mini review
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Increasing sodium removal on peritoneal dialysis: applying dialysis mechanics to the peritoneal dialysis prescription Michel Fischbach1, Claus Peter Schmitt2, Rukshana Shroff3, Ariane Zaloszyc1 and Bradley A. Warady4 1
Service de Pédiatrie 1, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France; 2Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany; 3Renal Unit, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK; and 4Division of Pediatric Nephrology, Children’s Mercy Hospital, Kansas City, Missouri, USA
Optimal fluid removal on peritoneal dialysis (PD) requires removal of water coupled with sodium, which is predominantly achieved via the small pores in the peritoneal membrane. On the other hand, free-water transport takes place through aquaporin-1 channels, but leads to sodium retention and over hydration. PD prescription can be adapted to promote small pore transport to achieve improved sodium and fluid management. Both adequate dwell volume and dwell time are required for small pore transport. The dwell volume determines the amount of “wetted” peritoneal membrane being increased in the supine position and optimized at dwell volumes of approximately 1400 ml/m2. Diffusion across the recruited small pores is time-dependent, favored by a long dwell time, and driven by the transmembrane solute gradient. According to the 3-pore model of conventional PD, sodium removal primarily occurs via convection. The clinical application of these principles is essential for optimal performance of PD and has resulted in a new approach to the automated PD prescription: adapted automated PD. In adapted automated PD, sequential shortand longer-dwell exchanges, with small and large dwell volumes, respectively, are used. A crossover trial in adults and a pilot study in children suggests that sodium and fluid removal are increased by adapted automated PD, leading to improved blood pressure control when compared with conventional PD. These findings are not explained by the current 3-pore model of peritoneal permeability and require further prospective crossover studies in adults and children for validation. Kidney International (2016) j.kint.2015.12.032
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KEYWORDS: coupled water; dwell time; dwell volume; free water; peritoneal dialysis prescription; sodium removal ª 2016 Published by Elsevier, Inc., on behalf of the International Society of Nephrology
Correspondence: M. Fischbach, Service de Pédiatrie 1, Centre Hospitalier Universitaire Hautepierre, Avenue Molière, 67098 Strasbourg Cedex, France. E-mail: [email protected] Received 18 August 2015; revised 28 November 2015; accepted 11 December 2015 Kidney International (2016) -, -–-
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olume control is increasingly recognized as a major determinant of dialysis adequacy.1 Indeed, during the last decade, the definition of peritoneal dialysis (PD) adequacy based on solute removal parameters such as urea kinetics (Kt/V) alone has been questioned. Despite increasing the urea dialysis dose by 30%, the morbidity and mortality of adult patients on chronic PD has not improved.2,3 In contrast, fluid status and the capacity for fluid removal have been shown to predict patient outcome in several studies.4,5 Sodium and water retention is common in PD patients: an increased ratio of extracellular water to total water has been documented by bioimpedance spectroscopy in >50% of adult PD patients.6 Both optimized ultrafiltration and optimized dialytic sodium removal are together associated with a reduction in patient mortality.7,8 Whereas hypervolemia in patients on PD is primarily the result of the loss of residual renal function, it is also correlated with peritoneal membrane permeability for solutes such as glucose and sodium.6 The achieved ultrafiltration (UF) is determined from the balance between the delivered and the drained dialysate and is used as a clinical definition of the dialytic water balance.1 Importantly, dialytic sodium removal (DSR) should be measured rather than estimated from the achieved UF,9 as the DSR is the result of peritoneal absorption (composed of direct lymphatic absorption and absorption into interstitial tissues, such as the peritoneal membrane), and primarily convective transport, with a small contribution of diffusive mass transport.1,10,11 The DSR also changes with modification of dietary sodium intake and is not strictly correlated with changes in UF.12 This dynamic, dissociated process of PD water and sodium transport limits the accuracy of estimating sodium transport from fluid removal. To optimize the PD prescription in terms of sodium and fluid management, it is important for clinicians to understand the impact of varying dwell time and dwell volume on the DSR,13 and to have a working knowledge of the 3-pore model of peritoneal membrane transport. The principles of dialytic water balance and how varying dwell time and dwell volume influence it is discussed extensively in other reviews.1,11,13 The 3-pore model: clinical application
The physiology of water and solute transport across the peritoneal membrane during PD is well described by the 1
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3-pore model.14 There are 3 types of pores, and their number is inversely related to their size. The ultrasmall pores, also known as endothelial aquaporin-1 (AQP-1) channels, are most abundant and are involved in sodium-free water transport driven by a crystalloid osmotic gradient created by the high dialysate glucose concentrations. The small pores, which are 10,000-fold less abundant than AQP-1 channels, allow both diffusion and convection to take place. The small pores permit small solute transport from blood to dialysate as well as from dialysate to blood. The large pores, which are a million-fold less abundant than AQP-1 channels, facilitate convective mass transport, but also leakage of macromolecules into the peritoneal cavity. Their role in the determination of the total amount of UF is negligible. Their function is increased by inflammation.1 Finally, the lymphatic route is responsible for fluid, solute, and macromolecular reabsorption. The small pore function manifests in the permeability of the peritoneal membrane during the peritoneal dialysis exchange, as is routinely analyzed through performance of the peritoneal equilibrium test.15,16 The small pores facilitate solute-coupled water movement driven by diffusive and convective mass transport. Solute (urea, glucose) removal across the small pores is mainly a diffusive process determined by the number of small pores present in the membrane and recruited by the dwell volume, as well as by the diffusion gradient and the diffusion time (Figure 1).10,11,13–15 Osmotic conductance drives the transport of free water across the AQP-1 channels and is counteracted by absorption of glucose via the small pores, the latter resulting in a time-dependent loss of the crystalloid osmotic gradient.1,15,17,18 Hence, it is the glucose diffusive process via the small pores that affects the ability of AQP-1 channels to produce free water. The total UF, and thereby the weight loss achieved in PD, is in turn the sum of free water (AQP-1) and coupled-water (small pore) removal. The transport process of water and sodium during PD is a dynamic process throughout the dwell. Specifically, the contribution of free water transport to total UF is highest during the early phase of an exchange, whereas small pore– driven UF predominates beyond 60 to 90 minutes, depending on the glucose concentration and individual transporter
