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The renin–angiotensin–aldosterone system in peritoneal dialysis: is what is good for the kidney also good for the peritoneum?
mini review
http://www.kidney-international.org & 2010 International Society of Nephrology
The renin–angiotensin–aldosterone system in peritoneal dialysis: is what is good for the kidney also good for the peritoneum? Sharon J. Nessim1, Jeffrey Perl2 and Joanne M. Bargman3 1
Division of Nephrology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; 2Division of Nephrology, Department of Medicine, St Michael’s Hospital, Toronto, Ontario, Canada and 3Division of Nephrology, Department of Medicine, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
Morphological changes of the peritoneal membrane that occur over time among patients on peritoneal dialysis include fibrosis and neoangiogenesis. While the pathophysiologic mechanisms underlying these changes are not fully understood, the activation of the renin–angiotensin–aldosterone system (RAAS) may have an important role. Components of the RAAS are constitutively expressed within peritoneal mesothelial cells, and are upregulated in the presence of acute inflammation and chronic exposure to peritoneal dialysate. The high glucose concentration, low pH, and the presence of glucose degradation products in peritoneal dialysis solutions have all been implicated in modulation of peritoneal RAAS. Furthermore, activation of the RAAS, as well as the downstream production of transforming growth factor-b, contributes to epithelial-to-mesenchymal transformation of mesothelial cells, resulting in progressive fibrosis of the peritoneal membrane. This process also leads to increased vascular endothelial growth factor production, which promotes peritoneal neoangiogenesis. Functionally, these changes translate into reduced ultrafiltration capacity of the peritoneal membrane, which is an important cause of technique failure among patients on long-term peritoneal dialysis. This brief review will describe our current state of knowledge about the role of peritoneal RAAS in peritoneal membrane damage and potential strategies to protect the membrane. Kidney International (2010) 78, 23–28; doi:10.1038/ki.2010.90; published online 24 March 2010 KEYWORDS: angiotensin; fibrosis; neoangiogenesis; peritoneal dialysis; peritoneal membrane; renin
Correspondence: Joanne M. Bargman, Division of Nephrology, Department of Medicine, University Health Network, Toronto General Hospital, 200 Elizabeth Street, 8N-840, Toronto, Ontario M5G 2C4, Canada. E-mail: [email protected] Received 29 September 2009; revised 15 February 2010; accepted 17 February 2010; published online 24 March 2010 Kidney International (2010) 78, 23–28
The renin–angiotensin–aldosterone system (RAAS) has long been an important focus in nephrology because of its involvement in renal injury across all stages of chronic kidney disease. Its role in peritoneal membrane changes that occur over time in patients on peritoneal dialysis (PD) is an area of increasing interest. In this review, we will discuss the changes that occur in the peritoneal membrane of patients on PD, provide evidence for the presence of a local peritoneal RAAS, and highlight its potential role in the pathogenesis of progressive peritoneal membrane damage. We will also discuss potential therapeutic strategies for the prevention of this injury. PERITONEAL MEMBRANE CHANGES IN PATIENTS ON PD
The peritoneal membrane consists of a mesothelial monolayer, under which lies the submesothelial compact zone. This submesothelial layer consists of connective tissue with interspersed fibroblasts, mast cells, and macrophages. Within and deep to the submesothelial compact zone lie the peritoneal capillaries. It is across these layers that the processes of diffusion and ultrafiltration (UF) occur. Importantly, although the rare entity of encapsulating peritoneal sclerosis involves extensive changes within the visceral peritoneum, the morphological changes that commonly occur with increasing time on PD are seen predominantly within the parietal peritoneal membrane.1 Peritoneal membrane changes that occur in patients with advanced chronic kidney disease and on PD have been assessed in several peritoneal biopsy studies.2–6 In the largest of these studies, using careful specimen processing, control peritoneal biopsy samples obtained from living kidney donors were compared with uremic samples from predialysis patients and with samples from PD patients.5 These data showed that uremic patients relative to controls exhibited reactive mesothelial cell changes and an increased submesothelial compact zone thickness. When biopsies from uremic patients not on dialysis were compared with biopsies from PD patients, it was found that PD patients had more pronounced mesothelial cell changes, ranging from a reactive appearance to mesothelial cell loss. In addition, the median 23
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thickness of the submesothelial compact zone increased from 40 mm in normal subjects to 150 mm in uremic patients and to 270 mm in PD patients. Duration of PD therapy was also associated with increased compact zone thickness. In addition to these findings, prominent vascular changes were seen among patients on PD, including progressive subendothelial hyalinization with luminal narrowing or obliteration. These vascular changes, which involved venules to a greater degree than arterioles, were increasingly prevalent with time on PD, such that 89% of patients on PD for at least 6 years had evidence of vasculopathy. Another important vascular change observed with time on PD is peritoneal neoangiogenesis. This was first noted in the early 1990s in autopsies of PD patients.7 It was subsequently observed that rats exposed to daily infusions of standard 4.25% dextrose dialysis solution had significantly more peritoneal neoangiogenesis relative to rats infused with Ringer’s lactate.8 Human peritoneal biopsy data show an increase in peritoneal vessel number with time on PD, with the most vessels among those with peritoneal sclerosis.9 The peritoneal membrane changes that occur with time in PD patients are shown in Figure 1. Although the presence of morphological changes within the peritoneal membrane is not in and of itself meaningful, a relationship between these morphological changes and functional impairment of the peritoneal membrane in patients on PD make these findings relevant. In a study examining the changes in peritoneal membrane function over time, Davies10 reported both an increase in small solute transport and a reduction in peritoneal UF capacity over time
