Peritoneal Transport: From Basics to Bedside

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1 Review Article Peritoneal Transport: From Basics to Bedside Tao Wang, Bengt Lindholm 1 Comprehensive understanding of peritoneal solute and fluid transport is of clinical significance to nephrologists in guiding prescription of peritoneal dialysis. In this review, we discuss the basic knowledge of peritoneal transport and its relationship with the prescription of peritoneal dialysis and new peritoneal dialysis solutions. The roles of neoangiogenesis, peritoneal inflammation and changes in peritoneal hydraulic permeability, especially changes in tissue hyaluronan content and peritoneal surface layer, are also discussed. [Hong Kong J Nephrol 2003;5(2):65 72] Key words: peritoneal transport, membrane permeability, kinetics, neoangiogenesis, peritoneal surface layer!"#$%&'()%&)*+,-. /0!"12) :;<=>? %!"#$%&'()*+,-%()*+./ :7;<=%()>?!"#$%&'()*+, -./012"#34()567"#289: INTRODUCTION Peritoneal dialysis therapy is based on the understanding of how solutes and fluids are transferred across the peritoneal membrane [1 3]. Therefore, a comprehensive understanding of peritoneal solute and fluid transport is of clinical significance to nephrologists in guiding prescription of peritoneal dialysis. In this review, we discuss the basis for peritoneal transport and its relationship with peritoneal dialysis prescription and new peritoneal dialysis solutions. PERITONEAL TRANSPORT PHYSIOLOGY The kinetics of solute and fluid removal from the peritoneal cavity during peritoneal dialysis have been studied extensively, yet the precise transport pathways remain incompletely understood [4,5]. Although various mathematical models have been used to describe peritoneal transport [6 8], the simple approach shown in Figure 1 deals with the net transferred solutes and fluid, which are clinically relevant regardless of the complexity of the peritoneal membrane [9]. Solute transport Removal of uremic toxins (solutes) from the patient occurs across the peritoneal membrane by two major mechanisms: diffusion and convection [10,11]. As shown in Equation 1, the rate of solute transport by diffusion is proportional to the solute concentration difference between blood (or, more precisely, plasma water) and the dialysis fluid within the peritoneal cavity, the membrane diffusive transport coefficient (KBD), which is a lumped parameter determined by surface area, and solute permeability, which is inversely proportional to the molecular weight of the solutes [9, 12,13]. It follows that, for any specific peritoneal membrane transport characteristic, the higher the molecular weight of the solute, the lower the KBD. It is thus not difficult to understand that the removal of small solutes in peritoneal dialysis is dialysate-flowdependent since their equilibration rate is quick compared to the removal of large solutes, which is dialysis-time-dependent (Figure 2). Convective transport during peritoneal dialysis refers to solute removal as a direct result of fluid movement into and out of the peritoneal cavity [14]. The rate of convective solute transport that occurs from Institute of Nephrology, First Hospital, Peking University, Beijing, P.R. China; and 1 Divisions of Baxter Novum and Renal Medicine, Karolinska Institute, Stockholm, Sweden. Address correspondence and reprint requests to: Dr. Tao Wang, Institute of Nephrology, First Hospital, Peking University, 8 Xishiku Street, Beijing , P.R. China. Fax: (+86) ; wangt@bjmu.edu.cn Hong Kong J Nephrol October 2003 Vol 5 No 2 65

2 T. Wang, B. Lindholm Figure 1. Simple model describing peritoneal fluid and solute transport. Fluid and solute are transferred from the blood to dialysate simultaneously with the opposite transfer process. Equation 1 Blood Membrane Dialysate Qs = KBD (CB CD) + Qu S Cm Qa C Dav Qs = net transferred mass; KBD = diffusive mass transport coefficient; CB = solute concentration in blood; CD = solute concentration in dialysate; Qu = transcapillary ultrafiltration rate; S = sieving coefficient; Cm = mean tissue concentration of the solute; Qa = peritoneal fluid absorption rate (which can be estimated using the elimination rate of intraperitoneal high molecular weight substances such as albumin); C Dav = mean dialysate concentration of the solute. the blood into the dialysis solution is proportional to the transcapillary ultrafiltration rate and sieving coefficient of the peritoneal membrane. A sieving coefficient of 1 indicates no rejection of the solute by