status.1 The coefficient of variation of total UF is only 8% applying the 3.86% peritoneal equilibrium test, whereas it has been reported as being close to 50% with the use of 2.27% peritoneal equilibrium test and presumably is highly variable with 1.36% dialysate.15 Sodium transport in peritoneal dialysis
The factors contributing to peritoneal sodium transport are less well studied than those that influence peritoneal water transport. Because dialytic sodium removal only involves the small pores (Figure 1), the amount of “wetted peritoneal membrane,” the portion of the membrane in contact with dialysate, is exceedingly important in recruiting small pores for DSR. In conventional PD, sodium is primarily transported by convection, by peritoneal absorption, and quantitatively less by diffusion.19,20 After a 6-hour dwell with a dwell volume of 2 l of 1.36% glucose solution, the fraction of sodium removed attributable to convection is 2-fold higher than that attributable to diffusion, and the sodium absorption into the peritoneal tissue and lymphatics is almost equal to the combined diffusive and convective fractions.19 As mentioned, in addition to the volume of dialysate available for diffusion and the number of small pores recruited, additional influential factors consist of the transmembrane osmotic gradient and the diffusion time.10,11,13–15 The diffusive sodium gradient is related to the plasma and dialysate (NaD) sodium concentrations. The dietary sodium intake is another important determinant of DSR and accounts for its variability.9–12 Currently, commercially available PD solutions contain NaD of 132 to 134 mmol/l, which is only slightly lower than the normal physiological sodium plasma concentration. This sodium gradient between blood and dialysate is variable over the dwell time, with an initial decrease of the NaD (sodium sieving) due to the transient predominance of free water transfer across the AQP-1 channels, presumably leading to some degree of hemoconcentration. The contribution of free water transport to total ultrafiltration during the first hour of a 3.86% glucose exchange averages 35% to 40% with large interindividual variability,21 but decreases to 20% after 4 hours due to the absorption of glucose across the peritoneal membrane. Thus, the diffusion time available for solute removal is of importance: a short dwell
Water and sodium transport across the peritoneal membrane
Ultrafiltration (AQP-1 and small pores) 1. AQP-1 (40% to 50%), solute-free water transport, by osmotic gradient 2. Small pores (50% to 60%), solute-coupled water transport, by osmotic and hydrostatic pressure gradient
Sodium transport (Small pores) 1. Convective mass transport (coupled water) 2. Diffusive mass transport (determined by diffusion gradient, volume, and time)
3. Peritoneal absorption (fluid and solutes absorbed to interstitial tissue and lymphatics)
Figure 1 | Peritoneal dialysis permeability for water and sodium: role of aquaporin-1 (AQP-1) channels and small pores. 2
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time favors UF by free water movement across AQP-1 channels; conversely, coupled-water removal via the small pores requires longer dwells;13 too long dwells with 1.36% solutions may not achieve any significant amount of sodium removal mainly due to peritoneal absorption.19,20 In turn, when a large peritoneal surface area is available for exchange (and recruitment of small pores), the NaD dipping that occurs early during the exchange can be counteracted by the diffusion of sodium from the plasma to the dialysate. Practically, DSR can be calculated by determining the amount of drained sodium minus the sodium infused during a PD session. Of note, measurement of dialysate sodium can be subject to error due to the high glucose content and osmotic strength of dialysis fluid, and needs to be carefully validated in each laboratory. There are additional factors that influence sodium removal during PD, including the peritoneal membrane integrity, with an emphasis on capillary density and perfusion, as well as the patient’s posture.22 The proportion of the peritoneal surface area recruited for exchange with a defined dwell volume is 30% higher in the supine position than in the upright position.13,22 The extent of recruited peritoneal surface progressively increases with the dwell volume and plateaus at approximately 1400 ml/m2 body surface area in children >2 years of age and adults.22,23 In children, the dwell volume is ideally prescribed in milliliters per meters squared body surface area as the peritoneal surface area correlates more closely with body surface area than with weight and permits the safe use of higher dwell volumes.13 On the other hand, sodium removal is counteracted by back-diffusion and backfiltration via the small pores (a dynamic process that occurs as the osmotic gradient changes over the course of the dwell time and convection decreases). Whereas the dwell volume, and hence the intraperitoneal pressure (IPP), is an important determinant of the amount of “wetted” membrane, it is also likely that high IPPs compromise UF through the development of tissue edema, a fall in oncotic pressure of the peritoneal tissues, and a subsequent alteration of the osmotic gradient favoring fluid reabsorption into the peritoneal capillaries.13,14 The IPP may also lead to variations in UF obtained in different individuals with the same fill volume. IPP measurement by manometry does provide an objective assessment
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of the optimal dwell volume and is more accurate than the patient’s perception of the intra-abdominal pressure.13,23 In adults on APD, a safe IPP has been determined to be 20% at a higher IPP.23 However, clinical experience and observational data suggest an increased risk for enteric peritonitis, hernia, and leak development at this level of IPP;13,24 thus, an upper limit of approximately 14 cm of H20, which corresponds to a mean dwell volume of 1400 ml/m2 appears appropriate.13 Increasing sodium removal: clinical implementation of PD mechanics