Peritoneal cavity
on PD. The more rapid removal of solute has been attributed to peritoneal neoangiogenesis with a resultant increase in effective peritoneal surface area, while the decline in UF is likely multifactorial. Not only is there more rapid dissipation of the glucose osmotic gradient as a result of the increased blood vessel number, but there is also a simultaneous reduction in the osmotic conductance of the membrane to glucose as a result of progressive peritoneal membrane fibrosis. UF failure remains an important cause of technique failure among patients on long-term PD. In one series, UF failure accounted for 24% of PD discontinuation overall, and 51% among those on PD for greater than 6 years.11,12 Understanding the basis for these peritoneal membrane changes is therefore highly relevant to prolonging technique survival in patients on PD. LOCAL PERITONEAL RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM
Although the systemic (or endocrine) RAAS is well understood, it has become increasingly clear that many tissues are able to locally synthesize all of the components of the RAAS. One of the most studied examples of such tissues is the kidney, where it has been shown that renal tubular cells express renin and angiotensin.13 These locally produced hormones then behave in an autocrine or paracrine manner, and one result is upregulation of transforming growth factor-b (TGF-b) and other factors such as aldosterone that promote interstitial fibrosis.14–16 Similarly, peritoneal mesothelial cells appear to have their own local RAAS. This has been shown in studies in which cultured human peritoneal mesothelial cells were shown to constitutively express angiotensinogen, angiotensin converting enzyme (ACE), the angiotensin II type 1 and type 2 receptors, as well as TGF-b and fibronectin.17,18
Mesothelial monolayer
MEDIATORS OF PERITONEAL RAAS ACTIVATION
Submesothelial compact zone
Deeper loose adipose connective tissue
Figure 1 | Changes in the peritoneal membrane with time on therapy. (a) Represents the peritoneal membrane at baseline. (b) Represents changes over time on therapy. The mesothelial monolayer undergoes injury and denudation with epithelial-tomesenchymal transition of mesothelial cells to a myofibroblastlike appearance. The submesothelial compact zone increases in thickness with increasing extracellular matrix deposition. In the deeper, loose, adipose connective tissue lies the vascular network that undergoes neovascularization and increased vasculopathy characterized by arteriolar and venular hyalinization, luminal distension, and obliteration. 24
Although peritoneal mesothelial cells constitutively express the genes of the RAAS and their effector cytokines, the infusion of dialysate into the peritoneal cavity appears to upregulate the expression of these genes. The basis for the RAAS activation may relate to one or more components of the bioincompatible solutions that are used, including the high glucose concentration, hyperosmolality, low pH, high lactate concentration, and the presence of glucose degradation products (GDPs). One of the most important activators of the RAAS is glucose. This is evidenced by the local RAAS activation that is seen in multiple tissues in diabetic patients.19 PD patients using conventional solutions have a local peritoneal microenvironment that consists of glucose concentrations ranging from 76 mmol/l (for a 1.5% dextrose solution) to 215 mmol/l (for a 4.25% dextrose solution). Because mesothelial cells have the capacity for glucose uptake,20 the glucose-rich environment leads to intracellular signaling that results in RAAS activation. It has been shown that exposing human peritoneal mesothelial cells to a glucose-rich environment Kidney International (2010) 78, 23–28
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SJ Nessim et al.: Role of local RAAS in peritoneal membrane injury
leads to upregulation of angiotensinogen, ACE, and angiotensin II receptor type 1 expression.17 Exposure to glucose has also been shown to increase angiotensin II production and secretion, leading to upregulation of TGF-b and fibronectin expression, and the stimulation of vascular endothelial growth factor (VEGF) and procollagen secretion.21,22 The increase in TGF-b associated with peritoneal glucose exposure may be further augmented in the presence of mesothelial cell stretch or fluid shear stress.23 In addition to the high glucose concentration in standard dialysis solutions, conventional peritoneal dialysate has an acidic pH of approximately 5.4. The potential role of this ‘unphysiologic’ pH in RAAS activation was shown in a study in which exposure of rats to acidic dialysate was associated with peritoneal thickening and mesothelial cell loss, with abrogation of this effect in the presence of systemic RAAS blockade.24 The role of the acidic pH of dialysate and GDPs was assessed in a study in which rats were treated with either standard dialysate or neutral pH, low GDP dialysate. In this study, TGF-b and VEGF expression, both of which are upregulated by RAAS, were significantly increased in the standard dialysate relative to the more biocompatible dialysate, suggesting a role for low pH, GDPs or both in dialysate-induced RAAS activation.25 Beyond the chronic exposure of the peritoneum to unphysiologic dialysis solutions, acute inflammatory stimuli such as peritonitis can activate the RAAS. Peritonitis has been shown to cause marked upregulation of the expression of angiotensin II in human peritoneal mesothelial cells, leading to increased fibronectin expression.18 Furthermore, rat models of PD peritonitis have shown the ability of peritonitis to increase TGF-b levels and induce peritoneal fibrosis, and the effectiveness of both irbesartan and spironolactone in the mitigation of this fibrosis.26 The benefit of aldosterone antagonism highlights the multiple mediators of the profibrotic effects of RAAS activation, with contributions from both angiotensin-II-mediated TGF-b production and aldosterone.
