Ao/ x/cm²/cm/1.73m² Effect of posture on PSA recruitment : Ao/ x fell significantly when the patients were standing compared to the value obtained in a supine position (N=6) using the same fill volume 1000 ml/m² *P< * SUPINE UPRIGHT Fischbach M, Haraldsson B, JASN 2001;

27 Evaluation of peritoneal membrane characteristics: a clinical advice for prescription management by the ERBP working group Wim van Biesen et al. NDT 2010; 25: Use larger volumes rather than more dwells (be aware of sodium sieving when using «too» short dwells) When negative UF (low UF) is registered, shortening the dwell time rather than increasing glucose concentration is advocated. Fill volume can potentially influence the «exchange/membrane permeability»: using «too low» fill volumes can falsely induce the impression of a fast transporter status (exchange permeability)

28 Fill volume, membrane recruitment, geometry/distance of diffusion and exchange permeability Plasma Plasma Dialysate Dialysate Fill volume: 1000 ml/m 2 Fill volume: 1500 ml/m 2

29 Of mice and men, a matter of scale : area/volume, diffusion distance, exchange permeability Mouse Rat Man Infant Weight 27 gr 300 gr 70 kg 5 kg PSA (cm²) Fill volume (ml) / /250 Area/volume /5.6 26/10.6 Time to D/P = 0.7 (min) Exchange permeability Time to V max (4 % gl) (min) /? less 60/ /hypo 60/120 PSA (cm²/kg) / / (cm²/m²) / / Modified from Rippe B, PDI 2009,S32-35

30 Fill volume : PSA recruitment more pores (small pores) more distance of diffusion (preservation from too rapid a glucose loss) Endothelium Mesothelium Peritoneal cavity dialysate Sodium Diffusion(Napl>NaD) Convection (drag+lag) Volume and Distance of diffusion Glucose Diffusion gradient Crystalloid osmotic gradient macromolécu les Small pore AQ1 Small pore crystalloid osmosis colloid osmosis pressure gradient concentration gradient larger fill volume : PSA recruitment and enhanced volume/distance of diffusion

31 the small pores (peritoneal small solute transport rate/permeability) and PSA recruitment From blood to dialysate: more small pores more exchanges, especially enhanced diffusive process for the uremic toxins, small solute transport rate as peritoneal permeability assessment (urea Na) From the dialysate to the blood: more small pores more exchanges, diffusive gradient (glucose) and volume/distance of diffusion (large fill volume) convective gradient (IPP)

32 Automated peritoneal dialysis prescriptions for enhancing sodium and fluid removal: a predictive analysis of optimized, patientspecific dwell times for the day period A. Akonur, S. Guest, JA Sloand, JK. Leypoldt. Perit Dial Int 2012; 3: standard Therapy % 5hrs Therapy 2 2x (2.27% 7hrs) Therapy 3 14hr, ico Therapy % 5hrs and 9hr, ico 24-hr NaR, mmol 24-hr UF, ml Importance of varying dwell time to avoid dialysate reabsorption (back filtration): adapted day dwell

33 Determination of the APEX time and the PPT (phosphate purification time), D/P = 0.6. Example ( 2 years ) : APEX = 36 minutes and PPT = 154 minutes. Normal values : APEX 18 to 71 minutes, PPT 105 to 238 minutes Fischbach M. PDI 1998 D/D0 or D/P A P E X 2 to 4 x longer P P T

34 «long» dwell time in PD - Risk of reduced total amount of UF, but less «free water» (time dependent cristalloid osmotic gradient loss), and more coupled water - achieved acceptable urea purification - appropriated for purification of solute which are more dwell time related (creatinine;phosphate;sodium) and coupled water

35 «conventional APD prescription»is since 1980/1985, (Kesaviah P) based on «total dialysate volume per session», with only the possibility of «the repetition» of the same exchanges/cycles: 1) same dwell volume, 2) same dwell time DPA conventional, limiting prescription, «old fashion»?

