Successful long-term peritoneal dialysis (PD) requires

Transcription

1 Proceedings of the ISPD 2001 The IXth Congress of the ISPD June 26 29, 2001, Montréal, Canada Peritoneal Dialysis International, Vol. 21 (2001), Supplement /01 $ Copyright 2001 International Society for Peritoneal Dialysis Printed in Canada. All rights reserved. WHAT HAPPENS TO THE PERITONEAL MEMBRANE IN LONG-TERM PERITONEAL DIALYSIS? An S. De Vriese, Siska Mortier, Norbert H. Lameire Successful long-term peritoneal dialysis (PD) requires preservation of the transport function of the peritoneal membrane. Adequate dialysis is not only a matter of achieving the targets for Kt/V urea and creatinine clearance, but also and maybe even more importantly of maintaining an optimal volume status. The development of ultrafiltration failure (UFF) remains one of the most important causes of treatment drop-out. It is also associated with a poor prognosis. Evidence is mounting that the incidence of UFF increases with time spent on PD, suggesting that the peritoneal membrane is progressively damaged during PD. However, the nature and the causes of the structural and functional alterations of the peritoneal membrane in long-term PD remain to be fully defined. Undoubtedly, continuous exposure to unphysiologic dialysis solutions is an important pathogenetic element in this respect. In addition, the repeated acute inflammatory damage conferred by recurrent peritonitis episodes and the chronic low-grade inflammation associated with the uremic state are likely to contribute. The present article reviews the extant studies on the functional and structural alterations of the peritoneal membrane in long-term PD. In addition, it focuses on the evidence for dialysate bioincompatibility in the genesis of these changes. Finally, therapeutic strategies with the potential to preserve long-term peritoneal membrane function and structure are addressed. FUNCTIONAL ALTERATIONS OF THE PERITONEAL MEMBRANE Epidemiology of UFF: Definitions of UFF vary substantially, making comparisons between studies very difficult. KEY WORDS: Ultrafiltration failure; small-solute transport; neoangiogenesis; vascular endothelial growth factor; glucose; glucose degradation products; advanced glycation end-products. Correspondence to: A. De Vriese, Renal Unit, University Hospital, OK12, De Pintelaan 185, Gent B-9000 Belgium. an.devriese@rug.ac.be Renal Unit, University Hospital, Gent, Belgium Several authors have relied on clinical features, including inability to maintain target weight or blood pressure, and presence of pitting edema despite excessive utilization of hypertonic solutions and severe reduction of fluid and sodium intake. Using this approach, the cumulative risk of UFF was reported to be 10% at 1 year and 30% at 2 years in cohort of 171 PD patients (1). Another study, involving 227 PD patients, calculated a cumulative risk for clinical UFF of 2.6% at 1 year, 9.5% at 2 years, and 30.9% at 6 years (2). Other, more objective, definitions are based on peritoneal function studies, using the peritoneal equilibration test (PET) or an equivalent. A negative net ultrafiltration 4 hours after instillation of 2 L of 1.36% glucose dialysate was reported in 57.3% of 68 patients with a PD duration between 0.3 months and 178 months, but many of these patients did not present with clinical problems (3). Subsequent studies revealed that 23% of the patients had an net ultrafiltration of less than 400 ml after 4 hours of 3.86% glucose dialysate; those patients were considered to have clinically relevant UFF (3). Based on the latter definition, UFF was prevalent in 35% of 37 unselected patients with a mean duration of PD of 6 years (4). Alternatively, a net ultrafiltration of less than 100 ml after 4 hours of 2.27% glucose dialysate has been suggested to represent UFF (5). Using this definition, the prevalence of UFF was reported to be 14% in a population of 104 PD patients. Based on computer simulations, however, the most sensitive method to examine UFF appears to be that using 3.86% glucose dialysate (6). Longitudinal and cross-sectional studies examining the influence of duration of PD on ultrafiltration rate have yielded conflicting results. Some small-scale studies failed to find a relationship between time spent on PD and ultrafiltration rate (7 11). In contrast, several others found ultrafiltration rates that decreased with treatment duration (1,12 15). In keeping with these findings, the mean time spent on PD was significantly longer in selected patients with UFF, defined either clinically (2) or by means of a PET (3). In a case-control study, net fluid removal was lower S9