expression of the antifibrotic gene, which produced a TGF-binhibiting proteoglycan, dramatically reduced the degree of compact zone fibrosis induced by exposure to standard dialysate. In addition, expression of the antiangiogenic gene, angiostatin, prevented the neoangiogenesis and improved the UF dysfunction seen in the rats exposed to the dialysate. The cascade of events that leads to UF dysfunction and membrane failure is shown in Figure 2. The mechanism by which TGF-b and other inflammatory stimuli lead to peritoneal fibrosis and neoangiogenesis appears to be the induction of the process of epithelial-tomesenchymal transition of peritoneal mesothelial cells.29,30 Specifically, with time on PD, mesothelial cells show a progressive loss of epithelial phenotype and acquire myofibroblast-like characteristics that allow them to migrate into the submesothelial compact zone and produce extracellular matrix, along with elaboration of growth factors such as VEGF. The stimuli for epithelial-to-mesenchymal transition, reviewed in detail by Aroeira et al.,31 include inflammation, advanced glycation end products, GDPs, low pH, mechanical injury, hemoperitoneum, and angiotensin II. Because angiotensin II, acting both directly as well as indirectly via TGF-b production, has been shown to be an important mediator of this process,32 reducing RAAS activation may be of critical importance in preventing or limiting the extent of epithelialto-mesenchymal transition. Although the data are highly suggestive of a role for RAAS activation in peritoneal membrane injury, it is important to point out that some of the animal studies involved only
Glucose
Uremic serum
On the basis of the above data, it is clear that peritoneal RAAS activation leads to upregulation of profibrotic factors such as TGF-b and angiogenic factors such as VEGF. Several studies have shown the direct role of these factors in the submesothelial compact zone fibrosis and neoangiogenesis that is observed in PD patients. In an elegant gene transfer study, Margetts et al.27 looked at the effect of overexpression of TGF-b in rat peritoneal mesothelial cells on several histologic and clinical endpoints. In this study, the rats exposed to higher peritoneal TGF-b levels had an increased submesothelial compact zone thickness. In addition, they had higher effluent VEGF levels, along with increased peritoneal blood vessel number and decreased net UF. This was followed by another rat study involving transfer of antifibrotic and antiangiogenic genes to the rat peritoneum.28 As expected, Kidney International (2010) 78, 23–28
GDPs
Peritonitis
Peritoneal mesothelium AT1-R AT2-R
ACE
Angiotensinogen
ROLE OF PERITONEAL RAAS ACTIVATION IN PERITONEAL MEMBRANE DAMAGE
Acidic pH
Ang-I
TGF-β
VEGF
Fibrosis
Angiogenesis
Ang-II
Peritoneal membrane dysfunction and UF failure
Small solute permeability
Figure 2 | Peritoneal effects of the Renal–Angiotensin–Aldosterone system (RAAS). Activation of the RAAS is induced by a variety of local and systemic stimuli. Local peritoneal autocrine/paracrine activity of the RAAS stimulates mesothelial cell production of profibrotic and pro-angiogenic cytokines leading to peritoneal membrane neoangionesis, fibrosis and progressive peritoneal membrane injury. Abbreviations: ACE, angiotensin converting enzyme; Ang-I, angiotensin I; Ang-II, angiotensin II; AT1-R, angiotensin II type 1 receptor; AT2-R, angiotensin II type 2 receptor; GDP, glucose degradation product; TGF-b, transforming growth factor-b; VEGF, vascular endothelial growth factor; UF, ultrafiltration. 25
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short-term exposure to the potential mediators of the RAAS, and almost all involved rats with intact renal function. It is unknown whether these data can be extrapolated to long-term exposure to dialysate in a uremic host. POTENTIAL STRATEGIES FOR PERITONEAL MEMBRANE PRESERVATION
Given the important role of the local peritoneal RAAS in the peritoneal membrane damage that occurs over time in PD patients, it follows that peritoneal injury may be abrogated or prevented by targeting the peritoneal RAAS. Therapeutic measures can be divided into (1) systemic blockade of the RAAS and (2) strategies to decrease local peritoneal RAAS activation. Systemic RAAS blockade
The effect of RAAS blockade in the prevention of peritoneal membrane damage has been studied in vitro, as well as in animal and human studies. Although the majority of studies have involved use of ACE inhibitors and angiotensin-receptor blockers (ARBs), other agents that block the RAAS such as direct renin inhibitors and aldosterone antagonists could also be of potential benefit. In vitro, it has been shown that both losartan and captopril inhibit glucose-induced TGF-b and fibronectin expression in cultured human peritoneal mesothelial cells.17 Further, addition of captopril results in a concentrationdependent decrease in VEGF synthesis.33 These results were supported by a study in which rats were administered either intraperitoneal saline, 4.25% dextrose, or 4.25% dextrose in combination with oral enalapril.34 In this study, the rats treated with the ACE inhibitor had a dramatic reduction in the degree of submesothelial fibrosis relative to those who were exposed to dialysate alone. In addition, effluent TGF-b levels, which were elevated in the rats exposed to dialysate, were undetectable in the ACE inhibitor-treated rats. Another study by the same authors showed that use of an ACE inhibitor or ARB had similar beneficial effects on peritoneal morphology and function.35 The human data to date have been limited. The first study to have looked at this retrospectively studied 66 patients who were on PD for at least 2 years.36 Changes in transport status over time were assessed in those who had been on ACE inhibitors or ARBs, as well as those who were not on any form of RAAS blockade. In this study, although small solute transport increased with time on PD in the control group, there was no appreciable change in transport status among those on ACE inhibitors or ARBs. The same authors subsequently examined changes in solute transport as well as technique survival in a larger cohort of patients.37 Once again, the group of patients who were on ACE inhibitors or ARBs did not show the increased solute transport with time on therapy seen in the controls. However, no difference in PD technique survival was observed. In a recent retrospective analysis, a powerful survival benefit in those PD patients who received an ACE inhibitor or ARB was shown. However, the association of these medications with peritoneal membrane function was not examined.38 26