In view of the above-mentioned principles of peritoneal sodium and water transport, the performance of automated PD (APD) in the supine position and the use of an optimal dwell volume should fully exploit the small pore capacity of the peritoneal membrane for DSR.13 Increases in the dwell volume should be performed in small increments, ideally based on serial measurements of the IPP.13 The diffusive sodium transport capacity, driven by the gradient between plasma and dialysate sodium concentrations, is modified by the degree of hydration and dietary sodium intake of the patient, and the sodium removal accomplished with the preceding dwells.12 Although all commercially available PD fluids have a sodium concentration of 132 to 134 mmol/l, the use of dialysate solutions containing 115 to 126 mmol/l of sodium and increased glucose concentrations up to 2.5% (to maintain dialysate osmolality) have resulted in increased sodium removal in some adult studies.25,26 A novel technique for lowering the NaD concentration and enhancing diffusive sodium removal may be the intraperitoneal retention of free water UF generated in the previous dialysis cycle, as speculated in the concept of adapted APD (A-APD) (Figure 2). Icodextrin is an alternative osmotic agent in dialysate that also improves sodium removal. The transperitoneal absorption rate of icodextrin is much lower than that of glucose: only 40% of the icodextrin molecules are absorbed during a 12- to 14-hour dwell.27 Icodextrin-containing dialysate creates a colloid osmotic gradient inducing UF mainly via the small pores and not via AQP-1.27 Therefore, the UF is slower but more sustained, requiring longer dwell times as compared with glucose-containing PD fluids, but associated with maximal
The concept of adapted APD small/short exchange followed by large/long exchange to optimize dialytic sodium removal
Exchange favoring UF
Exchange favoring dialytic Na removal
Short/small cycle (Free water transfer via AQP-1) - Hemoconcentration - Incomplete drainage (low IPP) - Low NaD
Long/large cycle (Small pore recruitment) - Na-coupled water transport - Long diffusion time - High diffusion gradient (NaPl/NaD)
Figure 2 | The concept of adapted automated peritoneal dialysis (A-APD): a hypothesis of the involved mechanisms. AQP-1, aquaporin-1 channels; IPP, intraperitoneal pressure; NaD, dialysate sodium concentration; NaPl, plasma sodium concentration; UF, ultrafiltration. Kidney International (2016) -, -–-
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Volume (l)
3 2 1 0 0
1
2
3
4 5 Time (h)
6
7
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Figure 3 | An adapted automated peritoneal dialysis session.29 The adapted automated peritoneal dialysis procedure consists of 2 sequences of dialysis, using the same dialysate glucose concentration. Exchanges of short dwells with low dwell volumes to promote ultrafiltration are followed by exchanges of longer dwells with larger dwell volumes to favor blood purification of solutes (sodium) and uremic toxins. Suggested individual adapted automated peritoneal dialysis prescription is based on an optimized large dwell volume (in ml/m2; with intraperitoneal pressure measurement potentially being helpful in predicting patient tolerance) and a small dwell volume that is one-half of the maximum tolerated large volume; short dwell time equal to the crossing time point of the glucose (D/D0) and urea (D/P) curves on the peritoneal equilibrium test—the APEX time—and long dwell time equal to 3 to 4 times APEX time. APEX, accelerated peritoneal examination.
convective sodium removal.27 Accordingly, once-daily administration of icodextrin significantly increases DSR.27 Icodextrin dialysate is suitable for the long nocturnal dwell in continuous ambulatory PD and the long day dwell exchange in APD.27 The concept of A-APD
A session of APD is classically prescribed as a series of exchanges, each of them having the same dwell time and dialysate volume. Nevertheless, a prescription characterized by a fixed dwell time or fixed dwell volume throughout the PD treatment may not optimally meet individual patient needs.13,17,28 APD efficiency in terms of sodium and water removal may be improved by an individually adapted prescription as proposed in A-APD, a novel approach to the performance of APD in which the above-mentioned peritoneal solute and water transport mechanisms are incorporated into the prescription process.17,28,29 The A-APD procedure (Figure 3) consists of 2 different sequences of exchanges during a single PD session. The first sequence is prescribed to promote UF, using a short dwell time and a small dwell volume. The subsequent sequence is prescribed to facilitate the removal of solutes (sodium) and uremic toxins, using a long dwell time and a large dwell volume. Both the dwell time and dwell volume are determined for each patient individually: the dwell volume is prescribed in milliliters per meter squared body surface area and the dwell time is determined based on the patient’s membrane transport characteristics.1,17,28 A-APD sequences are applied using the same total amount of dialysate and the same total therapy time as for conventional APD based on clinical needs and the same total amount of prescribed glucose, same glucose dialysate concentration.29 The short dwell time in A-APD may be determined according to the transporter status obtained from the peritoneal equilibrium test, or directly assessed from the crossing time point of the glucose (D/D0) and urea (D/P) curves on the peritoneal equilibrium test, the so-called APEX (accelerated peritoneal examination) time.1,13,28 The duration of the long dwell time may, in turn, be prescribed as 3 to 4 times the 4
APEX time.28 The large dwell volume is the highest dwell volume tolerated in the supine position, not to exceed an IPP of 18 cm of H20.23 In patients with an increased risk of hernia and leakage, the IPP should be limited to 14 cm of H20.13,24 By convention, the short, small dwell volume is one-half of the large volume, thereby achieving a low IPP and relatively more free water transfer via AQP-1 channels. The sequence with the long dwell (longer diffusion time) and large volume (recruitment of wetted peritoneal membrane) exchanges favors coupled water removal via the small pores, and thus enhanced clearance of sodium and other uremic toxins such as phosphate.17,29 The free water UF in the short cycle is only partially drained by gravity due to the small dwell volume and low IPP. It is speculated that the removal of free water from plasma, as well as its retention in the abdominal cavity results in 2 important effects: a lower NaD concentration in the subsequent cycle as a result of the dilution effect caused by the presence of the retained free water, as well as hemoconcentration and an increase in plasma sodium concentration Table 1 | The concept of adapted automatic peritoneal dialysis, a teaching process of applying dialysis mechanics to the peritoneal dialysis prescription ➢ The importance of an individually adapted peritoneal prescription for dwell volume and time taking into account the availability of the peritoneal membrane surface area related to the body surface area and the patient membrane characteristics. It is reasonable to individualize dwell volume prescription by lowering the intraperitoneal pressure.13,23,24 ➢ The importance of the small pores for solute peritoneal transport (combined convective transport and diffusive transport), their recruitment dependent on the “wetted” membrane and their functional relation with the aquaporins (osmotic conductance, milliliters of ultrafiltration per gram of glucose absorbed). Importantly, dialytic sodium removal should be measured rather than estimated from the achieved ultrafiltration. ➢ The importance of the mechanics of the peritoneal dialysis prescription: a short/small exchange named “aquaporin exchange” favors ultrafiltration and a long/large exchange named “small pore exchange” favors blood purification. ➢ The potential impact of an exchange on the following exchange (the intraperitoneal residual volume; the solute diffusive gradient).