2 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD DECEMBER 2001 VOL. 21, SUPPL 3 PDI in long-term PD patients as compared with patients that had recently started (16). Taken together, the data have led to the consensus that ultrafiltration capacity is progressively lost with time on PD and that the problem becomes apparent after 4 or more years of treatment (14,15). Because loss of ultrafiltration capacity is an important cause of patient drop-out due to technical failure and death, studies of long-term membrane performance are biased in favor of membrane stability, which may explain some of the initial controversy. One study reported that patients with UFF were younger than those with a preserved ultrafiltration rate, reflecting the fact that they had a longer survival on PD and therefore more opportunity to lose ultrafiltration capacity (1). Several studies have failed to find a relationship between peritonitis incidence and long-term peritoneal membrane performance (1,2,8,17 19), but others reported that the peritonitis rate significantly affected peritoneal function (7,14,15,20,21). Although these discrepancies are certainly related to small patient numbers or short follow-up in several of the studies, difficulties in grading the severity of the peritonitis episodes may also be a source of disparity. Indeed, one study found that the functional alterations of the peritoneal membrane were related to the number of peritonitis episodes occurring in close proximity, and to the intensity of the associated peritoneal inflammation, rather than to the number of infections per se (15). Causes of UFF: In theory, UFF can be caused by varying mechanisms: (A) mechanical problems, including catheter malfunction, hernia, or extraperitoneal leakage of dialysate; (B) decreased membrane surface area and permeability; (C) increased diffusive solute transport with rapid loss of the osmotic gradient, leading to decreased transcapillary ultrafiltration; (D) increased lymphatic absorption; and (E) impaired transcellular aquaporin-mediated water transport. Few studies have examined the relative contribution of each of these conditions to the occurrence of UFF. In a group of 8 patients with UFF, as defined by net ultrafiltration of less than 400 ml after a 4-hour dwell with 3.86% dialysate, 3 had a high mass transfer area coefficient (MTAC) for creatinine, 4 had evidence for an increased effective lymphatic absorption rate, and 1 patient s results suggested the presence of a combination of factors (3). In addition, evidence interpreted as impaired transcellular water transport was found in 3 of the 8 patients (3). Another study examined 9 patients with UFF as defined by clinical criteria and found increased transport rates for small solutes in 7 patients and increased lymphatic absorption in 2 patients (2). In 6 patients with severe UFF S10 that could not be explained by high solute transport or increased lymphatic absorption, transport characteristics suggested a defect in transcellular water transport (22). Finally, an ongoing multicenter study reported that, among 13 patients with UFF, 1 had a large vascular surface area, 3 had transport profiles interpreted as impaired channel-mediated water transport, 7 had a combination of these factors, and 2 had a high lymphatic absorption rate (4). The evolution of peritoneal transport characteristics over time on PD has been extensively explored. An apparent stability of membrane function has been reported in several smaller studies (7,9 11,17,21,23). In contrast, a significant increase in the small-solute transport rate, accompanied by a reduction in ultrafiltration rate, was found in more recent studies (13 16,24). Several explanations for these discrepancies can be put forward. First, only a subgroup of patients may experience a rise in small-solute transport. This situation was illustrated by a typical finding of stable average transport rates for urea and creatinine in 49 PD patients although 25% of patients showed a trend toward increased transport over time, and transport rates tended to decrease in approximately 10% of cases (21). When changes in small-solute transport over time were analyzed according to the initial transport category, it appeared that, over the first 18 months of PD, transport rates tended to decrease in those who initially were high transporters and to increase in those who initially were low transporters (19). The tendency of the extremes to migrate toward the mean may help to explain the apparent stability of transport that has been observed during the first years of PD in some studies (14,15). However, this centripetal direction of change occurred only during the first 18 months of PD; transport rates increased progressively thereafter (19). Second, as mentioned earlier, high transporters with low ultrafiltration rates may be preferentially lost to follow-up owing to early death or technical failure. Finally, peritoneal kinetic studies performed very early in the course of PD may not give a reliable representation of actual peritoneal function. Solute transport was found to be higher 1 month after the initiation of PD than 4 months later (13). The initial contact with dialysate may induce transient changes in the peritoneal microcirculation leading to a higher effective vascular surface area. Baseline studies of peritoneal membrane function should therefore not be performed earlier than 2 3 months after the start of PD. Taken together, these issues result in a sizeable chance that changes in peritoneal transport rates that may exist will not be detected. The current consensus is, therefore, that small-solute transport rates tend

