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Inflammation and Fibrosis |
Department of Medicine, University of Hong Kong, Hong Kong SAR, PR China
Correspondence to: T.M. Chan, Department of Medicine, Room 303, New Clinical Building, Queen Mary Hospital, Pokfulam, Hong Kong SAR, PR China. dtmchan{at}hkucc.hku.hk
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ABSTRACT |
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 TOP ABSTRACT DISCUSSIONCONCLUSIONSREFERENCES |
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Background: Compelling data underscore the
bioincompatible nature of glucose-based peritoneal dialysis (PD) solutions and
their detrimental effects on peritoneal physiology and morphology. New PD
solutions have been formulated to tackle common clinical problems such as
inadequate ultrafiltration or malnutrition, and to improve
biocompatibility—the latter aimed at preserving the structural and
functional integrity of the peritoneum and reducing adverse systemic effects
on the patient. Methods: This article reviews the factors in PD fluids
that alter normal peritoneal anatomy and physiology, and the data that
illustrate approaches to investigating the local and systemic biocompatibility
of new PD solutions. Results: Chronic exposure of the peritoneal membrane to
glucose-based PD solutions results in denudation of the mesothelium, thickened
submesothelium, and hyalinization of the vasculature, often resulting in
reduced or lost solute and water clearance. Data from in vitro or
animal experiments and clinical studies have shown improved biocompatibility
profiles with new PD solutions that are glucose-free (that is, dialysates with
amino acids or icodextrin), bicarbonate-buffered, or compartmentalized during
heat sterilization to reduce levels of glucose degradation products. Improved
biocompatibility is denoted by reduced induction of proinflammatory,
profibrotic, or angiogenic growth factors in mesothelial cells and
macrophages, or by less perturbation of leukocyte phagocytic function. Conclusions: Data from in vitro and animal
experiments show more favorable biocompatibility profiles with new PD fluids
than with glucose-based dialysates. Clinical studies are ongoing to assess the
impact of the new PD fluids on peritoneal function, morbidity, and
mortality.
KEY WORDS: Peritoneum; glucose; amino acid; icodextrin; bicarbonate.
Peritoneal dialysis (PD) has been established as an effective, affordable, and flexible home-based therapy, but its long-term success is limited by progressive deterioration of peritoneal transport functions (1,2). The main reasons for technique failure include fibrosis following peritonitis, ultrafiltration failure related to neoangiogenesis, and solute transport failure related to mesothelial denudation and progressive submesothelial fibrosis and thickening consequent to chronic exposure to unphysiologic dialysates (3,4). The present review describes the morphologic changes in the peritoneum after long-term PD with glucose-based dialysates, and the accumulating data regarding the effects of new PD solutions on the structural and functional integrity of the peritoneum.
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DISCUSSION |
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TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
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Progressive thickening of the submesothelium is observed with increasing duration on PD, reaching 600 µm in a cohort of patients that underwent PD for more than 8 years (6). Severe vascular changes are also observed in patients maintained on PD for more than 6 years, manifesting as narrowing and distortion of the vascular lumen with hyalinization, reduplication of the capillary basement membrane, and deposition of extracellular matrix and advanced glycation end-products within the media of arterioles and arterial wall (4–6). These changes can appear similar to those seen in diabetic patients, and they are associated with ultrafiltration failure (7–9). The greater severity of the abnormalities in the parietal membrane indicates that PD occurs predominantly across the parietal peritoneal membrane (5).
ADVERSE EFFECTS OF GLUCOSE-BASED PD FLUIDS
In long-term continuous ambulatory PD or automated PD, a patient is exposed
to 2200 – 7000 L of PD fluid annually. Glucose has been used as the
conventional osmotic agent in PD fluids because it is inexpensive, safe, and
easily metabolized to provide an energy source
(10). To generate an osmotic
drive, the glucose concentration in PD solutions exceeds 15 – 40 times
the physiologic concentration. After intraperitoneal equilibration, the
glucose concentration remains at 6 – 16 times that of the physiologic
concentration.
Solutions for PD are heat-sterilized at a low pH in the presence of lactate buffer to prevent glucose caramelization and metabolic acidosis. Heat sterilization leads to the generation of glucose degradation products (GDPs), and GDPs promote the formation of advanced glycation end-products (AGEs) which compromise cellular function (in both resident and infiltrating cells) and peritoneal membrane integrity (Table 1).