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(Figure 2). This theoretically establishes a higher concentration gradient for sodium and thus a greater diffusive flux of sodium across the small pores during a long dwell period (Figure 2). Together, we hypothesize that these divergent changes in dialysate and plasma sodium can increase sodium removal via the small pores during the long-large cycle and can potentially reduce peritoneal sodium absorption.19 The concepts that form the basis for A-APD need to be confirmed in clinical studies. In a small pilot study in adults using 1.5% glucose dialysate, the use of A-APD versus conventional APD was associated with improved UF (absolute UF and UF relative to the amount of glucose administered), solute removal (urea, creatinine, sodium, and phosphate), and blood pressure control.29 Similar findings were obtained in a small pediatric observational study conducted almost 20 years ago.17 Only now have these findings received further attention in association with the recent availability of a new generation of cyclers that permit individualization of each PD exchange. The DSR increase did not correlate with the UF increase. The physiology behind the unmatched clearance of sodium and other solutes such as urea and fluid removal12 obtained with A-APD29 is not clear and remains speculative (Figure 2). In fact, a computer simulation study reported only a 5% increase in sodium clearance and marginal improvement in UF with A-APD versus conventional PD.30 In these computer scenarios, the wetted membrane appears more important than the IPP as a function of the dwell volume. In this simulation, the UF achieved in the APD exchanges were similar from one exchange to the other, whereas in clinical practice there is a significant variability in the UF between exchanges, particularly with 1.36% glucose dialysate.15 In summary, applying the principles of dialysis mechanics to the daily PD prescription process may help achieve optimal sodium removal. Varying dwell time and dwell volume, as in A-APD, is a potential new strategy to improve sodium and volume control,17,29 but the proposed benefits of the technique need to be confirmed in clinical studies in children and adults. Optimal sodium removal by A-APD also needs to be balanced against potential risks associated with higher IPP.24 Importantly, the mechanisms of the speculated enhanced diffusive transport in A-APD remain elusive and are not readily explained by the current 3-pore model.19,20 Nevertheless, the concept of A-APD and the availability of new cycler technology to facilitate its clinical implementation will stimulate new interest among clinicians and researchers about the mechanics of PD and its translation into clinical practice across all age groups (Table 1). A French national registry (Suivi et Evaluation des Prescriptions Individualisées Adaptées [SEPIA]), an international registry (PD-improved dialysis efficiency with adapted-APD [PD-IDEA]) and a proof of concept study are ongoing. Additional data specific to children collected via the International Pediatric Peritoneal Dialysis Network may also prove informative. DISCLOSURE
All the authors declared no competing interests. Kidney International (2016) -, -–-
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REFERENCES 1. Van Biesen W, Heimburger O, Krediet R, et al. Evaluation of peritoneal membrane characteristics: clinical advice for prescription management by the ERBP working group. Nephrol Dial Transplant. 2010;25: 2052–2062. 2. Paniagua R, Amato D, Vonesh E, et al., for the Mexican Nephrology Collaborative Study Group. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol. 2002;13:1307–1320. 3. Lo WK, Ho YW, Li CS, et al. Effect of Kt/V on survival and clinical outcome in CAPD patients in a randomized prospective study. Kidney Int. 2003;64: 649–656. 4. Kircelli F, Asci G, Yilmaz M, et al. The impact of strict volume control strategy on patient survival and technique failure in peritoneal dialysis patients. Blood Purif. 2011;32:30–37. 5. Paniagua R, Ventura MD, Avila-Diaz M, et al. NT-proBNP, fluid volume overload and dialysis modality are independent predictors of mortality in ESRD patients. Nephrol Dial Transplant. 2010;25:551–557. 6. Van Biesen W, Williams JD, Covic AC, et al., for the EuroBCM Study Group. Fluid status in peritoneal dialysis patients: the European Body Composition Monitoring (EuroBCM) study cohort. PLoS One. 2011;6:e17148. 7. Ates K, Nergizoglu G, Keven K, et al. Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int. 2001;60:767–776. 8. Brown EA, Davies SJ, Rutherford P, et al., for the EAPOS Group. Survival of functionally anuric patients on automated peritoneal dialysis: the European APD Outcome Study. J Am Soc Nephrol. 2003;14:2948–2957. 9. Domenici A, Scabbia L, Sivo F, et al. Determinants of sodium removal with tidal automated peritoneal dialysis. Adv Perit Dial. 2012;28:16–20. 10. Coelho S, Yu Z, Davies S. Do we really know the meaning of sodium removal? Perit Dial Int. 2011;31:383–386. 11. Coester AM, Smit W, Struijk DG, Krediet RT. Peritoneal function in clinical practice: the importance of follow-up and its measurement in patients. Recommendations for patient information and measurement of peritoneal function. NDT Plus. 2009;2:104–110. 12. Dong J, Li Y, Yang Z, et al. Time-dependent associations between total sodium removal and mortality in patients on peritoneal dialysis. Perit Dial Int. 2011;31:412–421. 13. Fischbach M, Zaloszyc A, Schaefer B, Schmitt CP. Optimizing peritoneal dialysis prescription for volume control: the importance of varying dwell time and dwell volume. Pediatr Nephrol. 2014;29:1321–1327. 14. Rippe BA. three-pore model of peritoneal transport. Perit Dial Int. 1993;13(suppl 2):S35–38. 15. La Milia V, Pozzoni P, Virga G, et al. Peritoneal transport assessment by peritoneal equilibration test with 3.86% glucose: a long-term prospective evaluation. Kidney Int. 2006;69:927–933. 16. Nolph KD, Twardowski ZJ, Popovich RP, Rubin J. Equilibration of peritoneal dialysis solutions during long-dwell exchanges. J Lab Clin Med. 1979;93:246–256. 17. Fischbach M, Desprez P, Donnars F, et al. Optimization of CCPD prescription in children using peritoneal equilibration test. Adv Perit Dial. 1994;10:307–309. 18. Waniewski J, Paniagua R, Stachowska-Pietka J, et al. Threefold peritoneal test of osmotic conductance, ultrafiltration efficiency, and fluid absorption. Perit Dial Int. 2013;33:419–425. 19. Wang T, Waniewski J, Heimburger O, et al. A quantitative analysis of sodium transport and removal during peritoneal dialysis. Kidney Int. 1997;52:1609–1616. 20. Rippe B, Venturoli D, Simonsen O, de Arteaga J. Fluid and electrolyte transport across the peritoneal membrane during CAPD according to the three-pore model. Perit Dial Int. 2004;24:10–27. 21. Parikova A, Smit W, Struijk DG, et al. The contribution of free water transport and small pore transport to the total fluid removal in peritoneal dialysis. Kidney Int. 2005;68:1849–1856. 22. Fischbach M, Haraldsson B. Dynamic changes of the total pore area available for peritoneal exchange in children. J Am Soc Nephrol. 2001;12: 1524–1529. 23. Durand PY, Chanliau J, Gamberoni J, et al. APD: clinical measurement of the maximal acceptable intraperitoneal volume. Adv Perit Dial. 1994;10: 63–67. 24. Outerelo MC, Gouveia R. Teixeira e Costa F, Ramos A. Intraperitoneal pressure has a prognostic impact on peritoneal dialysis patients. Perit Dial Int. 2014;34:652–654.