3 PDI DECEMBER 2001 VOL. 21, SUPPL 3 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD to increase progressively with time on PD, at least in a proportion of patients. Solute transport across the peritoneal membrane is determined both by the effective peritoneal surface area and by the intrinsic permeability of the membrane (25). Transport of small solutes is not influenced by a size-dependent restriction barrier, but depends fundamentally on the available surface area. The implication is that measures of the transport of small molecules can be used as a parameter of effective peritoneal surface area. Elevated transport of small solutes thus reflects an increased surface area. Because a change in the size of the peritoneum is unlikely, an increased effective peritoneal surface area must be due to a rise of the number of capillaries that contribute to transport, either by recruitment of previously unperfused capillaries or by formation of new capillaries. It can thus be derived that a stable increase in the rate of the transport of small solutes points to the presence of peritoneal neoangiogenesis. Consequences of UFF: Several lines of evidence indicate that peritoneal membrane function has a significant impact on both technique and patient survival. Next to recurrent peritonitis, UFF appears to be the most important cause of technique drop-out. Loss of ultrafiltration capacity accounted for 16% 27% of cases of technical failure (26 30), although lower figures of 1.6% 9% have also been reported (31 33). As the prevalence of UFF increases with time on PD, it becomes the predominant reason for withdrawal from PD in long-term patients. This situation is illustrated by the typical finding that UFF caused 23.5% of treatment failure in the total PD population, but 51.4% of such failure in the population that had spent more than 6 years on PD (29). High transport characteristics have consistently been associated with low survival rates (34 37), a finding that can be ascribed to various mechanisms. First, adequacy of dialysis may be lower in these patients. Peritoneal Kt/V urea increases progressively from low to low-average to high-average transporters, but decreases again in the high transport group, most probably owing to low drain volumes (36). In addition, the nutrition status of high transporters is worse than in low transporters. The dialysate-to-plasma (D/P) ratio of creatinine is inversely correlated with serum albumin (34). A proposed mechanism is that high-transport patients experience rapid absorption of glucose from the dialysate (with inhibition of appetite) and a greater loss of protein in the dialysate. Both of these factors contribute to poor nutrition status. However, high solute transport was associated with poor clinical outcome, independent of serum albumin (37). The most important element contributing to the poor prognosis associated with high solute transfer is probably chronic fluid overload secondary to decreased ultrafiltration capacity; and, in accordance, cardiovascular disease was reported to be the only cause of death in a group of high-transport patients (35). Summary: Long-term PD is characterized by a progressive loss of ultrafiltration capacity. In most cases, the decrease in ultrafiltration rate is associated with an elevation in the transport of smallmolecular-weight solutes, indicative of the presence of an enlarged effective peritoneal surface area. The presence of impaired ultrafiltration capacity and high solute transport confers an increased relative risk for treatment failure and death. The association of changes in peritoneal function with time spent on PD suggests that the changes are caused by chronic exposure of the peritoneal membrane to bioincompatible dialysis solutions. Recurrent episodes of peritonitis may contribute to, or accelerate, the development of these changes, but peritonitis is not a prerequisite. Clearly, some patients survive on PD for extended periods in the absence of significant changes in peritoneal function, suggesting that individual susceptibility to as-yet-undefined factors plays a role. STRUCTURAL ALTERATIONS OF THE PERITONEAL MEMBRANE The current understanding of peritoneal morphology during long-term PD rests heavily on the compilation