SJ Nessim et al.: Role of local RAAS in peritoneal membrane injury
Although these studies are informative, there are no studies in PD patients to date that have assessed the longitudinal effect of RAAS blockade on peritoneal membrane histology. Moreover, of critical importance, the retrospective nature of the human studies to date leads to potential for residual confounding, in that those patients who were on some form of RAAS blockade may have been systematically different from those who did not receive these agents. To avoid these biases, it is clear that randomized controlled trials are needed. Because membrane failure only accounts for a fraction of PD technique failure, large numbers of patients would be required to have adequate power to detect an effect of RAAS blockade on PD technique failure. Furthermore, because many PD patients are already on some form of RAAS blockade for evidence-based indications such as vascular protection or preservation of residual renal function, the smaller number of PD patients eligible for randomization would make recruitment more difficult and could potentially affect the generalizability of the results. Attenuation of local RAAS activation
Although systemic RAAS blockade may be an effective strategy to preserve peritoneal membrane integrity, it has been postulated that long-term use of more physiologic PD solutions might reduce local RAAS activation. Use of a ‘glucose-sparing regimen’ substituting icodextrin or aminoacid-based PD solutions could minimize the glucosemediated effects discussed above. Studies of human peritoneal mesothelial cells incubated with icodextrin have shown improvement in markers of mesothelial cell function and proliferation.39 However, these results have been refuted by other studies that have shown equal mesothelial cell cytotoxicity when incubated with either icodextrin or glucose-based PD solutions.40,41 In rats exposed to either icodextrin or a 2.5% dextrose solution, the icodextrin-treated rats showed a reduction in both peritoneal membrane thickness and TGF-b staining on histologic examination.42 Furthermore, a recent study compared the effect of 8 weeks of intraperitoneal exposure to 4.25% dextrose solution vs icodextrin in diabetic rats with 5/6 kidney ablation.43 In this study, as compared with the rats exposed to the dextrose solution, the icodextrin-treated rats showed less of an increase in submesothelial fibrosis and neoangiogenesis, as well as reduced fibronectin, VEGF, and advanced glycation end-product expression. Further data come from a subgroup analysis of the European Automated PD Outcome Study, which prospectively followed 177 anuric automated PD patients for 2 years. In this study, those who were treated with icodextrin vs glucose-based solution experienced a slower increase in small solute transport over the course of the 2-year study period, despite more rapid peritoneal transport status and worse peritoneal UF capacity at baseline.44 An alternative dialysis strategy would involve the longterm use of neutral pH, low GDP solutions. In animal models, use of neutral pH, low GDP dialysate has been Kidney International (2010) 78, 23–28
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associated with reduced TGF-b and VEGF expression,25 less peritoneal fibrosis and neoangiogenesis, and less of an increase in peritoneal transport status compared to conventional dialysate.45 In human studies, several reports have revealed higher levels of dialysate effluent CA-125 with the use of the neutral pH solutions when compared to conventional PD solutions.46,47 However, markers of peritoneal membrane fibrosis such as dialysate effluent TGF-b and procollagen I C-terminal peptide are not influenced by the use of neutral pH, low GDP solutions.48 Of concern, several randomized controlled trials have revealed a tendency to both a reduction in peritoneal UF capacity and an increase in peritoneal transport status with the use of the neutral pH, low GDP solutions compared to conventional dialysis solutions.46,47 Because long-term, prospective human data are lacking and the cost of the newer solutions is higher than conventional dialysate, it is difficult to make a recommendation at this time regarding the optimal dialysate regimen for peritoneal membrane preservation. Another avenue that has yet to be explored is the vitamin D axis. Vitamin D is known to modulate RAAS activation in other tissues, such as the kidney. Deficiency of vitamin D is associated with upregulation of RAAS activity and vitamin D supplementation has been shown to reduce RAAS activation.49–51 Although it is known that most PD patients are deficient in both 25-hydroxyvitamin D and 1,25dihydroxyvitamin D,52 any potential role for supplementation with active and/or inactive forms of vitamin D in mitigating peritoneal RAAS activation has yet to be studied.
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SUMMARY
Long-term PD is associated with both morphological and functional changes within the peritoneal membrane. Although the etiology of these changes is likely multifactorial, there are in vitro, animal and human data to suggest an important role for the RAAS in the pathogenesis of the peritoneal membrane fibrosis and neoangiogenesis that occurs over time. Although blockade of the RAAS using ACE inhibitors and ARBs may be important in ‘peritoneoprotection’, this approach requires further study. Additional research is required to determine the optimal PD regimen that will provide effective solute clearance and UF while reducing local peritoneal RAAS activation and preserving peritoneal membrane integrity. DISCLOSURE
SJN, JP, and JMB have received speaker honoraria from Baxter Healthcare.
