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Molecular mechanisms involved in the peritoneal membrane exposed to peritoneal dialysis
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NEFROLOGÍA. Vol. XXIII. Suplemento 3. 2003 Molecular mechanisms involved in the peritoneal membrane exposed to peritoneal dialysis O. Devuyst, MD, PhD Division of Nephrology. Université Catholique de Louvain Medical School. Brussels. Belgium. INTRODUCTION Peritoneal dialysis (PD) is a mode of renal replacement therapy that is used for more than 130,000 patients worldwide. The most frequent complication of PD is acute peritonitis. However, loss of ultrafiltration (UF) represents the most important cause for technical failure in long-term PD patients 1. Longitudinal studies have shown that PD is associated with a progressive increase in the permeability for small solutes across the peritoneal membrane (PM), which induces a faster absorption of glucose, an early dissipation of the osmotic gradient, and eventually UF failure 1, 2. The relevance of these modifications is illustrated by the fact that high PM permeability is a significant risk factor, predicting both technical failure and death in PD patients 3. Rare, additional causes of UF dysfunction have been recognized 4, including increased fluid reabsorption by lymphatics; reduction of the transcellular water transport, which is putatively related to an alteration of the aquaporin-1 (AQP1) water channel 5; and modifications of the hydraulic conductance of the interstitium 6. In this brief review, we will discuss how recent structural, functional and molecular data provide new insights in the pathophysiology of the modifications of the PM exposed to PD. Altogether these data fit an hypothetical framework illustrated in figure 1. 1. STRUCTURAL MODIFICATIONS OF THE PERITONEUM The endothelium lining peritoneal capillaries represents the major functional barrier to water and Correspondence: Oliver Devuyst, MD, PhD Division of Nephrology UCL Medical School 10 Avenue Hippocrate B-1200 Brussels (Belgium) E-mail: devuyst@nefr.ucl.ac.be small solutes transport during PD. The amount of perfused capillaries within the PM determines the «effective peritoneal surface area» (EPSA), i.e. the functional area of exchange between blood and dialysate 1. The permeability for water and solutes across the endothelium is best described by the three-pore model, which includes transcellular, ultrasmall pores (radius: 3 to 5 Å) exclusively permeable to water, small pores (radius: 40 to 50 Å) permeable to water and small solutes, and large pores (radius > 150 Å) permeable to macromolecules 7. The water channel AQP1 is the molecular counterpart of the ultrasmall pore, which mediates up to 50% of UF during an hypertonic dwell with glucose as a crystalloid osmotic agent 8. Colloid osmosis (e.g. with icodextrin) occurs at the level of interendothelial small pores that allow the diffusion of water and small solutes 9. It is well documented that long-term PD induces structural modifications of the PM, including submesothelial fibrosis, vascular proliferation, vascular diabetiform changes, and alterations of the mesothelium 10-13. In a large peritoneal biopsy study, Williams et al reported a progressive increase in the thickness of submesothelial area with PD duration, as well as vascular changes including subendothelial hyalinisation and increased vascular density in high-transporter PD patients 14. The correlation between the extent of submesothelial fibrosis and vascularization suggests a pathophysiological link between the two structural changes 13, 14. Submesothelial vascularization, vasodilatation, and increased reactivity for nitrotrosine secondary to peroxynitrite release have also been observed in rat models of acute peritonitis 15. Thus, vascular proliferation and, possibly, vasodilatation of preexisting vessels, might represent the structural basis for increased EPSA encountered in acute peritonitis and long-term PD 10, 15. 2. THE LINK BETWEEN STRUCTURAL CHANGES AND UF FAILURE IN PD The recent development and characterization of experimental rat models provided key insights into 32 MOLECULAR MECHANISMS INVOLVED IN P. P. Fig. 1.--A model for the different molecular mechanisms involved in the peritoneal membrane dysfunction in long-term peritoneal dialysis. Chronic uremia is associated with high levels of circulating RCOs, which initiate AGE protein modifications in the PM. During PD, RCOs contained in glucose-based dialysate will amplify the AGE formation in the PM. RCOs and AGEs initiate a number of cellular responses, including stimulation of VEGF expression. In turn, VEGF interacts with endothelial cells, and, together with eNOS and NO, stimulates angiogenesis and increases vascular permeability. These combined modifications increase EPSA, and eventually impair UF. Fibrosis will also be involved in PM dysfunction. Of note, uremia itself might stimulate VEGF and bFGF, the latter being also released by VEGF interaction with the extracellular matrix. Episodes of acute peritonitis participate in the progressive dysfunction of the PM, for instance by releasing NO and peroxynitrite. the pathophysiology of UF failure in PD. These models include rats with acute peritonitis 15, 16, chronic exposure to diabetes 17, 18 or uremia 19, and chronic exposure to dialysate 20. A common feature of these models is the release of growth factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF-) in the PM, leading to the development of areas of neovascularization and/or submesothelial fibrosis. These structural modifications, which have been documented both at the morphological and molecular levels, are associated with a higher permeability for glucose and small solutes, a decreased sodium sieving, and a reduced UF. Furthermore, an inverse relationship between vascular density in the PM and UF volume has been demonstrated in the chronic exposure rat model2 0, and a similar relationship exists in the human PM 14. Du- ring acute peritonitis, the loss of UF is also mediated by a massive release of nitric oxide (NO) secondary to the upregulation of the inducible NO synthase (iNOS) isoform (see below) 15, 16. 