of information derived from peritoneal biopsies taken during various events. Because the peritoneal membrane is not routinely accessible, biopsies are generally obtained during the removal, for various reasons, of a catheter or during renal transplantation. A systematic bias is thus introduced. An added difficulty is that, in view of the reported heterogeneity of the peritoneal membrane alterations, representative biopsies require multiple samples (38). Until recently, studies of the morphology of the peritoneum have focused mainly on the mesothelial cell layer and the interstitial tissue. However, the mesothelium does not appear to be an important barrier to solute transport (39). In contrast, the vascular wall is essential to the transfer of solutes during PD. That the peritoneal microvasculature has so far been approached with an aloof regard is therefore surprising. Several authors have described thickening and reduplication of the basement membrane, of mesothelial cells, and of stromal blood vessels (40 44). Before the start of PD, the mesothelium in non diabetic and diabetic patients has a normal morphology. After several months of PD, the mesothelial basement membrane shows replication in both groups of patients. The basal lamina of stromal blood vessels is normal before treatment in non diabetic patients, but features doubling after a few months on PD. Later, multiple S11

4 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD DECEMBER 2001 VOL. 21, SUPPL 3 PDI reduplication even exceeding five layers can be seen. In diabetic patients, the reduplication of the capillary basement membrane is already present in the initial biopsy and aggravates rapidly upon exposure to dialysate, even to complete occlusion of the vessels. The presence of pericyte debris in the blood vessel wall, similar to what is observed in diabetic angiopathy, implies increased cell death and turnover (43). These pathologic changes were reported to occur more frequently in patients with a history of multiple episodes of peritonitis (43), but patient numbers were small and no prospective evidence currently supports the suggested association. The changes in the basement membrane are associated with variable degrees of expansion and alterations in the composition of the interstitial matrix (38,42 45). Whereas the collagen deposition in idiopathic peritoneal sclerosis consists mainly of collagen type I and type III, the thickening of the interstitial layer in PD patients is characterized by the increased presence of collagen type IV (45). Similarly, the vasculature is characterized by fibrosis and hyalinization of the media (46,47) owing to increased deposition of collagen type IV and laminin (46). The prevalence of this vasculopathy correlated nicely with the degree of submesothelial fibrosis, and increased with time spent on PD (47). Although a few early reports mention the presence of hypervascularization in the peritoneal membrane of patients on long-term PD (38,48), very little attention has been paid to the density of the microvasculature in the years since. Recently, neovascularization and capillary dilation were reported in biopsies of long-term PD patients. The number of microvessels per area increased with treatment duration and correlated with the degree of interstitial fibrosis (45). In accordance with that finding, an upregulation of endothelial nitric oxide synthase, corresponding with increased vascular density, was reported in the peritoneum of long-term PD patients (49). Finally, in 56 biopsies from the Peritoneal Biopsy Registry, a doubling of vessel density was observed with time on PD (47). In summary, long-term PD is associated with the appearance of diverse structural changes in the peritoneal membrane, including reduplication of the basal lamina of the mesothelium and of the blood vessels, interstitial fibrosis, and hyalinization of the blood vessel media with preferential deposition of collagen type IV. Evidence for neoangiogenesis is also seen. POTENTIAL CAUSATIVE FACTORS Glucose: As noted earlier, various structural changes have been observed in the peritoneal membrane of PD patients. Several of these alterations S12 in particular, the thickening of the basement membrane, the deposition of collagen type IV in the extracellular matrix and the blood vessel wall, and the extensive neoangiogenesis are clearly reminiscent of the changes characteristic of diabetic vasculopathy. Hence comes the hypothesis that chronic exposure to the high glucose concentrations in peritoneal dialysate is at least in part responsible for the development of the functional and structural alterations of the peritoneal membrane in long-term PD. Several lines of evidence support this contention. In a chronic peritoneal infusion model in the rat, exposure to 3.86% glucose dialysate caused severe neoangiogenesis and fibrosis of