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Kidney International (2010) 78, 23–28
http://www.kidney-international.org & 2010 International Society of Nephrology
The renin–angiotensin–aldosterone system in peritoneal dialysis: is what is good for the kidney also good for the peritoneum? Sharon J. Nessim1, Jeffrey Perl2 and Joanne M. Bargman3 1
Division of Nephrology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; 2Division of Nephrology, Department of Medicine, St Michael’s Hospital, Toronto, Ontario, Canada and 3Division of Nephrology, Department of Medicine, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
Morphological changes of the peritoneal membrane that occur over time among patients on peritoneal dialysis include fibrosis and neoangiogenesis. While the pathophysiologic mechanisms underlying these changes are not fully understood, the activation of the renin–angiotensin–aldosterone system (RAAS) may have an important role. Components of the RAAS are constitutively expressed within peritoneal mesothelial cells, and are upregulated in the presence of acute inflammation and chronic exposure to peritoneal dialysate. The high glucose concentration, low pH, and the presence of glucose degradation products in peritoneal dialysis solutions have all been implicated in modulation of peritoneal RAAS. Furthermore, activation of the RAAS, as well as the downstream production of transforming growth factor-b, contributes to epithelial-to-mesenchymal transformation of mesothelial cells, resulting in progressive fibrosis of the peritoneal membrane. This process also leads to increased vascular endothelial growth factor production, which promotes peritoneal neoangiogenesis. Functionally, these changes translate into reduced ultrafiltration capacity of the peritoneal membrane, which is an important cause of technique failure among patients on long-term peritoneal dialysis. This brief review will describe our current state of knowledge about the role of peritoneal RAAS in peritoneal membrane damage and potential strategies to protect the membrane. Kidney International (2010) 78, 23–28; doi:10.1038/ki.2010.90; published online 24 March 2010 KEYWORDS: angiotensin; fibrosis; neoangiogenesis; peritoneal dialysis; peritoneal membrane; renin
Correspondence: Joanne M. Bargman, Division of Nephrology, Department of Medicine, University Health Network, Toronto General Hospital, 200 Elizabeth Street, 8N-840, Toronto, Ontario M5G 2C4, Canada. E-mail: [email protected] Received 29 September 2009; revised 15 February 2010; accepted 17 February 2010; published online 24 March 2010 Kidney International (2010) 78, 23–28
The renin–angiotensin–aldosterone system (RAAS) has long been an important focus in nephrology because of its involvement in renal injury across all stages of chronic kidney disease. Its role in peritoneal membrane changes that occur over time in patients on peritoneal dialysis (PD) is an area of increasing interest. In this review, we will discuss the changes that occur in the peritoneal membrane of patients on PD, provide evidence for the presence of a local peritoneal RAAS, and highlight its potential role in the pathogenesis of progressive peritoneal membrane damage. We will also discuss potential therapeutic strategies for the prevention of this injury. PERITONEAL MEMBRANE CHANGES IN PATIENTS ON PD
The peritoneal membrane consists of a mesothelial monolayer, under which lies the submesothelial compact zone. This submesothelial layer consists of connective tissue with interspersed fibroblasts, mast cells, and macrophages. Within and deep to the submesothelial compact zone lie the peritoneal capillaries. It is across these layers that the processes of diffusion and ultrafiltration (UF) occur. Importantly, although the rare entity of encapsulating peritoneal sclerosis involves extensive changes within the visceral peritoneum, the morphological changes that commonly occur with increasing time on PD are seen predominantly within the parietal peritoneal membrane.1 Peritoneal membrane changes that occur in patients with advanced chronic kidney disease and on PD have been assessed in several peritoneal biopsy studies.2–6 In the largest of these studies, using careful specimen processing, control peritoneal biopsy samples obtained from living kidney donors were compared with uremic samples from predialysis patients and with samples from PD patients.5 These data showed that uremic patients relative to controls exhibited reactive mesothelial cell changes and an increased submesothelial compact zone thickness. When biopsies from uremic patients not on dialysis were compared with biopsies from PD patients, it was found that PD patients had more pronounced mesothelial cell changes, ranging from a reactive appearance to mesothelial cell loss. In addition, the median 23
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thickness of the submesothelial compact zone increased from 40 mm in normal subjects to 150 mm in uremic patients and to 270 mm in PD patients. Duration of PD therapy was also associated with increased compact zone thickness. In addition to these findings, prominent vascular changes were seen among patients on PD, including progressive subendothelial hyalinization with luminal narrowing or obliteration. These vascular changes, which involved venules to a greater degree than arterioles, were increasingly prevalent with time on PD, such that 89% of patients on PD for at least 6 years had evidence of vasculopathy. Another important vascular change observed with time on PD is peritoneal neoangiogenesis. This was first noted in the early 1990s in autopsies of PD patients.7 It was subsequently observed that rats exposed to daily infusions of standard 4.25% dextrose dialysis solution had significantly more peritoneal neoangiogenesis relative to rats infused with Ringer’s lactate.8 Human peritoneal biopsy data show an increase in peritoneal vessel number with time on PD, with the most vessels among those with peritoneal sclerosis.9 The peritoneal membrane changes that occur with time in PD patients are shown in Figure 1. Although the presence of morphological changes within the peritoneal membrane is not in and of itself meaningful, a relationship between these morphological changes and functional impairment of the peritoneal membrane in patients on PD make these findings relevant. In a study examining the changes in peritoneal membrane function over time, Davies10 reported both an increase in small solute transport and a reduction in peritoneal UF capacity over time