36 Which Fill volume - Which Dwell-time : Not a unique choice short (and small)? UF favored large (and long? Purification favored APD «conventional» APD «adapted» adapted interest of sequentially short and longer dwell-time exchanges, and small and larger fill volume exchanges

37 Prescription parameters of conventional or adapted (optimized) CCPD (manually performed) Conventional CCPD Adapted CCPD Number of exchanges 5 5 Duration of session Dwell volume Dialysate tonicity (dextrose %) 5x2 h = 10 h 5 x 800 ml/m² = 4000 ml/m² 5 x mixed half Iso (1.36) and half hyper (3.86) 2x APEX Time (35-45 min) 3 x Purification Time ( min) = 10 h 20 min (9 h h 55) 2 x 600 ml/m² 3 x 1000 ml/m² = 4200 ml/m² = 4200 ml/m² 2 x hyper (3.86) 3 x iso (1.36) Fischbach M. Advances in Perit Dial 1994

38 Efficiency of adapted CCPD vs. conventional CCPD: lower metabolic cost (UF/absorbed Glu) and improved phosphate purification Conventional CCPD Adapted CCPD UF ml UF/G ml/gr * * D/P phosphate * * K P ml/min/kg * * Protein intake (g/kg/day) Calcium carbonate (mg/kg) Phosphate plasma (mmoll) * * *: p<0.01 Fischbach M. Advances in Perit Dial1994

39 Determination of the APEX time and the PPT (phosphate purification time), D/P = 0.6 Normal values : APEX 18 to 71 minutes, PPT 105 to 238 minutes Fischbach M. PDI ,2 D/D0 or D/P 1 0,8 0,6 0,4 0, APEX PPT D/D0 glucose D/Purea D/Phosphate Les Hô p ita ux U niversita ires

40 sequential ultrafiltration, adapted APD : small fill volume, short dwell time (isotonic dialysate) Improved UF related to a low IPP/IPV and a preserved glucose osmotic gradient (isotonic dialysate), More free water than sodium extraction, a risk or a chance Lower metabolic cost (ml of UF/gr of absorbed glucose)? Change in diffusion gradient (hemoconcentration/dilution of the following dialysate) with an impact on purification sequence?

41 Sequential purification, adapted APD : large fill volume, long dwell time (isotonic dialysate) More volume, more time, more membrane: diffusion gradient PSA recruitment: importance of small pores (coupled water) Enhanced diffusion volume (urea, Na) Enhanced diffusion time (phosphate) Effect of the intraperitoneal residual volume (diffusive gradient?)

42 Ultrafiltration (UF; ml/day): increased with APD-A, enhanced osmotic conductance N = 19 APD-C APD-A 1000 Mean ± SD 656 ± ± 358.3* Min Max Number of pairs 49 Ultrafiltration, ml/day * p value < 0.05 (0.023) 400 APD-C APD-A * Significant p<0.05

43 A-APD : lower metabolic cost, more UF per gr of glucose UF/Deliv erd Glucose (ml/g) * 2 APD-C APD-A * Significant p<0.05 N = 19 APD-C APD-A Mean ± SD 3.64 ± ± 1.97 Min / Max 0.85 / / 8.62 Number of pairs 48 p value < 0.05 (0.0109) Delivered Glucose = [(total volume infused) / (total volume of all solutions hung)] x (total CHO of all solutions hung)

44 Dialytic sodium removal (mmol/day): improved with APD-A sodium dialytic removal, mmol/day APD-C APD-A * Significant p<0.01 * + 90%!,? N = 19 APD-C APD-A Mean ± SD ± ± 52.00* Min / Max / / Number of pairs 47 p value < 0.01 (0.01)

45 Arterial blood pressure: lowered BP under APD-A 160 Systolic Blood Pressure 90 Diastolic blood pressure * mm Hg 140 * mm Hg APD-C APD-A 70 APD-C APD-A * Significant p<0,05 * significant p<0.05 Mean blood pressure 120 MAP = PAd + PP/3 mm Hg * 90 APD-C * Significant p<0,01 APD-A

46 Dialytic sodium removal (mmol/day): improved with APD-A sodium dialytic removal, mmol/day APD-C APD-A * Significant p<0.01 * + 90%!,? N = 19 APD-C APD-A Mean ± SD ± ± 52.00* Min / Max / / Number of pairs 47 p value < 0.01 (0.01)

47 Time-dependent associations between total sodium removal (TSR) and mortality in patients on peritoneal dialysis Dong J et all. Pert Dial Inter 2011, TSR, sodium removal is largely dependent from diet and nutrition parameters +++ (Napl) A high TSR remained predictive of low risk of death even after RRF and other covariates were included in the Cox regression model Notably, the high TSR observed is the result of higher peritoneal sodium removal: TSR was doubled in high TSR group that seen in low TSR group (0;96 versus 1;99 gramme per session), even though ultrafiltration was only 30% greater, dissociation+++