the peritoneal membrane, whereas a lower value indicates hindrance to solute transport relative to fluid movement [15]. Convective solute transport from the dialysis solution into the peritoneal tissues and blood occurs during peritoneal fluid absorption [16]. The mechanism of this process is not yet completely understood. Fluid transport by this pathway is directed out of the peritoneal cavity and includes both direct absorption into peritoneal tissues and transport into lymphatic vessels [17]. Therefore, the overall rate of peritoneal solute transport by convection is the difference between the two separate pathways, as shown in Equation 1 [6]. Fluid transport Peritoneal transcapillary ultrafiltration and peritoneal fluid absorption occur simultaneously during peritoneal dialysis [18 20]. Net fluid removal depends on the balance between these two processes [14], as shown in Equation 2 [21]. During peritoneal dialysis, significant peritoneal transcapillary ultrafiltration can be achieved only when osmotic agents are added to the dialysis solution, creating an osmotic gradient between the dialysate and blood. Peritoneal fluid absorption is mainly driven by the intraperitoneal hydrostatic pressure (IPP) [20], which is strongly dependent on the intraperitoneal dialysate volume. Equation 2 QV = LpA [(PB PD) i RT(CiB CiD)] Qa D/P ratio Sodium Low molecular weight solutes QV = change in intraperitoneal volume (the net result of peritoneal transcapillary ultrafiltration and peritoneal fluid absorption); LpA = total hydraulic permeability of the membrane; PB PD = hydrostatic pressure gradient between the blood and dialysate; i = Staverman reflection coefficient; RT (CiB CiD) = osmotic pressure gradient; Qa = fluid absorption rate (to tissues and lymphatics) High molecular weight solutes Time (hr) Figure 2. Solute transport across the peritoneal membrane as assessed by dialysate-to-plasma solute concentration ratio (D/P ratio). Due to the decrease in osmotic gradient with the prolongation of the dwell time and peritoneal fluid absorption, the intraperitoneal volume will decrease after an initial increase (Figure 3). Fluid absorption significantly decreases peritoneal dialysis efficiency [22 24]. Mactier et al found that peritoneal fluid absorption reduced the potential net ultrafiltration by % [25]. The contribution of peritoneal fluid absorption to low dialysis efficiency as regards the net 66 Hong Kong J Nephrol October 2003 Vol 5 No 2

3 Peritoneal transport Intraperitoneal volume (ml) % glucose solution 2.27% glucose solution 1.36% glucose solution Time (hr) Figure 3. Changes in intraperitoneal volume with dwell time for different glucose peritoneal dialysis solutions. removal of fluid is more significant in high transporters and when 1.36% glucose solution is used [23]. Solute clearance may also decrease accordingly, especially when the membrane transport rate is high, such as in high transporters. Mactier et al found that fluid absorption decreased urea clearance by % and creatinine clearance by % in one 6-hour exchange [25]. This suggests that prolonging the dwell time may not only worsen the fluid balance but also decrease the efficiency of small solute removal, although clearances for large molecular substances increase with dwell time [23]. Reduction in peritoneal fluid absorption may therefore provide an alternative means of augmenting the efficiency of long-dwell peritoneal dialysis. PERITONEAL MEMBRANE AND PERITONEAL TRANSPORT The importance of peritoneal transport has been increasingly recognized. There is a high variation in peritoneal transport rate among individual patients [3]. This will not only affect the choice of optimal dialysis prescription, but also patient outcome. Recent studies suggest that a patient s peritoneal transport pattern has a significant impact on clinical outcome, including patient and technique survival [26 28]. In these studies, an increased peritoneal transport rate was associated with lower patient survival. A high peritoneal transport rate is associated with increased peritoneal small solute transport and therefore increased peritoneal glucose absorption, resulting in a faster decrease in osmotic gradient. A high transport rate is also associated with increased peritoneal fluid absorption. These two processes significantly decrease peritoneal fluid removal and increase the risk of fluid overload [28]. Because of the negative impact of a high peritoneal solute transport rate on fluid removal, a high peritoneal solute transport rate is