Peritoneal cavity
on PD. The more rapid removal of solute has been attributed to peritoneal neoangiogenesis with a resultant increase in effective peritoneal surface area, while the decline in UF is likely multifactorial. Not only is there more rapid dissipation of the glucose osmotic gradient as a result of the increased blood vessel number, but there is also a simultaneous reduction in the osmotic conductance of the membrane to glucose as a result of progressive peritoneal membrane fibrosis. UF failure remains an important cause of technique failure among patients on long-term PD. In one series, UF failure accounted for 24% of PD discontinuation overall, and 51% among those on PD for greater than 6 years.11,12 Understanding the basis for these peritoneal membrane changes is therefore highly relevant to prolonging technique survival in patients on PD. LOCAL PERITONEAL RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM
Although the systemic (or endocrine) RAAS is well understood, it has become increasingly clear that many tissues are able to locally synthesize all of the components of the RAAS. One of the most studied examples of such tissues is the kidney, where it has been shown that renal tubular cells express renin and angiotensin.13 These locally produced hormones then behave in an autocrine or paracrine manner, and one result is upregulation of transforming growth factor-b (TGF-b) and other factors such as aldosterone that promote interstitial fibrosis.14–16 Similarly, peritoneal mesothelial cells appear to have their own local RAAS. This has been shown in studies in which cultured human peritoneal mesothelial cells were shown to constitutively express angiotensinogen, angiotensin converting enzyme (ACE), the angiotensin II type 1 and type 2 receptors, as well as TGF-b and fibronectin.17,18
Mesothelial monolayer
MEDIATORS OF PERITONEAL RAAS ACTIVATION
Submesothelial compact zone
Deeper loose adipose connective tissue
Figure 1 | Changes in the peritoneal membrane with time on therapy. (a) Represents the peritoneal membrane at baseline. (b) Represents changes over time on therapy. The mesothelial monolayer undergoes injury and denudation with epithelial-tomesenchymal transition of mesothelial cells to a myofibroblastlike appearance. The submesothelial compact zone increases in thickness with increasing extracellular matrix deposition. In the deeper, loose, adipose connective tissue lies the vascular network that undergoes neovascularization and increased vasculopathy characterized by arteriolar and venular hyalinization, luminal distension, and obliteration. 24
Although peritoneal mesothelial cells constitutively express the genes of the RAAS and their effector cytokines, the infusion of dialysate into the peritoneal cavity appears to upregulate the expression of these genes. The basis for the RAAS activation may relate to one or more components of the bioincompatible solutions that are used, including the high glucose concentration, hyperosmolality, low pH, high lactate concentration, and the presence of glucose degradation products (GDPs). One of the most important activators of the RAAS is glucose. This is evidenced by the local RAAS activation that is seen in multiple tissues in diabetic patients.19 PD patients using conventional solutions have a local peritoneal microenvironment that consists of glucose concentrations ranging from 76 mmol/l (for a 1.5% dextrose solution) to 215 mmol/l (for a 4.25% dextrose solution). Because mesothelial cells have the capacity for glucose uptake,20 the glucose-rich environment leads to intracellular signaling that results in RAAS activation. It has been shown that exposing human peritoneal mesothelial cells to a glucose-rich environment Kidney International (2010) 78, 23–28
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leads to upregulation of angiotensinogen, ACE, and angiotensin II receptor type 1 expression.17 Exposure to glucose has also been shown to increase angiotensin II production and secretion, leading to upregulation of TGF-b and fibronectin expression, and the stimulation of vascular endothelial growth factor (VEGF) and procollagen secretion.21,22 The increase in TGF-b associated with peritoneal glucose exposure may be further augmented in the presence of mesothelial cell stretch or fluid shear stress.23 In addition to the high glucose concentration in standard dialysis solutions, conventional peritoneal dialysate has an acidic pH of approximately 5.4. The potential role of this ‘unphysiologic’ pH in RAAS activation was shown in a study in which exposure of rats to acidic dialysate was associated with peritoneal thickening and mesothelial cell loss, with abrogation of this effect in the presence of systemic RAAS blockade.24 The role of the acidic pH of dialysate and GDPs was assessed in a study in which rats were treated with either standard dialysate or neutral pH, low GDP dialysate. In this study, TGF-b and VEGF expression, both of which are upregulated by RAAS, were significantly increased in the standard dialysate relative to the more biocompatible dialysate, suggesting a role for low pH, GDPs or both in dialysate-induced RAAS activation.25 Beyond the chronic exposure of the peritoneum to unphysiologic dialysis solutions, acute inflammatory stimuli such as peritonitis can activate the RAAS. Peritonitis has been shown to cause marked upregulation of the expression of angiotensin II in human peritoneal mesothelial cells, leading to increased fibronectin expression.18 Furthermore, rat models of PD peritonitis have shown the ability of peritonitis to increase TGF-b levels and induce peritoneal fibrosis, and the effectiveness of both irbesartan and spironolactone in the mitigation of this fibrosis.26 The benefit of aldosterone antagonism highlights the multiple mediators of the profibrotic effects of RAAS activation, with contributions from both angiotensin-II-mediated TGF-b production and aldosterone.