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In addition to the local consequences of glucose exposure on the peritoneum, excessive glucose load produces systemic adverse effects including hyperinsulinemia, hyperglycemia, obesity, and satiety (11).
BUFFER IN PD FLUIDS
A buffer is included in PD fluids to offset the hydrogen ions produced
during metabolic processes
(12). Although bicarbonate is
the most important buffer in the body, in PD fluids it can react with calcium
to precipitate as calcium carbonate. Thus, lactate was chosen as the buffer in
PD fluids.
Together with low pH, lactate reduces intracellular pH and is toxic to cultured mesothelial cells. Incubation of cultured mesothelial cells with lactate, alone or in combination with glucose, induces secretion of transforming growth factor-β (TGF-β) and monocyte chemoattractant protein-1 (13). Such induction is abrogated when lactate is replaced with pyruvate (13).
High lactate concentrations also impair neutrophil function and cytokine release in vitro—abnormalities that persist despite the subsequent removal of lactate (14). High levels of lactate in conventional PD solutions can cause pain during infusion. Partial or total replacement of lactate with bicarbonate in new PD fluids avoids the detrimental effects of lactate. In addition, bicarbonatebuffered PD solutions correct metabolic acidosis more effectively, thereby reducing the adverse consequences of metabolic acidosis such as peripheral vasodilatation and hypotension, impaired myocardial contractility, and malnutrition (12,15,16)
APPROACHES IN THE STUDY OF NEW PD SOLUTIONS
Compelling evidence now shows that the unphysiologic concentrations of
glucose and the GDPs in conventional PD fluids are major contributors to
structural and functional abnormalities in the peritoneum during PD. The study
of new PD solutions takes into account the abnormalities that have been
observed with the old dialysates.
The biocompatibility of new PD solutions or their components is often first studied using mesothelial cells, fibroblasts, macrophages, or leukocytes in vitro to assess effects on cell function (Figure 1). These in vitro studies allow the examination of specific cellular processes and molecular pathways in distinct homogeneous cell populations (17). Limitations of in vitro studies include an inability to capture the multifactorial interactions and molecular crosstalk that occurs in vivo, because most in vitro studies are performed on cells in isolation, with the use of two-dimensional rather than three-dimensional cultures, thereby hampering the investigation of some critical aspects such as cell polarity and apical–basolateral secretion of proteins and peptides. The choice of incubation periods and study time-points vary according to the parameter of interest and the clinical context. In this respect, short exposure times are commonly used for analysis of rapid responses such as those to pH and buffer components. Assessing the effect of osmolality often takes 1 – 4 hours, and more than 24 hours' exposure is often required for determination of gene expression and subsequent translation. Table 2 lists questions that, to ensure the relevance of experiments, should be addressed in advance of performing in vitro studies.
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Animal models provide an important study tool for the biocompatibility of PD fluids (Figure 1). Rabbits, rats, and mice have all been used to determine the effect of new PD solutions on peritoneal pathophysiology. Rats and mice have strong peritoneal host defense systems, while rabbits are expensive and extremely susceptible to peritoneal infection (18). In contrast to in vitro studies, animal experiments allow for an assessment of peritoneal histology and phenotypic manifestations.
To mimic clinical PD, experiments should ideally be performed in uremic animals, with repeated infusion and drainage of PD solutions. Peritoneal infusion models are often used to study the response of the peritoneum to chronic exposure to PD fluids (18). Whether data from animal experiments can be extrapolated to the human clinical setting is often challenged. Peritoneal biopsies obtained from PD patients predominantly show alterations in the parietal peritoneum, but the animal data published to date relate chiefly to the visceral peritoneum (5). In addition, rodents are not ideal for the investigation of icodextrin-based PD solutions, because these animals have high amylase levels that degrade icodextrin (19). The advantages and disadvantages of animal models in PD have been reviewed (18).
Human data from clinical trials are obviously desirable, yet clinical studies in PD are fraught with confounding parameters and individual variations, not to mention cost and requirements relating to sample size and follow-up duration. Moreover, performing serial assessments of peritoneal membrane histology in PD patients is practically impossible. In view of these difficulties, surrogate markers are often used in clinical studies. It is important to note that the various approaches illustrated in Figure 1 are complementary rather than hierarchical.