the peritoneal membrane and impaired ultrafiltration; infusion of Ringer s lactate solution produced no major alterations (50). Patients with peritoneal sclerosis on biopsy have a greater cumulative glucose exposure than do controls matched for duration of PD (45). Compelling evidence exists for the involvement of various growth factors, including transforming growth factor beta (TGFβ) and vascular endothelial growth factor (VEGF) in the pathophysiology of diabetic vascular complications (51,52). The multifunctional cytokine TGFβ is mainly involved in the regulation of cell growth and extracellular matrix composition and proliferation (53). The endothelial-specific growth factor VEGF plays a prominent role in physiologic and pathologic angiogenesis (54). In addition, VEGF causes endothelium-dependent vasodilatation and has been established as one of the most potent inducers of microvascular hyperpermeability (54). Both growth factors are known to be upregulated in diverse cell types cultured in a high glucose environment, in various tissues of experimental animals, and in humans with diabetes. Of relevance to PD is the finding that human peritoneal mesothelial cells exhibit increased TGFβ expression when cultured in high-glucose media or in the presence of spent dialysate (55). Co-stimulation of high glucose or spent dialysate with the pro-inflammatory cytokines interleukin-1β (IL-1β) or TNFα further augmented TGFβ protein synthesis by the mesothelial cells (55). These findings may provide an explanation for the clinical observation that diabetiform pathologic changes were most pronounced in patients who suffered repeated peritonitis episodes (43). Human peritoneal mesothelial cells recovered from spent dialysate and cultured in vitro have the capacity to produce substantial amounts of VEGF (56). Although this finding does not necessarily mean that mesothelial cells exposed to dialysate constitutively produce VEGF in vivo, it should be noted that cultured pleural mesothelial cells produce no detectable amounts of VEGF. However, no correlations were

5 PDI DECEMBER 2001 VOL. 21, SUPPL 3 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD found between supernatant VEGF levels and time on PD, solute transport characteristics, ultrafiltration rate, or accumulated dose of glucose (56). Other cell types present in the peritoneal cavity and capable of producing VEGF include peritoneal macrophages (57) and capillary endothelial cells (49). The concentration of VEGF and TGFβ in peritoneal effluent was found to be higher than could be attributed to transport from the circulation, implying local production (58). The amount of locally synthesized VEGF (but not TGFβ), correlated with the MTAC of creatinine and urate, with glucose absorption, and with transcapillary ultrafiltration (58). Local production of VEGF increased with time on PD, although the magnitude of the increase was independent of the initial VEGF levels and of the duration of PD at the start of follow-up (59). These findings indicate that individual susceptibility to as-yet-unknown factors may determine the extent of peritoneal VEGF production in response to dialysate exposure. Effluent concentrations of VEGF decreased after patients were switched to glucose-free dialysate, with a commensurate effect on the parameters of effective peritoneal surface area (59). Although these studies present ample circumstantial evidence to incriminate high glucose concentrations in the development of functional and structural alterations of the peritoneal membrane through the production of growth factors, they do not provide proof of causality. For a particular factor to be credible as a causal mediator of the peritoneal changes in long-term PD, demonstration is required either that elimination of the factor prevents development of the changes, or that introduction of the factor in the absence of other potential causal mediators produces similar changes. Glucose cannot be eliminated without dramatically altering the composition of peritoneal dialysate because ph, osmolality, and glucose degradation product (GDP) content will (for instance) also be affected. Our group has therefore chosen to introduce high ambient glucose concentrations in the absence of other factors by studying the effects of experimental diabetes on peritoneal function and structure (60). The peritoneal microcirculation in early streptozotocininduced diabetes in the rat is characterized by pronounced neoangiogenesis (Figure 1), associated on the functional level with increased transport of small solutes (Figure 2). The hyperglycemia-induced microvascular alterations were largely prevented by treatment with a neutralizing monoclonal anti-vegf antibody; treatment with an isotype-matched control antibody was without effect. These results are thus the first to support an casual role for glucose