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25. Davies S, Carlsson O, Simonsen O, et al. The effects of low-sodium peritoneal dialysis fluids on blood pressure, thirst and volume status. Nephrol Dial Transplant. 2009;24:1609–1617. 26. Nakayama M, Kasai K, Imai H, for the TRM-280 Study Group. Novel low Na peritoneal dialysis solutions designed to optimize Na gap of effluent: kinetics of Na and water removal. Perit Dial Int. 2009;29: 528–535. 27. Finkelstein F, Healy H, Abu-Alfa A, et al. Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration. J Am Soc Nephrol. 2005;16:546–554.
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28. Fischbach M, Lahlou A, Eyer D, et al. Determination of individual ultrafiltration time (APEX) and purification phosphate time by peritoneal equilibration test: application to individual peritoneal dialysis modality prescription in children. Perit Dial Int. 1996;16(suppl 1):S557–560. 29. Fischbach M, Issad B, Dubois V, Taamma R. The beneficial influence on the effectiveness of automated peritoneal dialysis of varying the dwell time (short/long) and fill volume (small/large): a randomized controlled trial. Perit Dial Int. 2011;31:450–458. 30. Öberg B, Rippe B. Is adapted APD more efficient than conventional APD? Nephrol Dial Transplant. 2015;30(suppl 3). FP574.iii265.
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Increasing sodium removal on peritoneal dialysis: applying dialysis mechanics to the peritoneal dialysis prescription Michel Fischbach1, Claus Peter Schmitt2, Rukshana Shroff3, Ariane Zaloszyc1 and Bradley A. Warady4 1
Service de Pédiatrie 1, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France; 2Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany; 3Renal Unit, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK; and 4Division of Pediatric Nephrology, Children’s Mercy Hospital, Kansas City, Missouri, USA
Optimal fluid removal on peritoneal dialysis (PD) requires removal of water coupled with sodium, which is predominantly achieved via the small pores in the peritoneal membrane. On the other hand, free-water transport takes place through aquaporin-1 channels, but leads to sodium retention and over hydration. PD prescription can be adapted to promote small pore transport to achieve improved sodium and fluid management. Both adequate dwell volume and dwell time are required for small pore transport. The dwell volume determines the amount of “wetted” peritoneal membrane being increased in the supine position and optimized at dwell volumes of approximately 1400 ml/m2. Diffusion across the recruited small pores is time-dependent, favored by a long dwell time, and driven by the transmembrane solute gradient. According to the 3-pore model of conventional PD, sodium removal primarily occurs via convection. The clinical application of these principles is essential for optimal performance of PD and has resulted in a new approach to the automated PD prescription: adapted automated PD. In adapted automated PD, sequential shortand longer-dwell exchanges, with small and large dwell volumes, respectively, are used. A crossover trial in adults and a pilot study in children suggests that sodium and fluid removal are increased by adapted automated PD, leading to improved blood pressure control when compared with conventional PD. These findings are not explained by the current 3-pore model of peritoneal permeability and require further prospective crossover studies in adults and children for validation. Kidney International (2016) j.kint.2015.12.032
-, -–-;
http://dx.doi.org/10.1016/
KEYWORDS: coupled water; dwell time; dwell volume; free water; peritoneal dialysis prescription; sodium removal ª 2016 Published by Elsevier, Inc., on behalf of the International Society of Nephrology
Correspondence: M. Fischbach, Service de Pédiatrie 1, Centre Hospitalier Universitaire Hautepierre, Avenue Molière, 67098 Strasbourg Cedex, France. E-mail: [email protected] Received 18 August 2015; revised 28 November 2015; accepted 11 December 2015 Kidney International (2016) -, -–-
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olume control is increasingly recognized as a major determinant of dialysis adequacy.1 Indeed, during the last decade, the definition of peritoneal dialysis (PD) adequacy based on solute removal parameters such as urea kinetics (Kt/V) alone has been questioned. Despite increasing the urea dialysis dose by 30%, the morbidity and mortality of adult patients on chronic PD has not improved.2,3 In contrast, fluid status and the capacity for fluid removal have been shown to predict patient outcome in several studies.4,5 Sodium and water retention is common in PD patients: an increased ratio of extracellular water to total water has been documented by bioimpedance spectroscopy in >50% of adult PD patients.6 Both optimized ultrafiltration and optimized dialytic sodium removal are together associated with a reduction in patient mortality.7,8 Whereas hypervolemia in patients on PD is primarily the result of the loss of residual renal function, it is also correlated with peritoneal membrane permeability for solutes such as glucose and sodium.6 The achieved ultrafiltration (UF) is determined from the balance between the delivered and the drained dialysate and is used as a clinical definition of the dialytic water balance.1 Importantly, dialytic sodium removal (DSR) should be measured rather than estimated from the achieved UF,9 as the DSR is the result of peritoneal absorption (composed of direct lymphatic absorption and absorption into interstitial tissues, such as the peritoneal membrane), and primarily convective transport, with a small contribution of diffusive mass transport.1,10,11 The DSR also changes with modification of dietary sodium intake and is not strictly correlated with changes in UF.12 This dynamic, dissociated process of PD water and sodium transport limits the accuracy of estimating sodium transport from fluid removal. To optimize the PD prescription in terms of sodium and fluid management, it is important for clinicians to understand the impact of varying dwell time and dwell volume on the DSR,13 and to have a working knowledge of the 3-pore model of peritoneal membrane transport. The principles of dialytic water balance and how varying dwell time and dwell volume influence it is discussed extensively in other reviews.1,11,13 The 3-pore model: clinical application