48 Peritoneal residual volume induces variability of ultrafiltration with icodextrin Akonur A, Holmes CJ, and Leypoldt JK. Perit Dial Int 2014;234(1):95-9 Peritoneal residual volume have a more profond effect on UF with icodextrin use than with glucose use. This phenomenon is attributed to a differential effect of V R on oncotic, rather than osmotic, pressure between the peritoneal cavity and plasma

49 Volume control with A-APD, impact of the sequences 1) First sequence Ultrafiltration favored : AQ1 sodium free water generated through the AQ1 but small IPV, therefore drained or building up an increased residual IPV a «chance» 2) Second sequence Purification favored : small pores++ increased diffusion volume, more diffusion time, higher gradient plasma (hemoconcentration: Napl ) to dialysate ( low sodium dialysate by dilution with the free water :NaD ); solute coupled water through the recruited PSA (small pores)+++ UF purification

50 Small/short exchange than large/long exchange : an optimized dialytic sequence for better diffusion gradient Napl hemoconcentration? and NaD dilution by free water retention? Exchange Hyper (500 ml/15 min) Iso (1250 ml/75 min) Residual volume urea+creat (ml) Pre Drained Post/ pre Drained Post Drained (ml) UF drained (ml) UF generated (ml) ( ) - ( ) 304 ( ) - ( ) 76 NaD (mmol/l) NaD removal (mmol/exchange) -1 29,6

51 Sequence «more» Ultrafiltration Sequence «more» Purification Sodium and Phosphatelimination First sequence (45min/1500mL)x2 «UF favored» Sodium mmol/seq + 4 +/- 2 «sodium retention» 3 days study 3 days study Second sequence (150min/3000mL)x3 «Purification favored» /-12 «sodium removal» mmol/min 0,15-0,7375 Phosphate mmol/seq - 0,469-17,71 mmol/min 0,0078 0,059

52 Adapted APD: a new concept of APD prescription: varying dwell time and dwell volume Based on a physiological approach of the exchange permeability short dwell/small fill favors ultrafiltration (water) long dwell/large fill favors blood purification (sodium and water) Taking into account the pores function aquaporins over the s/s sequence: solute free water (convection/osmotic crystalloid gradient) small pores over the l/l sequence: solute coupled water (diffusion, concentration gradient and, convection, pressure gradient)

53 Les Hô p ita ux U niversita ires Adapted APD a «simplified» bedside prescription Small fill: half the large fill Long dwell: 3-4 short dwell Hypopermeable 4x (longer session time?) Hyperpermeable 2.5/3x (more dialysate volume?) Largest fill volume «accepted» in supine position Large fill >>>>1000 ml/m 2 go up to 1500 ml/m 2 «full dialyzer» APEX time (membrane «permeability) Short dwell time Determination of the APEX time and the PPT (phosphate purification time), D/P = 0.6 Normal values : APEX 18 to 71 minutes, PPT 105 to 238 minutes Fischbach M. PDI ,2 D/D0 or D/P 1 0,8 0,6 0,4 0, APEX PPT D/D0 glucose D/Purea D/Phosphate for the same cost, more efficient

54

55 Merci

56 Adapted APD Same total volume of dialysate, no more economical costs Sequence of ultrafiltration, thereafter sequence of purification : Importance of varying dwell times and dwell volumes Importance of the order of the sequences (diffusion gradient) More peritoneal dialysis membrane, improved dialysis efficiency «good» tolerance of a larger fill volume (at rest, in supine position, overnight: APD)

57 Adapted APD Membrane recruitment that is more «pores» : importance of the small pores (solute coupled water) and UF efficiency (ml UF/gr of glucose absorbed, lowered metabolic load) Diffusion from blood to dialysate and from dialysate to blood (importance of the distance of diffusion)