expression of the antifibrotic gene, which produced a TGF-binhibiting proteoglycan, dramatically reduced the degree of compact zone fibrosis induced by exposure to standard dialysate. In addition, expression of the antiangiogenic gene, angiostatin, prevented the neoangiogenesis and improved the UF dysfunction seen in the rats exposed to the dialysate. The cascade of events that leads to UF dysfunction and membrane failure is shown in Figure 2. The mechanism by which TGF-b and other inflammatory stimuli lead to peritoneal fibrosis and neoangiogenesis appears to be the induction of the process of epithelial-tomesenchymal transition of peritoneal mesothelial cells.29,30 Specifically, with time on PD, mesothelial cells show a progressive loss of epithelial phenotype and acquire myofibroblast-like characteristics that allow them to migrate into the submesothelial compact zone and produce extracellular matrix, along with elaboration of growth factors such as VEGF. The stimuli for epithelial-to-mesenchymal transition, reviewed in detail by Aroeira et al.,31 include inflammation, advanced glycation end products, GDPs, low pH, mechanical injury, hemoperitoneum, and angiotensin II. Because angiotensin II, acting both directly as well as indirectly via TGF-b production, has been shown to be an important mediator of this process,32 reducing RAAS activation may be of critical importance in preventing or limiting the extent of epithelialto-mesenchymal transition. Although the data are highly suggestive of a role for RAAS activation in peritoneal membrane injury, it is important to point out that some of the animal studies involved only
Glucose
Uremic serum
On the basis of the above data, it is clear that peritoneal RAAS activation leads to upregulation of profibrotic factors such as TGF-b and angiogenic factors such as VEGF. Several studies have shown the direct role of these factors in the submesothelial compact zone fibrosis and neoangiogenesis that is observed in PD patients. In an elegant gene transfer study, Margetts et al.27 looked at the effect of overexpression of TGF-b in rat peritoneal mesothelial cells on several histologic and clinical endpoints. In this study, the rats exposed to higher peritoneal TGF-b levels had an increased submesothelial compact zone thickness. In addition, they had higher effluent VEGF levels, along with increased peritoneal blood vessel number and decreased net UF. This was followed by another rat study involving transfer of antifibrotic and antiangiogenic genes to the rat peritoneum.28 As expected, Kidney International (2010) 78, 23–28
GDPs
Peritonitis
Peritoneal mesothelium AT1-R AT2-R
ACE
Angiotensinogen
ROLE OF PERITONEAL RAAS ACTIVATION IN PERITONEAL MEMBRANE DAMAGE
Acidic pH
Ang-I
TGF-β
VEGF
Fibrosis
Angiogenesis
Ang-II
Peritoneal membrane dysfunction and UF failure
Small solute permeability
Figure 2 | Peritoneal effects of the Renal–Angiotensin–Aldosterone system (RAAS). Activation of the RAAS is induced by a variety of local and systemic stimuli. Local peritoneal autocrine/paracrine activity of the RAAS stimulates mesothelial cell production of profibrotic and pro-angiogenic cytokines leading to peritoneal membrane neoangionesis, fibrosis and progressive peritoneal membrane injury. Abbreviations: ACE, angiotensin converting enzyme; Ang-I, angiotensin I; Ang-II, angiotensin II; AT1-R, angiotensin II type 1 receptor; AT2-R, angiotensin II type 2 receptor; GDP, glucose degradation product; TGF-b, transforming growth factor-b; VEGF, vascular endothelial growth factor; UF, ultrafiltration. 25
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short-term exposure to the potential mediators of the RAAS, and almost all involved rats with intact renal function. It is unknown whether these data can be extrapolated to long-term exposure to dialysate in a uremic host. POTENTIAL STRATEGIES FOR PERITONEAL MEMBRANE PRESERVATION
Given the important role of the local peritoneal RAAS in the peritoneal membrane damage that occurs over time in PD patients, it follows that peritoneal injury may be abrogated or prevented by targeting the peritoneal RAAS. Therapeutic measures can be divided into (1) systemic blockade of the RAAS and (2) strategies to decrease local peritoneal RAAS activation. Systemic RAAS blockade
The effect of RAAS blockade in the prevention of peritoneal membrane damage has been studied in vitro, as well as in animal and human studies. Although the majority of studies have involved use of ACE inhibitors and angiotensin-receptor blockers (ARBs), other agents that block the RAAS such as direct renin inhibitors and aldosterone antagonists could also be of potential benefit. In vitro, it has been shown that both losartan and captopril inhibit glucose-induced TGF-b and fibronectin expression in cultured human peritoneal mesothelial cells.17 Further, addition of captopril results in a concentrationdependent decrease in VEGF synthesis.33 These results were supported by a study in which rats were administered either intraperitoneal saline, 4.25% dextrose, or 4.25% dextrose in combination with oral enalapril.34 In this study, the rats treated with the ACE inhibitor had a dramatic reduction in the degree of submesothelial fibrosis relative to those who were exposed to dialysate alone. In addition, effluent TGF-b levels, which were elevated in the rats exposed to dialysate, were undetectable in the ACE inhibitor-treated rats. Another study by the same authors showed that use of an ACE inhibitor or ARB had similar beneficial effects on peritoneal morphology and function.35 The human data to date have been limited. The first study to have looked at this retrospectively studied 66 patients who were on PD for at least 2 years.36 Changes in transport status over time were assessed in those who had been on ACE inhibitors or ARBs, as well as those who were not on any form of RAAS blockade. In this study, although small solute transport increased with time on PD in the control group, there was no appreciable change in transport status among those on ACE inhibitors or ARBs. The same authors subsequently examined changes in solute transport as well as technique survival in a larger cohort of patients.37 Once again, the group of patients who were on ACE inhibitors or ARBs did not show the increased solute transport with time on therapy seen in the controls. However, no difference in PD technique survival was observed. In a recent retrospective analysis, a powerful survival benefit in those PD patients who received an ACE inhibitor or ARB was shown. However, the association of these medications with peritoneal membrane function was not examined.38 26