The physiology of water and solute transport across the peritoneal membrane during PD is well described by the 1
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3-pore model.14 There are 3 types of pores, and their number is inversely related to their size. The ultrasmall pores, also known as endothelial aquaporin-1 (AQP-1) channels, are most abundant and are involved in sodium-free water transport driven by a crystalloid osmotic gradient created by the high dialysate glucose concentrations. The small pores, which are 10,000-fold less abundant than AQP-1 channels, allow both diffusion and convection to take place. The small pores permit small solute transport from blood to dialysate as well as from dialysate to blood. The large pores, which are a million-fold less abundant than AQP-1 channels, facilitate convective mass transport, but also leakage of macromolecules into the peritoneal cavity. Their role in the determination of the total amount of UF is negligible. Their function is increased by inflammation.1 Finally, the lymphatic route is responsible for fluid, solute, and macromolecular reabsorption. The small pore function manifests in the permeability of the peritoneal membrane during the peritoneal dialysis exchange, as is routinely analyzed through performance of the peritoneal equilibrium test.15,16 The small pores facilitate solute-coupled water movement driven by diffusive and convective mass transport. Solute (urea, glucose) removal across the small pores is mainly a diffusive process determined by the number of small pores present in the membrane and recruited by the dwell volume, as well as by the diffusion gradient and the diffusion time (Figure 1).10,11,13–15 Osmotic conductance drives the transport of free water across the AQP-1 channels and is counteracted by absorption of glucose via the small pores, the latter resulting in a time-dependent loss of the crystalloid osmotic gradient.1,15,17,18 Hence, it is the glucose diffusive process via the small pores that affects the ability of AQP-1 channels to produce free water. The total UF, and thereby the weight loss achieved in PD, is in turn the sum of free water (AQP-1) and coupled-water (small pore) removal. The transport process of water and sodium during PD is a dynamic process throughout the dwell. Specifically, the contribution of free water transport to total UF is highest during the early phase of an exchange, whereas small pore– driven UF predominates beyond 60 to 90 minutes, depending on the glucose concentration and individual transporter
status.1 The coefficient of variation of total UF is only 8% applying the 3.86% peritoneal equilibrium test, whereas it has been reported as being close to 50% with the use of 2.27% peritoneal equilibrium test and presumably is highly variable with 1.36% dialysate.15 Sodium transport in peritoneal dialysis
The factors contributing to peritoneal sodium transport are less well studied than those that influence peritoneal water transport. Because dialytic sodium removal only involves the small pores (Figure 1), the amount of “wetted peritoneal membrane,” the portion of the membrane in contact with dialysate, is exceedingly important in recruiting small pores for DSR. In conventional PD, sodium is primarily transported by convection, by peritoneal absorption, and quantitatively less by diffusion.19,20 After a 6-hour dwell with a dwell volume of 2 l of 1.36% glucose solution, the fraction of sodium removed attributable to convection is 2-fold higher than that attributable to diffusion, and the sodium absorption into the peritoneal tissue and lymphatics is almost equal to the combined diffusive and convective fractions.19 As mentioned, in addition to the volume of dialysate available for diffusion and the number of small pores recruited, additional influential factors consist of the transmembrane osmotic gradient and the diffusion time.10,11,13–15 The diffusive sodium gradient is related to the plasma and dialysate (NaD) sodium concentrations. The dietary sodium intake is another important determinant of DSR and accounts for its variability.9–12 Currently, commercially available PD solutions contain NaD of 132 to 134 mmol/l, which is only slightly lower than the normal physiological sodium plasma concentration. This sodium gradient between blood and dialysate is variable over the dwell time, with an initial decrease of the NaD (sodium sieving) due to the transient predominance of free water transfer across the AQP-1 channels, presumably leading to some degree of hemoconcentration. The contribution of free water transport to total ultrafiltration during the first hour of a 3.86% glucose exchange averages 35% to 40% with large interindividual variability,21 but decreases to 20% after 4 hours due to the absorption of glucose across the peritoneal membrane. Thus, the diffusion time available for solute removal is of importance: a short dwell
Water and sodium transport across the peritoneal membrane
Ultrafiltration (AQP-1 and small pores) 1. AQP-1 (40% to 50%), solute-free water transport, by osmotic gradient 2. Small pores (50% to 60%), solute-coupled water transport, by osmotic and hydrostatic pressure gradient
Sodium transport (Small pores) 1. Convective mass transport (coupled water) 2. Diffusive mass transport (determined by diffusion gradient, volume, and time)
3. Peritoneal absorption (fluid and solutes absorbed to interstitial tissue and lymphatics)
Figure 1 | Peritoneal dialysis permeability for water and sodium: role of aquaporin-1 (AQP-1) channels and small pores. 2