58 La DAP-adaptée a permis de comprendre (redécouvrir) l impact d un cycle sur le suivant (PET test, et cycle précédent) UF = volume drainé (?) ou, UF = volume drainé + volume résiduel (?) importance de l UF (ml, ml/gr glucose absorbé et ml/min) : hémoconcentration/eau libre/aquaporines/échange court. volume résiduel et dilution du dialysat infusé : impact sur le gradient diffusif (exemple du NaD, «low sodium» physiologique selon le degré de surcharge hydrique du patient) La DPA-adaptée permet de faire précéder chaque cycle long et grand par un cycle court et petit

59 DPA-A optimisation UF/Na Cycle court/petit avant chaque cycle long : UF «free water» facilitée, drainée ou volume «résiduel» intrapéritonéal; impact sur gradiant de diffusion (Napl augmenté et NaD diminué) Cycle long/grand : temps de diffusion et volume de diffusion(gradiant de concentration), recrutement de membrane de dialyse (small pores)

60 Conclusions: UF and sodium removal Diet : sodium intake versus weight gain (water intake or food and calories) Volume control in PD: prescribe a weight loss but think not only about water (free water and/or coupled water) but also consider sodium dialytic removal (diffusion, convection) Importance of the small pores (recruitment of PSA, volume dependency) Diffusion time (dwell time) and diffusion gradient and distance of diffusion (exchange permeability)

61 L extraction sodée optimisée en DP est multifactorielle Temps de diffusion long Volume de diffusion grand Recrutement de surface péritonéale Optimisation du gradient de diffusion

62 Automated peritoneal dialysis prescriptions for enhancing sodium and fluid removal: a predictive analysis of optimized, patientspecific dwell times for the day period A. Akonur, S. Guest, JA Sloand, JK. Leypoldt. Perit Dial Int 2012; 3: Importance of varying dwell time to avoid dialysate reabsorption (back filtration): adapted day dwell

63 Time-dependent associations between total sodium removal (TSR) and mortality in patients on peritoneal dialysis Dong J et all. Pert Dial Inter 2011, TSR, sodium removal is largely dependent from diet and nutrition parameters +++ A high TSR remained predictive of low risk of death even after RRF and other covariates were included in the Cox regression model Notably, the high TSR observed is the result not only of better RRF, but also of higher peritoneal sodium removal: TSR was doubled in high TSR group that seen in low TSR group (0;96 versus 1;99 gramme per session), even though ultrafiltration was only 30% greater

64 Peritoneal small solute transport rate (PSTR) variability Individual genetic polymorphisms, AQ 1 function. Exchange membrane: PSA recruitment, capillaries perfusion, angiogenesis versus fibrosis. Differences between more pores due to increased fill volume (distance of diffusion from dialysate to blood) and more pores due to angiogenesis (inflammation/biocompatibility).

65 Do we really know the meaning of sodium removal? Editorial Comments Oelho S, Zanzhe Y, Davies S. Perit Dial Inter 2011, Higher dialytic sodium output and higher sodium input? Diffusion gradient increased (Napl increased) Larger dialysate volumes (5600/6000mL/day): more PSA, more small pores, more convective mass transport capacity (solute coupled water) More efficient membranes because of a higher osmotic conductance (a 30% increase in UF despite the same glucose exposure and transport status/pet test): diffusive process, diffusive gradient enhanced (Napl), diffusion distance enhanced (glucose disappearance), small pores/aquaporins: more coupled water (Na convection and diffusion) than free water(aq/glucose osmotic gradient)

66 the wetted membrane, the dialyzer, the number of recruited pores: large fill volume More PSA, that is more pores, overall the «workers pores», the small pores implicated in both diffusion process and convective mass transport More small pores, that is increased diffusion distance, that is potential improvement in the membrane osmotic conductance, maintained glucose osmotic cristalloid gradient, finally more UF (through the AQ1, free water) More small pores, that is increased diffusive/convective mass transport capacity, solute coupled water, water and sodium or others uremic toxins

67 Importance of the peritoneal residual volume on the «permeability of the exchange»: *pressure gradient (osmotic, oncotic) *diffusion gradient (dialysate «dilution») D/D0 or D/P

68 Improved volume control (blood pressure) under APD adapted Increased Na extraction +++ Increased UF Increased npcr (less cachexia?) : improved fluid balance (angiotensine II and inflammation)