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Although these studies are informative, there are no studies in PD patients to date that have assessed the longitudinal effect of RAAS blockade on peritoneal membrane histology. Moreover, of critical importance, the retrospective nature of the human studies to date leads to potential for residual confounding, in that those patients who were on some form of RAAS blockade may have been systematically different from those who did not receive these agents. To avoid these biases, it is clear that randomized controlled trials are needed. Because membrane failure only accounts for a fraction of PD technique failure, large numbers of patients would be required to have adequate power to detect an effect of RAAS blockade on PD technique failure. Furthermore, because many PD patients are already on some form of RAAS blockade for evidence-based indications such as vascular protection or preservation of residual renal function, the smaller number of PD patients eligible for randomization would make recruitment more difficult and could potentially affect the generalizability of the results. Attenuation of local RAAS activation
Although systemic RAAS blockade may be an effective strategy to preserve peritoneal membrane integrity, it has been postulated that long-term use of more physiologic PD solutions might reduce local RAAS activation. Use of a ‘glucose-sparing regimen’ substituting icodextrin or aminoacid-based PD solutions could minimize the glucosemediated effects discussed above. Studies of human peritoneal mesothelial cells incubated with icodextrin have shown improvement in markers of mesothelial cell function and proliferation.39 However, these results have been refuted by other studies that have shown equal mesothelial cell cytotoxicity when incubated with either icodextrin or glucose-based PD solutions.40,41 In rats exposed to either icodextrin or a 2.5% dextrose solution, the icodextrin-treated rats showed a reduction in both peritoneal membrane thickness and TGF-b staining on histologic examination.42 Furthermore, a recent study compared the effect of 8 weeks of intraperitoneal exposure to 4.25% dextrose solution vs icodextrin in diabetic rats with 5/6 kidney ablation.43 In this study, as compared with the rats exposed to the dextrose solution, the icodextrin-treated rats showed less of an increase in submesothelial fibrosis and neoangiogenesis, as well as reduced fibronectin, VEGF, and advanced glycation end-product expression. Further data come from a subgroup analysis of the European Automated PD Outcome Study, which prospectively followed 177 anuric automated PD patients for 2 years. In this study, those who were treated with icodextrin vs glucose-based solution experienced a slower increase in small solute transport over the course of the 2-year study period, despite more rapid peritoneal transport status and worse peritoneal UF capacity at baseline.44 An alternative dialysis strategy would involve the longterm use of neutral pH, low GDP solutions. In animal models, use of neutral pH, low GDP dialysate has been Kidney International (2010) 78, 23–28
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associated with reduced TGF-b and VEGF expression,25 less peritoneal fibrosis and neoangiogenesis, and less of an increase in peritoneal transport status compared to conventional dialysate.45 In human studies, several reports have revealed higher levels of dialysate effluent CA-125 with the use of the neutral pH solutions when compared to conventional PD solutions.46,47 However, markers of peritoneal membrane fibrosis such as dialysate effluent TGF-b and procollagen I C-terminal peptide are not influenced by the use of neutral pH, low GDP solutions.48 Of concern, several randomized controlled trials have revealed a tendency to both a reduction in peritoneal UF capacity and an increase in peritoneal transport status with the use of the neutral pH, low GDP solutions compared to conventional dialysis solutions.46,47 Because long-term, prospective human data are lacking and the cost of the newer solutions is higher than conventional dialysate, it is difficult to make a recommendation at this time regarding the optimal dialysate regimen for peritoneal membrane preservation. Another avenue that has yet to be explored is the vitamin D axis. Vitamin D is known to modulate RAAS activation in other tissues, such as the kidney. Deficiency of vitamin D is associated with upregulation of RAAS activity and vitamin D supplementation has been shown to reduce RAAS activation.49–51 Although it is known that most PD patients are deficient in both 25-hydroxyvitamin D and 1,25dihydroxyvitamin D,52 any potential role for supplementation with active and/or inactive forms of vitamin D in mitigating peritoneal RAAS activation has yet to be studied.
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SUMMARY
Long-term PD is associated with both morphological and functional changes within the peritoneal membrane. Although the etiology of these changes is likely multifactorial, there are in vitro, animal and human data to suggest an important role for the RAAS in the pathogenesis of the peritoneal membrane fibrosis and neoangiogenesis that occurs over time. Although blockade of the RAAS using ACE inhibitors and ARBs may be important in ‘peritoneoprotection’, this approach requires further study. Additional research is required to determine the optimal PD regimen that will provide effective solute clearance and UF while reducing local peritoneal RAAS activation and preserving peritoneal membrane integrity. DISCLOSURE
SJN, JP, and JMB have received speaker honoraria from Baxter Healthcare.
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