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time favors UF by free water movement across AQP-1 channels; conversely, coupled-water removal via the small pores requires longer dwells;13 too long dwells with 1.36% solutions may not achieve any significant amount of sodium removal mainly due to peritoneal absorption.19,20 In turn, when a large peritoneal surface area is available for exchange (and recruitment of small pores), the NaD dipping that occurs early during the exchange can be counteracted by the diffusion of sodium from the plasma to the dialysate. Practically, DSR can be calculated by determining the amount of drained sodium minus the sodium infused during a PD session. Of note, measurement of dialysate sodium can be subject to error due to the high glucose content and osmotic strength of dialysis fluid, and needs to be carefully validated in each laboratory. There are additional factors that influence sodium removal during PD, including the peritoneal membrane integrity, with an emphasis on capillary density and perfusion, as well as the patient’s posture.22 The proportion of the peritoneal surface area recruited for exchange with a defined dwell volume is 30% higher in the supine position than in the upright position.13,22 The extent of recruited peritoneal surface progressively increases with the dwell volume and plateaus at approximately 1400 ml/m2 body surface area in children >2 years of age and adults.22,23 In children, the dwell volume is ideally prescribed in milliliters per meters squared body surface area as the peritoneal surface area correlates more closely with body surface area than with weight and permits the safe use of higher dwell volumes.13 On the other hand, sodium removal is counteracted by back-diffusion and backfiltration via the small pores (a dynamic process that occurs as the osmotic gradient changes over the course of the dwell time and convection decreases). Whereas the dwell volume, and hence the intraperitoneal pressure (IPP), is an important determinant of the amount of “wetted” membrane, it is also likely that high IPPs compromise UF through the development of tissue edema, a fall in oncotic pressure of the peritoneal tissues, and a subsequent alteration of the osmotic gradient favoring fluid reabsorption into the peritoneal capillaries.13,14 The IPP may also lead to variations in UF obtained in different individuals with the same fill volume. IPP measurement by manometry does provide an objective assessment
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of the optimal dwell volume and is more accurate than the patient’s perception of the intra-abdominal pressure.13,23 In adults on APD, a safe IPP has been determined to be 20% at a higher IPP.23 However, clinical experience and observational data suggest an increased risk for enteric peritonitis, hernia, and leak development at this level of IPP;13,24 thus, an upper limit of approximately 14 cm of H20, which corresponds to a mean dwell volume of 1400 ml/m2 appears appropriate.13 Increasing sodium removal: clinical implementation of PD mechanics
In view of the above-mentioned principles of peritoneal sodium and water transport, the performance of automated PD (APD) in the supine position and the use of an optimal dwell volume should fully exploit the small pore capacity of the peritoneal membrane for DSR.13 Increases in the dwell volume should be performed in small increments, ideally based on serial measurements of the IPP.13 The diffusive sodium transport capacity, driven by the gradient between plasma and dialysate sodium concentrations, is modified by the degree of hydration and dietary sodium intake of the patient, and the sodium removal accomplished with the preceding dwells.12 Although all commercially available PD fluids have a sodium concentration of 132 to 134 mmol/l, the use of dialysate solutions containing 115 to 126 mmol/l of sodium and increased glucose concentrations up to 2.5% (to maintain dialysate osmolality) have resulted in increased sodium removal in some adult studies.25,26 A novel technique for lowering the NaD concentration and enhancing diffusive sodium removal may be the intraperitoneal retention of free water UF generated in the previous dialysis cycle, as speculated in the concept of adapted APD (A-APD) (Figure 2). Icodextrin is an alternative osmotic agent in dialysate that also improves sodium removal. The transperitoneal absorption rate of icodextrin is much lower than that of glucose: only 40% of the icodextrin molecules are absorbed during a 12- to 14-hour dwell.27 Icodextrin-containing dialysate creates a colloid osmotic gradient inducing UF mainly via the small pores and not via AQP-1.27 Therefore, the UF is slower but more sustained, requiring longer dwell times as compared with glucose-containing PD fluids, but associated with maximal
The concept of adapted APD small/short exchange followed by large/long exchange to optimize dialytic sodium removal
Exchange favoring UF
Exchange favoring dialytic Na removal
Short/small cycle (Free water transfer via AQP-1) - Hemoconcentration - Incomplete drainage (low IPP) - Low NaD
Long/large cycle (Small pore recruitment) - Na-coupled water transport - Long diffusion time - High diffusion gradient (NaPl/NaD)
Figure 2 | The concept of adapted automated peritoneal dialysis (A-APD): a hypothesis of the involved mechanisms. AQP-1, aquaporin-1 channels; IPP, intraperitoneal pressure; NaD, dialysate sodium concentration; NaPl, plasma sodium concentration; UF, ultrafiltration. Kidney International (2016) -, -–-
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Volume (l)
3 2 1 0 0
1
2
3
4 5 Time (h)
6
7
8
Figure 3 | An adapted automated peritoneal dialysis session.29 The adapted automated peritoneal dialysis procedure consists of 2 sequences of dialysis, using the same dialysate glucose concentration. Exchanges of short dwells with low dwell volumes to promote ultrafiltration are followed by exchanges of longer dwells with larger dwell volumes to favor blood purification of solutes (sodium) and uremic toxins. Suggested individual adapted automated peritoneal dialysis prescription is based on an optimized large dwell volume (in ml/m2; with intraperitoneal pressure measurement potentially being helpful in predicting patient tolerance) and a small dwell volume that is one-half of the maximum tolerated large volume; short dwell time equal to the crossing time point of the glucose (D/D0) and urea (D/P) curves on the peritoneal equilibrium test—the APEX time—and long dwell time equal to 3 to 4 times APEX time. APEX, accelerated peritoneal examination.