69 Muscle wasting in chronic kidney disease : the role of the ubiquitine proteasome system and its clinical impact VR Royan, WE Mitch. Pediatr Nephrol 2008; 23: Malnutrition Volume overload Metabolic acidosis Inflammation Insuline resistance (PTH) GH-IGF1 axis anomalies Cachexia in uremic patients : loss of protein stores, muscle wasting, growth impairment : ATP-dependent, ubiquitin-proteasome system

70 Improved npcr with APD-A 1.4 npcr, g/kg/day * 0.8 APD-C * Significant p<0.05 APD-A N = 19 APD-C APD-A Mean ± SD 1.10 ± ± 0.25* Min / Max 0.56 / / 2.04 Number of pairs 45 p value < 0.05 (0.044)

71 Tendency to an increased Lean Body Mass (Kg) 50 Lean body mass, kg * 30 APD-C * p>0.05 APD-A N = 19 APD-C APD-A Mean ± SD ± ± 9.94 Min / Max / / Number of pairs 47 p value NS (0.067)

72 Understanding discrepancies in Peritoneal Equilibration Test Results BF Prowant, HL Moore, R Khanna. PDI 2010, Vol 30, n 3: IPR Volume

73 The concept of adapted APD prescription The beneficial influence on the effectiveness of APD of varying the dwell time (short/long) and fill volume (small/large). A French Study. Michel Fischbach, Belkacem Issad, Vincent Dubois, Redouane Taamma. Perit Dial Inter 2011;31(4):450-8 same costs, more efficient - Tolerance: first sleep, thereafter fill large volume - Optimized purification : urea, creatinine, increased dialytic phosphate removal - Optimized UF and sodium removal: impact on blood pressure, volume control - Reduced metabolic cost to achieve ultrafiltration (and purification) Long term outcome for the patient: improved volume control, less protein wasting

74 The concept of Adapted APD : How to prescribe Fill volume adapted «individually», under intraperitoneal pressure control (small 750 ml/m² and larger 1500 ml/m²); IPP <15-18 cm Dwell time adapted «individually», short dwell (APEX time: min) and longer dwell (3 to 4 times APEX time: min) First sequence, UF favored : short dwell, small fill Second sequence, toxins removal favored : longer dwell, larger fill Evaluation of the patient, to adapt individually the prescription : more UF or more purification? Determination of the APEX time and the PPT (phosphate purification time), D/P = 0.6 Normal values : APEX 18 to 71 minutes, PPT 105 to 238 minutes Fischbach M. PDI ,2 D/D0 or D/P 1 0,8 0,6 0,4 0, APEX PPT D/D0 glucose D/Purea D/Phosphate Les Hô p ita ux U niversita ires

75 Les Hô p ita ux U niversita ires Adapted APD a «simplified» bedside prescription Small fill: half the large fill Long dwell: 3-4 short dwell Hypopermeable 4x (longer session time?) Hyperpermeable 2.5/3x (more dialysate volume?) Largest fill volume «accepted» in supine position Large fill >>>>1000 ml/m 2 go up to 1500 ml/m 2 «full dialyzer» APEX time (membrane «permeability) Short dwell time Determination of the APEX time and the PPT (phosphate purification time), D/P = 0.6 Normal values : APEX 18 to 71 minutes, PPT 105 to 238 minutes Fischbach M. PDI ,2 D/D0 or D/P 1 0,8 0,6 0,4 0, APEX PPT D/D0 glucose D/Purea D/Phosphate for the same cost, more efficient

76 Which Fill volume : large or small? Which Dwell-time : long or short? APD «conventional» APD «for more» adapted same costs but...more efficient

77 Conflicting goals of a peritoneal dialysis prescription. Fischbach M et al, PDI 2000; 20:603-6 Which fill volume for which goal? clinical tolerance : «small» fill volume ultrafiltration capacity : «small» fill volume (low IPP) purification capacity : «large» fill volume (the «dialyzer») Which dwell time for which goal? - ultrafiltration (maintained osmotic gradient) : «short» dwells - purification (urea/phosphate/na) : «long» dwells Ultrafiltration and/or purification : «small or large», «short or long» not a unique prescription, old fashion repetition of the same fill/dwell or adapted sequences (UF/purification)