associated with a decreased removal of rapidly equilibrating solutes such as urea, and especially of sodium [28]. The net removal of these solutes is mainly dependent on net fluid removal. Thus, patients with a high peritoneal solute transport rate are, in fact, characterized by a low net removal of small solutes. Unfortunately, it is not uncommon for peritoneal membrane permeability to increase with time on peritoneal dialysis, resulting in decreased peritoneal ultrafiltration in long-term peritoneal dialysis patients [29,30]. Although glucose has been blamed for the changes in the function of the peritoneum, the exact mechanism of increased peritoneal solute transport rate is unclear. Understanding the pathophysiology of increased peritoneal transport rate may thus be very important for the success of long-term peritoneal dialysis treatment. Neoangiogenesis and increased peritoneal transport rate An increased peritoneal solute transport rate may be due to increased peritoneal vascular surface area, either functionally (e.g. by opening previously closed capillaries) or anatomically (by increasing the number of new capillaries) [5]. This theory has been supported by two observations: that long-term peritoneal dialysis may result in an increase in the thickness of the peritoneal membrane and neoangiogenesis in the peritoneal membrane [31 33]; and that the concentration of vascular endothelial growth factor (VEGF), the most important growth factor involved in neoangiogenesis, in the dialysate was correlated with peritoneal membrane permeability and inversely correlated with peritoneal ultrafiltration rate [34]. A high glucose concentration in the dialysate can increase VEGF production, and the suppression of VEGF production may prevent functional changes in the peritoneal membrane [35 37]. Furthermore, increasing the peritoneal surface area by introducing vasodilatation agents such as nitroprusside into the dialysis solution could increase the peritoneal solute transport rate and clearance [38,39]. Although nitroprusside-induced vasodilatation increases the peritoneal small solute transport rate, it does not result in the typical peritoneal fluid transport kinetics of high peritoneal transporters [40], i.e. increased peritoneal fluid absorption rate and decreased peritoneal fluid removal [28]. Therefore, neoangiogenesis may not necessarily play a central role in increased peritoneal membrane permeability. Chronic inflammation and peritoneal transport rate Peritoneal inflammation can increase the peritoneal solute transport rate [11], and chronic peritoneal Hong Kong J Nephrol October 2003 Vol 5 No 2 67

4 T. Wang, B. Lindholm dialysis may itself induce (by incompatible peritoneal dialysis solutions) chronic inflammation of the peritoneal membrane [41]. Therefore, a high peritoneal solute transport rate might be caused by a state of chronic inflammation which also might result in increased mortality. However, we did not find that the peritoneal transport rate was associated with increased dialysate and serum cytokine levels and hyaluronan levels, suggesting that a high peritoneal transport rate is not necessarily related to a state of chronic inflammation in patients on continuous ambulatory peritoneal dialysis [42]. Peritoneal surface layer and peritoneal transport rate Peritoneal tissue hydraulic conductivity plays an important role in peritoneal fluid (both from blood to peritoneal cavity and vice versa) and solute transport [16]. Growing evidence suggests that the hyaluronan content in the interstitium may be the major determinant of the fluid exchange barrier in tissues [43]. Hyaluronan is a long chain polysaccharide that is made up of repeating disaccharide units of N-acetylglucosamine and glucuronic acid. It is found in most tissues in the body [44] and in the drainage dialysis fluid during peritoneal dialysis [45]. Hyaluronan exhibits a high resistance against water flow [43,46,47]. In the interstitium, hyaluronan decreases the water permeability of the membrane [48,49]. Hyaluronan is a water-soluble substance. Hyaluronan in the tissue may be easily extracted even by buffer solution [48]. Furthermore, hyaluronan may be washed out from the muscle of the anterior abdominal wall to its adjacent subcutaneous space and may thereby increase interstitial hydraulic conductivity [50]. Therefore, it is possible that the content of hyaluronan in the peritoneal membrane, especially that on the peritoneal surface and in the peritoneal interstitium, may be reduced during chronic