convective sodium removal.27 Accordingly, once-daily administration of icodextrin significantly increases DSR.27 Icodextrin dialysate is suitable for the long nocturnal dwell in continuous ambulatory PD and the long day dwell exchange in APD.27 The concept of A-APD
A session of APD is classically prescribed as a series of exchanges, each of them having the same dwell time and dialysate volume. Nevertheless, a prescription characterized by a fixed dwell time or fixed dwell volume throughout the PD treatment may not optimally meet individual patient needs.13,17,28 APD efficiency in terms of sodium and water removal may be improved by an individually adapted prescription as proposed in A-APD, a novel approach to the performance of APD in which the above-mentioned peritoneal solute and water transport mechanisms are incorporated into the prescription process.17,28,29 The A-APD procedure (Figure 3) consists of 2 different sequences of exchanges during a single PD session. The first sequence is prescribed to promote UF, using a short dwell time and a small dwell volume. The subsequent sequence is prescribed to facilitate the removal of solutes (sodium) and uremic toxins, using a long dwell time and a large dwell volume. Both the dwell time and dwell volume are determined for each patient individually: the dwell volume is prescribed in milliliters per meter squared body surface area and the dwell time is determined based on the patient’s membrane transport characteristics.1,17,28 A-APD sequences are applied using the same total amount of dialysate and the same total therapy time as for conventional APD based on clinical needs and the same total amount of prescribed glucose, same glucose dialysate concentration.29 The short dwell time in A-APD may be determined according to the transporter status obtained from the peritoneal equilibrium test, or directly assessed from the crossing time point of the glucose (D/D0) and urea (D/P) curves on the peritoneal equilibrium test, the so-called APEX (accelerated peritoneal examination) time.1,13,28 The duration of the long dwell time may, in turn, be prescribed as 3 to 4 times the 4
APEX time.28 The large dwell volume is the highest dwell volume tolerated in the supine position, not to exceed an IPP of 18 cm of H20.23 In patients with an increased risk of hernia and leakage, the IPP should be limited to 14 cm of H20.13,24 By convention, the short, small dwell volume is one-half of the large volume, thereby achieving a low IPP and relatively more free water transfer via AQP-1 channels. The sequence with the long dwell (longer diffusion time) and large volume (recruitment of wetted peritoneal membrane) exchanges favors coupled water removal via the small pores, and thus enhanced clearance of sodium and other uremic toxins such as phosphate.17,29 The free water UF in the short cycle is only partially drained by gravity due to the small dwell volume and low IPP. It is speculated that the removal of free water from plasma, as well as its retention in the abdominal cavity results in 2 important effects: a lower NaD concentration in the subsequent cycle as a result of the dilution effect caused by the presence of the retained free water, as well as hemoconcentration and an increase in plasma sodium concentration Table 1 | The concept of adapted automatic peritoneal dialysis, a teaching process of applying dialysis mechanics to the peritoneal dialysis prescription ➢ The importance of an individually adapted peritoneal prescription for dwell volume and time taking into account the availability of the peritoneal membrane surface area related to the body surface area and the patient membrane characteristics. It is reasonable to individualize dwell volume prescription by lowering the intraperitoneal pressure.13,23,24 ➢ The importance of the small pores for solute peritoneal transport (combined convective transport and diffusive transport), their recruitment dependent on the “wetted” membrane and their functional relation with the aquaporins (osmotic conductance, milliliters of ultrafiltration per gram of glucose absorbed). Importantly, dialytic sodium removal should be measured rather than estimated from the achieved ultrafiltration. ➢ The importance of the mechanics of the peritoneal dialysis prescription: a short/small exchange named “aquaporin exchange” favors ultrafiltration and a long/large exchange named “small pore exchange” favors blood purification. ➢ The potential impact of an exchange on the following exchange (the intraperitoneal residual volume; the solute diffusive gradient).
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(Figure 2). This theoretically establishes a higher concentration gradient for sodium and thus a greater diffusive flux of sodium across the small pores during a long dwell period (Figure 2). Together, we hypothesize that these divergent changes in dialysate and plasma sodium can increase sodium removal via the small pores during the long-large cycle and can potentially reduce peritoneal sodium absorption.19 The concepts that form the basis for A-APD need to be confirmed in clinical studies. In a small pilot study in adults using 1.5% glucose dialysate, the use of A-APD versus conventional APD was associated with improved UF (absolute UF and UF relative to the amount of glucose administered), solute removal (urea, creatinine, sodium, and phosphate), and blood pressure control.29 Similar findings were obtained in a small pediatric observational study conducted almost 20 years ago.17 Only now have these findings received further attention in association with the recent availability of a new generation of cyclers that permit individualization of each PD exchange. The DSR increase did not correlate with the UF increase. The physiology behind the unmatched clearance of sodium and other solutes such as urea and fluid removal12 obtained with A-APD29 is not clear and remains speculative (Figure 2). In fact, a computer simulation study reported only a 5% increase in sodium clearance and marginal improvement in UF with A-APD versus conventional PD.30 In these computer scenarios, the wetted membrane appears more important than the IPP as a function of the dwell volume. In this simulation, the UF achieved in the APD exchanges were similar from one exchange to the other, whereas in clinical practice there is a significant variability in the UF between exchanges, particularly with 1.36% glucose dialysate.15 In summary, applying the principles of dialysis mechanics to the daily PD prescription process may help achieve optimal sodium removal. Varying dwell time and dwell volume, as in A-APD, is a potential new strategy to improve sodium and volume control,17,29 but the proposed benefits of the technique need to be confirmed in clinical studies in children and adults. Optimal sodium removal by A-APD also needs to be balanced against potential risks associated with higher IPP.24 Importantly, the mechanisms of the speculated enhanced diffusive transport in A-APD remain elusive and are not readily explained by the current 3-pore model.19,20 Nevertheless, the concept of A-APD and the availability of new cycler technology to facilitate its clinical implementation will stimulate new interest among clinicians and researchers about the mechanics of PD and its translation into clinical practice across all age groups (Table 1). A French national registry (Suivi et Evaluation des Prescriptions Individualisées Adaptées [SEPIA]), an international registry (PD-improved dialysis efficiency with adapted-APD [PD-IDEA]) and a proof of concept study are ongoing. Additional data specific to children collected via the International Pediatric Peritoneal Dialysis Network may also prove informative. DISCLOSURE
All the authors declared no competing interests. Kidney International (2016) -, -–-
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28. Fischbach M, Lahlou A, Eyer D, et al. Determination of individual ultrafiltration time (APEX) and purification phosphate time by peritoneal equilibration test: application to individual peritoneal dialysis modality prescription in children. Perit Dial Int. 1996;16(suppl 1):S557–560. 29. Fischbach M, Issad B, Dubois V, Taamma R. The beneficial influence on the effectiveness of automated peritoneal dialysis of varying the dwell time (short/long) and fill volume (small/large): a randomized controlled trial. Perit Dial Int. 2011;31:450–458. 30. Öberg B, Rippe B. Is adapted APD more efficient than conventional APD? Nephrol Dial Transplant. 2015;30(suppl 3). FP574.iii265.
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