3. MOLECULAR MECHANISMS INVOLVED IN THE STRUCTURAL CHANGES Longitudinal studies have shown that the transport of small solutes across the PM increases with time on PD 2, suggesting that long-term exposure to glucose-based dialysis fluids plays a central role in the pathogenesis of the modifications of the PM. This hypothesis is supported by the observation that an early and high cumulative glucose exposure in PD patients is associated with higher permeability of the PM 21. 33 O. DEVUYST Heat sterilization of conventional, glucose-based dialysates generates glucose degradation products (GDPs) and reactive carbonyl species (RCOs) such as glyoxal, methylglyoxal (MGO) and 3-deoxyglucasone 22. Furthermore, high levels of RCOs are also present in the uremic plasma 23. Multiple studies have demonstrated that both GDPs and RCOs accelerate the formation of the advanced glycation end products (AGEs) in the PM, where they localize both in the mesothelium and endothelium 10, 24. Both RCOs and AGEs modify proteins and/or interact with receptors, which initiates cellular responses including secretion of inflammatory cytokines, proliferation of vascular smooth muscle cells, stimulation of growth factors, and secretion of matrix proteins 23, 25. In particular, a link between exposure to RCOs/AGEs and release of VEGF by peritoneal cells is supported by in vitro and in vivo studies with MGO 24, as well as by the colocalization of the AGE pentosidine and VEGF in peritoneal capillaries from long-term PD patients 10. The growth factor VEGF is a potent regulator of angiogenesis and vascular permeability (26, for review). The VEGF gene codes for several VEGF isoforms, which arrange into disulfide-linked homodimers. The binding of VEGF dimers to tyrosine-kinase receptors (VEGFR-1 and VEGFR-2) located in endothelial cells initiates a signal transduction cascade responsible for endothelial proliferation and migration, activation of plasminogen and collagenase, and vasodilation, all these steps resulting in physiological angiogenesis 26. Furthermore, by binding to the extracellular matrix, VEGF induces the release of bFGF, another potent angiogenic factor 27. Stimuli for VEGF expression include hypoxia, hypoglycemia, cytokines such as interleukin-6 (IL-6), growth factors, and hormones 28, 29. VEGF is synthesized by cultured mesothelial and endothelial cells isolated from the peritoneum 24, and its expression is upregulated in long-term PD patients 10. By analogy with other angiogenic diseases, it is tempting to speculate that the upregulation of VEGF may trigger vascular proliferation in the PM in long-term PD. Of note, plasma and dialysate concentrations of VEGF and IL-6 have recently been associated with high peritoneal solute transport rate 30. Nitric oxide is an attractive candidate to regulate EPSA and UF during PD, given its crucial role in the regulation of vascular tone and permeability 31 and its interactions with angiogenic growth factors 28. The paradigm has been provided by the loss of UF in a rat model of acute peritonitis, characterized by the upregulation of the endothelial and inducible NOS isoforms and a parallel increase in the permeabillity for glucose and small solutes 15. Accordingly, addition of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to the dialysate was able to restore most 34 of the UF capacity in this model 16. Other effect of NO that may affect the PM include generation of the powerful oxidant peroxynitrite 15, and post-translational modifications such as S-nitrosylation 16. Multiple interactions between NO, endothelial NOS and VEGF occur within endothelial cells. Both NO and the endothelial NOS are required for VEGFdriven angiogenesis and vascular permeability 32. On the other hand, VEGF is able to activate endothelial cells and it upregulates the production of NO 33. In turn, NO modulates and even suppresses the hypoxic induction of VEGF, creating a negative feed-back between NO and VEGF induction 28. Interestingly, such cross-talk exists in the PM, since upregulation of eNOS in a rat model of acute peritonitis is associated with down-regulation of VEGF 15. 