peritoneal dialysis. We have previously demonstrated that adding 0.01% hyaluronan to the peritoneal dialysis fluid in rats increases peritoneal fluid removal mainly by decreasing peritoneal fluid absorption, resulting in increased peritoneal urea clearance [51]. We also demonstrated that the decreasing effect of hyaluronan on the peritoneal fluid absorption rate is even more marked when a high dialysate fill volume is used [52]. We speculated that the observed effect of hyaluronan on peritoneal fluid absorption might be due to the accumulation of a restrictive filter cake of hyaluronan chains at the tissue-cavity interface, resulting in a high resistance to fluid flow [51]. This decreasing effect may depend on both the molecular weight and the concentration of hyaluronan [53]. To support our hypothesis, we recently demonstrated that there is, in fact, a peritoneal surface layer that consists of glycosaminoglycans (including hyaluronan), as well as surface-active substances (surfactants) on the peritoneal surface, and that this layer may play an important role in peritoneal transport, especially in peritoneal fluid transport [54]. We also found that repeated intraperitoneal addition of hyaluronan may prevent the increase in peritoneal membrane transport rate caused by currently used hypertonic dialysis solutions, and that this is associated with a better preservation of the peritoneal surface layer [55]. Surfactants were first identified in peritoneal dialysis effluent in 1985 by Grahame and co-workers [56], and have since raised great interest in peritoneal dialysis society due to their special physical properties. Recently, Hills et al demonstrated the presence of a phospholipid layer (surfactant) on the peritoneal surface by applying the hydrophobic probe phosphin E [57]. The surfactant consists of a mixture of phospholipids (67%), proteins (8%), neutral lipids (21%), carbohydrates (2%), and minor constituents (2%) [58]. In general, besides lowering alveolar surface tension, surfactants play important roles in local host defense, tissue permeability and in maintaining fluid balance in the alveoli [57,59]. However, despite extensive studies on surfactant physiology, the function of the individual constituents of surfactants, and especially the role of the different phospholipids, are, to a large extent, unknown [60]. In a recent study, we found that the phosphatidylcholine content significantly decreased both in the dialysate and in the peritoneal surface layer when membrane permeability was increased, indicating that, in addition to lubrication of the peritoneal cavity, the surfactant, and especially its phosphatidylcholine content, may play an important role in peritoneal transport [54]. In fact, several previous studies have demonstrated that phospholipids, especially phosphatidylcholine, decrease peritoneal fluid absorption rate and increase peritoneal fluid removal [61 63]. Furthermore, we recently found that damaging the peritoneal surface layer by intraperitoneal use of pentobarbital and peritoneal shaking significantly increased the peritoneal solute transport rate and peritoneal fluid absorption rate, changes similar to those observed in high transporters, suggesting the importance of the peritoneal surface layer in peritoneal membrane transport (unpublished data). It has also been suggested that peritoneal membrane fibrosis may have an impact on increased membrane permeability [33,64,65]. However, we think that the association between fibrosis and increased membrane permeability may not necessarily be explained by fibrosis per se, but may be due to the neoangiogenesis and decreased tissue hyaluronan content that link to tissue fibrosis. The role of water channels in the changes in membrane permeability 68 Hong Kong J Nephrol October 2003 Vol 5 No 2

5 Peritoneal transport remains to be determined [66,67]. We therefore believe that an increased peritoneal membrane solute transport rate may be the consequence of different complicated pathologic processes. Changes in the tissue hydraulic conductivity by alteration in the tissue hyaluronan content and changes in the peritoneal surface layer may play important roles in this process. In addition, an increased peritoneal surface area due to increased angiogenesis and increased permeability of peritoneal microvessels due to local chronic inflammation may have synergetic effects on increased peritoneal solute transport rate. NEW PERITONEAL DIALYSIS SOLUTIONS AND THEIR IMPACT ON PERITONEAL TRANSPORT Peritoneal transport has