in the development of peritoneal neoangiogenesis and to identify VEGF as an important downstream mediator (60). Glucose Degradation Products: The effects of GDPs on fibroblast and mesothelial cell viability on the one hand, and on peritoneal host defense on the other, have been extensively investigated in vitro, but information on the potential vascular effects of GDPs is in short supply. Cultured rat mesothelial cells and human endothelial cells expressed VEGF in response to methylglyoxal, but not to glyoxal or 3-deoxyglucosone (61). Intraperitoneal exposure to methylglyoxal increased VEGF expression in the peritoneal tissue of experimental animals (61). Although these results clearly need confirmation, they suggest that GDPs may contribute to peritoneal neoangiogenesis by augmenting local production of VEGF. A marked loss of ultrafiltration capacity was reported with the use of dialysis solutions that had been stored for more than 18 months (62). This phenomenon may be attributed to formation of GDPs during long-term storage, but no direct evidence to support this hypothesis is available. Advanced Glycation End Products: Glucose and a variety of other reactive carbonyl compounds are known to bind nonenzymatically to free amino groups on proteins or lipids. Through a series of oxidative and non oxidative reactions, advanced glycation end products (AGEs) are irreversibly formed (63). Formation of AGEs occurs during normal aging, but is accelerated when concentrations of the substrate molecules are increased and when the prevailing oxidant stress is high (64). The peritoneum is chronically exposed to high glucose concentrations, vastly in excess of those found in diabetes, and large amounts of glucose are continuously absorbed across the peritoneal membrane. The uremic environment is associated with high oxidative stress, thus further promoting the generation of AGEs. Breakdown of AGE-modified tissue proteins yields low-molecularweight AGEs, which are normally cleared through the kidney (65). As residual renal function deteriorates, the plasma concentration of these low-molecularweight AGEs rises and the AGEs retain their biologic activity. Increased levels of AGEs have been found in the serum of PD patients (66,67). The presence of GDPs in peritoneal dialysate facilitates the formation of AGEs (68,69). Taken together, these conditions in the peritoneal cavity of PD patients are optimal for dramatically accelerated AGE formation and accumulation. In vitro studies have demonstrated that AGE formation indeed occurs in PD fluid at a rate higher than can be explained by glucose concentration alone (70,71). Using immunocytochemistry methods, AGEs have been detected in the mesothelium, submesothelial stroma, and vascular wall of PD patients (24,49,72 74) as early as 3 months after the start of S13

6 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD DECEMBER 2001 VOL. 21, SUPPL 3 PDI A B C Figure 1 Intravital microscopy of the peritoneal membrane. In contrast to control peritonea (A), peritonea of diabetic rats are characterized by the presence of dense and irregular vascular networks (B). These microvascular alterations were prevented by administration of neutralizing monoclonal anti vascular endothelial growth factor (anti-vegf) antibodies (C), but not by treatment with an isotype-matched control antibody (D). Magnification: 64. From reference 60, with permission. D PD (72). The degree of AGE accumulation correlated with the time spent on PD (24,74). The pathogenicity of AGEs is related to their accumulation in tissues (with the formation of cross-links) and their ability to generate oxygen-derived free radicals. Once the initial glycation reaction has taken place, the formation of cross-links continues, even in the absence of substrate. In addition, the interaction of AGEs with their cellular receptors (RAGEs) on endothelial, smooth muscle, and inflammatory cells triggers sustained cellular activation and a further increase in oxidative stress (75). Finally, AGEs have the potential to promote VEGF expression (76 79) and may thus present a third pathway to peritoneal neoangiogenesis. The VEGF and the carboxymethyllysine (61) or pentosidine (49) were found to co-localize in the mesothelial layer and the vascular endothelium of the peritoneal membrane of PD patients. These findings are, however, purely descriptive and do not demonstrate causality. Attempts have been made to correlate the extent of AGE accumulation with functional parameters (24,73,74). The presence of AGEs in the peritoneal membrane increased with treatment duration and was associated with higher permeability to various solutes (24,74). In another study, the extent of interstitial fibrosis correlated with the degree of interstitial staining for AGEs (73). Similarly, the grade of vascular sclerosis was commensurate with the amount of AGE accumulation in the vascular wall (73). An inverse correlation was found between ultrafiltration volume and these changes in peritoneal histology (73). These results incriminate AGE accumulation in the pathophysiology of the interstitial fibrosis and microvascular sclerosis associated with ultrafiltration failure. S14