4. CONTRIBUTION OF UREMIA AND GLYCEMIC CONTROL By analogy with the increased permeability of serosal membranes such as the pleurae or the pericardium, it has been suggested that uremia per se might increase PM permeability 34. That hypothesis has recently been supported by the association of several molecular mechanisms --upregulation of NOS, high levels of circulating RCOs and AGEs, increased growth factors-- with higher peritoneal permeability in a chronic uremic rat model 19. Diabetes may represent another factor that affect the PM. The CANUSA prospective study showed a greater proportion of diabetics among high transporter PD patients 3, and it has been suggested that diabetic patients have higher permeability for creatinine and lower UF than non-diabetic patients 35, 36. Recent studies performed in a streptozotocin-induced diabetic rat model 17, 18 showed that chronic hyperglycemia alone is sufficient to induce functional (increased permeability for small solutes) and structural (areas of vascular proliferation) changes in the PM, in parallel with the selective regulation of NOS isoforms and AGEs deposits 18. All the alterations were prevented by chronic insulin treatment, demonstrating that adequate control of glycemia in this diabetic rat model is sufficient to preserve PM integrity 18. Taken together, these data suggest an independent contribution of uremia and hyperglycemia in peritoneal changes during PD. 5. NEW THERAPEUTIC STRATEGIES AND PERSPECTIVES FOR PD The development of two-chamber bags has allowed a dramatic reduction in the GPDs generated du- MOLECULAR MECHANISMS INVOLVED IN P. P. ring heat sterilization of PD solutions. The twochamber system separates highly concentrated glucose from other components, allowing to sterilize glucose at a very low pH. Mixing of the two compartments results in a solution characterized by a very low level of GDPs and a more physiologic pH, and in which bicarbonate can replace lactate as buffer 37. When tested in vitro, such biocompatible dialysates have been shown to reduce AGE formation 38; decrease acute vasoactive effects on the peritoneal circulation 39; and improve ex vivo peritoneal macrophage function 40. Two randomized clinical trials using such solutions have shown no significant modifications of peritoneal transport parameters but an increase in dialysate CA125 (taken as a marker of mesothelial cell mass) and a decrease in dialysate hyaluronan (taken as a marker of peritoneal inflammation) 41, 42. Glucose-free PD solutions including icodextrin and amino-acids have also been recently introduced in order to minimize the deleterious effect of long-term exposure to hypertonic glucose 9. The development of animal models has provided rationale for other therapeutic strategies against structural and functional alterations of the PM. Inhibition of the formation of AGEs with compounds such as aminoguanidine or OPB-9195 are being currently evaluated, as well as the possibility of detoxifying RCOs by the glyoxalase pathway 37. Inhibition of the L-arginine: NO pathway, for instance with L-arginine analogues, has been shown to dramatically improve UF in rat model of acute peritonitis 16, but the clinical application of such compounds is currently limited by lack of specificity 43. Modulation of angiogenesis with agents that inhibit endothelial cell growth, adhesion or migration, or interfere with growth factors and their receptors have been proposed 44. Recently, adenovirus-mediated gene transfer of the endogenous inhibitor angiostatin was shown to improve structural and functional parameters in a chronic infusion rat model 20. However, it should be kept in mind that (i) different molecular pathways are probably involved in cancerous vs non-cancerous angiogenesis; (ii) angiogenic growth factors may participate in other physiological processes; (iii) there is little information on safety, longterm side-effects, and impact of antiangiogenic therapy on processes such as healing 44. The pharmacologic induction of AQP1 may also provide a target for manipulating water permeability across the PM and treating some cases of UF failure 45. Finally, a better knowledge of the molecular mechanisms operating in the PM will probably allow to identify genetic determinants involved in the individual variability of the PM permeability at the onset of PD. ACKNOWLEDGMENTS The author's studies were supported in part by the belgian agencies FNRS and FRSM, an ARC, grants from Baxter, the Fondation Saint-Luc and the Société de Néphrologie. The author wishes to thank Drs. G. Gillerot, E. Goffin, R. Krediet, N. Lameire, and T. Miyata for helpful discussions. ABBREVIATIONS AGEs, advanced glycation end products; AQP1, aquaporin-1; bFGF, basic fibroblast growth factor; EPSA, effective peritoneal surface area; GDPs, glucose degradation products; IL-6, interleukin-6; LNAME, NG-nitro-L-arginine methyl ester; MGO, methylglyoxal; NO, nitric oxide; NOS, nitric oxide synthase (eNOS, endothelial NOS ; iNOS, inducible NOS ; nNOS, neuronal NOS); PD, peritoneal dialysis; PM, peritoneal membrane; RCOs, reactive carbonyl compounds; TGF-, transforming growth factor ; UF, ultrafiltration; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. REFERENCES 1. Krediet RT: The peritoneal membrane in chronic peritoneal dialysis. Kidney Int 55: 341-356, 1999. 2. Davies SJ, Phillips L, Griffiths AM, Russell LH, Naish PF, Russell GI: What really happens to people on long-term peritoneal dialysis? Kidney Int 54: 2207-2217, 1998. 3. 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Stoenoiu MS, Ni J, Verkaeren C, Debaix H, Jonas J-C, Lameire N, Verbavatz J-M, Devuyst O: Corticosteroids induce expression of aquaporin-1 and increase transcellular water transport in rat peritoneum. J Am Soc Nephrol (in press). 37
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