78 Relationship between body size, fill volume, and mass transfer area coefficient in peritoneal dialysis. Kesaviah P, Emerson PF, Vonesh EF, Brandes JC. JASN 1994,4(10): positive relation between fill volume and clearance : K urea = D/PxV, more valid for urea (volume dependency) than for phosphate (time dependency) Peak volume : (risk for retrofiltration ; high IPP) Fill volume and dialytic efficiency (MTAC) : PSA recruitement; «wetted» membrane; more «pores» (small pores: coupled solute and water removal) +++

79 Sequence «more» Ultrafiltration Sequence «more» Purification Sodium and Phosphatelimination First sequence (45min/1500mL)x2 «UF favored» Sodium mmol/seq + 4 +/- 2 «sodium retention» 3 days study 3 days study Second sequence (150min/3000mL)x3 «Purification favored» /-12 «sodium removal» mmol/min 0,15-0,7375 Phosphate mmol/seq - 0,469-17,71 mmol/min 0,0078 0,059

80 Importance of the peritoneal residual volume on the «permeability of the exchange»: *pressure gradient (osmotic, oncotic) *diffusion gradient (dialysate «dilution») D/D0 or D/P

81 Threefold peritoneal test of osmotic conductance, ultrafiltration efficiency, and fluid absorption Waniewski J, Paniagua R et al. Perit Dial Int 2013; 4(vol 33): Results : the osmotic conductance of glucose was 0.067±0.042 (milliliters per minute divided by millimoles per milliliter), the ultrafiltration effectiveness of glucose was 16.77±7.97 ml/g of absorbed glucose, and the peritoneal fluid absorption rate was 0.94±0.97 ml/min (if estimated concomitantly with osmotic conductance) or 0.93±0.75 ml/min (if estimated concomitantly with ultrafiltration effectiveness). These fluid transport parameters were independent of small-solute transport characteristics, but proportional to total body water estimated by bioimpendance.

82 Peritoneal small solute transport rate (PSTR) High PSTR has been linked to worse survival (Brimble KS et al, JASN 2006) and bad growth in children (Schaefer F. et al, JASN 1999; The Mid European Pediatric Peritoneal Study Group : peritoneal transport properties and dialysis dose affect growth and nutritional status in children on chronic peritoneal dialysis.) Dialysate IL-6 concentration, representing local intraperitoneal inflammation, is the most significant known predictor of PSTR, but does not determine patient survival (Lambre M. et al, JASN 2013) Attention to membrane function (membrane permeability and exchange permeability) in dialysis prescription is important for patient survival.

83 Growth in very young children undergoing chronic peritoneal dialysis Rees L et al. for the international Pediatric Peritoneal Dialysis Network (IPPN) registry. J Am Soc Nephrol 2011; 22: Among the children followed prospectively for at least 6 months, lenght SDS did not change in children on conventional solutions (-0.06±1.96 SDS/year, NS), whereas significant catch-up growth was observed in those dialyzed with biocompatible PD fluid (+0.52±1.82 SDS/year) (supplemental Fig.2)

84 Time-dependent associations between total sodium removal (TSR) and mortality in patients on peritoneal dialysis Dong J et all. Pert Dial Inter 2011, A high TSR remained predictive of low risk of death even after RRF and other covariates were included in the Cox regression model Notably, the high TSR observed is the result not only of better RRF, but also of higher peritoneal sodium removal: TSR was doubled in high TSR group that seen in low TSR group (0;96 versus 1;99 gramme per session), even though ultrafiltration was only 30% greater TSR is largely dependent from diet and nutrition parameters +++ (Napl «able» for dialytic removal)

85 Peritoneal residual volume induces variability of ultrafiltration with icodextrin Akonur A, Holmes CJ, and Leypoldt JK. Perit Dial Int 2014;234(1):95-9 Peritoneal residual volume have a more profond effect on UF with icodextrin use than with glucose use. This phenomenon is attributed to a differential effect of V R on oncotic, rather than osmotic, pressure between the peritoneal cavity and plasma

86 Designing a Low Sodium Dialysate: the impact of diffusion Napl-NaD Rippe et al, PDI 2004;24:10-27

87 A-APD, impact of the sequences UF/purification on the sodium removal 1) First sequence Ultrafiltration : only isotonic dialysate applied, not only or limited amount of free water, drained or residual intraperitoneal volume «constitution» 2) Second sequence Purification : increased diffusion volume, more small pores, more diffusion time, higher gradient plasma to dialysate, low sodium dialysate by dilution into residual peritoneal volume related to the first sequence