recently been used as a parameter to test the biocompatibility of peritoneal dialysis solutions. It has been suggested that the bioincompatibility of the currently used glucose-based peritoneal dialysis solutions may be one of the main reasons for the changes in membrane permeability [68]. The bioincompatibility factors of the solutions include low ph, high glucose content, high lactate content, high osmolality, and high levels of glucose degradation products that are generated during heat sterilization [69]. Numerous studies have investigated how the problems with conventional glucose dialysis solutions may be overcome [69]. The obvious choice for replacing the conventional low-ph, high-lactate buffered peritoneal dialysis solution is a bicarbonate solution. Recent clinical trials show that, compared to conventional lactate-based solutions, bicarbonate/ lactate (B/L) solutions result in an increased CA 125 concentration (a possible indicator of mesothelial cell mass) and a decreased hyaluronan concentration (an indicator of inflammation) in dialysate effluent. These observations suggest that continuous therapy with B/L solution may reduce the pro-inflammatory potential and improve mesothelial cell integrity within the dialyzing peritoneum, possibly indicating better preservation of peritoneal homeostasis and long-term function of the peritoneal membrane in patients dialyzed with more biocompatible solutions [70]. Similar results have been reported with peritoneal dialysis solutions containing only a low amount of glucose degradation products (GDPs), indicating a possible role of GDPs in altering the peritoneal membrane during long-term peritoneal dialysis [71]. It is worthwhile to note that there was a small but significant increase in peritoneal ultrafiltration with the B/L solution compared to the conventional lactate-based solution [70]. These observations support a previous statement by Oreopoulos and Breborowicz that more biocompatible solutions in combination with more adequate dialysis, would allow peritoneal dialysis patients to stay on peritoneal dialysis for longer periods with less fibrosis of the peritoneal membrane, the maintenance of the peritoneal membrane ultrastructure and its ability to regenerate, and lower incidence of ultrafiltration capacity failure [72]. On the other hand, dialysis solutions with lowmolecular-weight osmotic agents are not ideal for long dwell-time because the osmotic agent is absorbed, resulting in a decrease in transcapillary ultrafiltration. During long dwell-time, high-molecular-weight osmotic agents are therefore more suitable. Icodextrin is the only available high-molecular-weight osmotic agent for peritoneal dialysis solution in clinical practice so far. It is a polymer of glucose produced by the hydrolysis of starch. The solution contains a spectrum of icodextrin molecules with an average molecular weight of 16,200 d. The polymers consist of glucose units linked predominantly by 1-4 glucosidic bonds, with a small proportion of branches linked by 1-6 glucosidic bonds [73]. Clinical studies show that the ultrafiltration generated by icodextrin solution for 8 to 12 hours in peritoneal dialysis patients is equivalent to, or even better than, that of 3.86% glucose solution. Continuous use of icodextrin solution in peritoneal dialysis patients improves the control of fluid balance, decreases blood pressure and the use of antihypertensive medications, improves lipid profile, and extends patients technical survival [74 77]. Icodextrin solution is especially effective during peritonitis and in high transporters in whom ultrafiltration is significantly reduced with glucose solution due to increased absorption of glucose from the peritoneal cavity [39,78 80]. In summary, after several decades of experience with peritoneal dialysis therapy, we have a much better understanding of the functional properties of the peritoneal membrane and the causes of its changes during long-term dialysis. Several new, more biocompatible solutions are now available in the clinic and the outcome of peritoneal dialysis therapy is expected to be further improved. ACKNOWLEDGMENT This study was supported by grants from the National Natural Science foundation of China (No , No ) and Peking University (No. 36-1). REFERENCES 1. Popovich RP, Moncrief JW, Nolph KD, Ghods AJ, Twardowski ZJ, Pyle WK. Continuous ambulatory peritoneal dialysis. Ann Intern Med 1978;88: Hong Kong J Nephrol October 2003 Vol 5 No 2 69

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