7 PDI DECEMBER 2001 VOL. 21, SUPPL 3 PROCEEDINGS OF THE IXTH CONGRESS OF THE ISPD Figure 2 Peritoneal transport studies. The mass transfer area coefficients (MTAC) for urea and creatinine were measured after a 2-hour dwell with 3.86% glucose dialysate in the peritoneal cavity of control rats, of control rats treated with anti vascular endothelial growth factor (anti-vegf) antibodies, of diabetic rats, of diabetic rats treated with anti-vegf antibodies, and of diabetic rats treated with control antibodies. * p < 0.05 compared with control rats; ** p < 0.05 compared with diabetic rats and with diabetic rats treated with control antibodies. From reference 60, with permission. The precise mechanisms underlying the development of ultrafiltration failure related to AGE formation remain to be determined. Notably, glycation of aquaporins involved in transcellular water transport has been suggested to contribute to loss of ultrafiltration capacity (22), although direct evidence for the actual occurrence of this phenomenon is lacking. PREVENTION OF FUNCTIONAL AND STRUCTURAL ALTERATIONS OF THE PERITONEAL MEMBRANE Several lines of evidence support the involvement of dialysate glucose and GDP concentrations in the pathogenesis of peritoneal membrane alterations in long-term PD. Any strategy that reduces glucose and GDP exposure therefore has the potential to better preserve peritoneal membrane integrity. Non-glucose-based dialysates are currently being used, including ones containing icodextrin, glycerol, and amino acids; but none of those substances can entirely replace glucose as an osmotic agent. In addition, dialysates with low GDP content (owing to separate sterilization of glucose at a very low ph) have become available. Extensive in vitro testing has suggested that these new dialysates may be more biocompatible than conventional dialysate (80), but superiority in regard to in vivo peritoneal membrane function remains to be demonstrated. Heat-sterilized icodextrin dialysate results in less glycation and AGE formation in vitro as compared with conventional heat-sterilized glucose-based dialysate (65,81). In keeping with these findings, less AGE-specific immunostaining was observed in the peritonea of animals dialyzed with icodextrin than in the peritonea of animals treated with conventional dialysate (82). A switch to icodextrin-based and glycerol-based dialysis in a small group of patients with severe UFF resulted in reduced dialysate levels of pentosidine and in some improvement in ultrafiltration (50). However, a randomized trial in continuous cycling PD patients, with a follow-up of 2 years, showed no difference in peritoneal transport characteristics and peritoneal membrane markers between the icodextrin and the standard dialysate groups (83). In vitro AGE formation was reduced in doublechamber dialysate solutions with low GDP content (84). In accord with those results, less AGE staining in the peritoneal membrane, better ultrafiltration (85), and less pronounced submesothelial thickening (86) were reported in rats exposed to low-gdp dialysate as compared with those exposed to conventional dialysate. CONCLUSION The current evidence suggests that long-term PD is associated with a progressive loss of ultrafiltration capacity, which can be attributed in most cases to an increased effective vascular surface area. The morphology correlate appears to be extensive neoangiogenesis. In addition, interstitial fibrosis and vascular sclerosis are commonly found in the peritoneal membrane of long-term PD patients. In the genesis of these changes, evidence increasingly incriminates chronic exposure to bioincompatible conventional dialysis solutions in particular, exposure to the high glucose concentrations and GDPs associated with accelerated AGE formation. The promising preliminary results obtained with new dialysis solutions in vitro and in animal models now leave us poised to demonstrate in clinical trials that these solutions preserve long-term peritoneal function. REFERENCES 1. Slingeneyer A, Canaud B, Mion C. Permanent loss of ultrafiltration capacity of the peritoneum in long-term peritoneal dialysis: an epidemiological study. Nephron 1983; 33: Heimbürger O, Waniewski J, Werynski A, Tranæus A, Lindholm B. Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney Int 1990; 38: Ho-dac-Pannekeet MM, Atasever B, Struijk DG, Krediet RT. Analysis of ultrafiltration failure in peritoneal dialysis patients by means of standard perito- S15

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