DATA ON NEW PD SOLUTIONS
The biocompatibility of a PD solution can be defined as the ability of the
solution formulation to support long-term dialysis without causing significant
changes in the functional or structural characteristics of the normal
peritoneal membrane
(20,21).
Bicarbonate- and Bicarbonate/Lactate–Buffered Chambered PD Solutions with Low GDP Content: New glucose-based PD solutions buffered with bicarbonate or bicarbonate and lactate combined have an osmolarity is similar to that of conventional PD fluids, but the pH is higher (possibly neutral) and significantly more physiologic. These solutions come in a chambered format, so that no mixing of bicarbonate with calcium occurs, and the glucose is maintained in a low-pH chamber during heat sterilization to reduce the formation of GDPs.
As compared with traditional lactate-buffered solutions, these new solutions have shown better preservation of cellular functions in mesothelial cells, leukocytes, and macrophages in both in vitro and animal studies (22–24). In addition, improved peritoneal anatomy, reduced mesothelial and endothelial cell activation, reduced peritoneal inflammation, and reduced synthesis and deposition of VEGF, TGF-β1, AGEs, and AGE receptors (25–27) were seen. Data from clinical studies have shown increased cancer antigen 125 levels (indicating increased mesothelial cell mass) and decreased hyaluronic acid levels (indicating reduced inflammation) in the peritoneum following treatment with bicarbonate/lactate–based PD fluid, suggesting that use of these solutions could help preserve the integrity of the peritoneal membrane and thus its dialytic efficacy (28). Further clinical studies of the impact of neutral-pH, low-GDP solutions are ongoing.
Amino Acid–Based PD Solutions: Malnutrition predicts lower survival in PD patients. Albumin constitutes 63% of the total protein lost in dialysis effluent (29). Amino acid–based PD solutions more than compensate for amino acid loss through PD exchanges and can improve nitrogen balance. Reducing glucose and GDP exposure is another potential advantage of amino acid–based PD fluid (30).
We recently reported that, after incubation with spent amino-acid dialysate (as compared with glucose-based dialysate), mesothelial cells showed improved ultrastructure and morphology, viability, and protein synthesis; reduced mitochondrial damage; and increased interleukin-6 secretion (31). Together with data from animal experiments, those data suggest that amino-acid PD fluid is more biocompatible than is glucose-based PD solution (26,32). Clinical studies have shown a modest nutritional benefit with the use of amino-acid PD solution (33,34).
Icodextrin-Based PD Solutions: Icodextrin is a mixture of high-molecular-weight glucose polymer fractions produced by the hydrolysis of cornstarch (35). Icodextrin-based PD fluid has a pH of 5.8, uses lactate as a buffer, contains relatively low levels of GDPs, and is iso-osmolar to plasma. In contrast to the crystalloid osmotic pressure induced by glucose-based PD solutions, icodextrin solution exerts a colloid osmotic pressure gradient (29). In vitro studies showed improved phagocytic and respiratory burst activity in polymorphonuclear cells and monocytes exposed to icodextrin as compared cells exposed to glucose-based PD fluids (36). Mesothelial cell proliferation also showed improvement when cells were incubated with icodextrin as compared with glucose-based PD solution (37). However, other investigators reported that exposure of mesothelial cells to undiluted icodextrin could reduce cell viability and proliferation and produce DNA damage similar to that observed with glucose-based PD solutions (38). Mesothelial dysplastic changes have also been observed in rats exposed to icodextrin (39).
Our own data show that icodextrin induces hyaluronan and interleukin-6 secretion in mesothelial cells, which could suggest enhanced inflammation (unpublished data). Data from clinical studies have also implicated activation of both systemic and peritoneal inflammation in patients using icodextrin (40,41). Therefore, although icodextrin-based PD fluid has undisputed advantage in improving free-water clearance in patients with suboptimal ultrafiltration, its effects on mesothelial cell function and peritoneal inflammation require further investigation (42,43).
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CONCLUSIONS |
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
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production by peritoneal macrophages.
Perit Dial Int 1997;17
: 546-53.This article has been cited by other articles:
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  M. N. Schilte, J. W.A.M Celie, P. M. t. Wee, R. H.J. Beelen, and J. van den Born FACTORS CONTRIBUTING TO PERITONEAL TISSUE REMODELING IN PERITONEAL DIALYSIS Perit. Dial. Int., November 1, 2009; 29(6): 605 - 617. [Abstract] [Full Text] [PDF]
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