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*Institute of Nephrology, Medical Microscopy Sciences, and Department of Pathology, University of Wales College of Medicine, Cardiff, United Kingdom.
Correspondence to Professor John D. Williams, Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, UK, CF14 4XN. Phone: +44-29-2074-8467; Fax: +44-29-2074-8470; E-mail: williamsjd4{at}cf.ac.uk
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previously published data suggested a strong causal relationship between peritonitis (its frequency and severity) and long-term loss of peritoneal membrane function (2,4). Those studies did not examine the relationship between functional changes and possible morphologic changes in the peritoneal membrane, however. In addition, a number of articles attempted to address the relationship between morphologic changes and specific clinical events. In an autopsy study, Rubin et al. (17) demonstrated that chronic changes in the peritoneal "serosa" were correlated with the number of episodes of peritonitis.
More recently, investigators have focused on changes within the peritoneal vascular bed, because it is presumed that changes in vessel density or morphologic features might directly affect membrane function (18). Honda et al. (7,8) observed (in a small number of samples) structural changes in venular walls and related those changes to ultrafiltration changes in the same patients. There was a correlation between decreased ultrafiltration and the appearance of vasculopathy, with the development of submesothelial fibrosis. Mateijsen et al. (9) demonstrated an increase in blood vessel density in the submesothelial zone among patients with peritoneal "sclerosis," compared with control subjects. Vessel wall thickening and capillary dilation were also observed. More recently, increased expression of nitric oxide synthase (a putative surrogate marker of blood vessel density) was observed to be directly correlated with the duration of PD therapy (19).
There is thus significant evidence that changes occur in both the interstitial and vascular compartments of the dialyzed peritoneal membrane. Although it is likely that these changes are related to the duration of dialysis, to peritonitis, and perhaps to dialysis solution components, the exact relationships are poorly understood, as is the potential contribution of uremia.
The aim of this study was to establish a system whereby peritoneal biopsies could be collected in a standard reproducible manner, specifically to avoid collection- or fixation-induced artifacts. In addition, peritoneal function data were simultaneously collected from the same individuals. These samples allowed the precise structural changes in dialyzed peritoneal membranes to be characterized in a large number of well preserved samples, as well as allowing initial evaluation of some of the potential factors responsible for the observed structural alterations.
Our data provide evidence of both fibrotic and vascular changes being related to uremia and the duration of therapy. These changes are exacerbated among patients who experience PD complications while undergoing dialysis.
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Materials and Methods |
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Biopsies were collected, during abdominal surgery, from four patient groups, as follows: (1) kidney donors (biopsies obtained during donor nephrectomies were classified as normal if there was no history of abdominal pathologic conditions or previous surgery); (2) uremic patients, defined as patients who underwent biopsies either at the time of insertion of the PD catheter or during kidney transplantation but who had never previously undergone dialysis; (3) patients undergoing hemodialysis (who had never undergone PD); and (4) patients undergoing PD. Surgery was undertaken for renal transplantation, because of some incidental abdominal condition, or because of a PD-related problem (excluding recent peritonitis), e.g., catheter repositioning, catheter replacement, or catheter removal because of membrane failure. Patients with membrane failure were defined as patients who could no longer continue PD because of altered solute transport. Approval for the study was obtained from local ethics committees, and all patients gave written informed consent.
Biopsy Collection and Processing
Samples of the parietal peritoneum were obtained in a standardized manner. Briefly, the peritoneum was exposed and a suture loop was inserted through the part of the peritoneum to be sampled. A loose knot was tied, to facilitate orientation during fixation. By using the suture to lift the peritoneum, an ellipse (approximately 2 cm in length and up to 5 mm in depth) that included the knot at one end was excised. The sample was placed in Sorensen’s phosphate buffer with 2% sucrose (SPBS), immediately pinned onto a silicone elastomer surface (Sylgard 184; Dow Corning, Barry, UK) with the mesothelial surface uppermost, and fixed with 0.2% gluteraldehyde/4% formaldehyde in SPBS. After 24 h of fixation at room temperature, samples were washed and stored at 4°C in SPBS before processing.
Fixed samples were examined and dissected by using a stereo-microscope. Two pieces (5 x 5 mm) were routinely processed for scanning electron microscopy by full dehydration through graded ethanol mixtures, critical-point drying, and sputter coating with gold. Specimens were viewed at 10 kV with a JEOL 840A scanning electron microscope (JEOL, Tokyo, Japan). Four pieces (5 x 1 mm) were routinely processed for light microscopy and/or transmission electron microscopy by postfixation in uranyl acetate, partial dehydration through graded ethanol mixtures to 70%, infiltration with hard-grade LR White acrylic resin (Light Resin Co., Reading, UK), embedding in acrylic resin, and cold catalytic polymerization at 4°C (20). Semithin (0.35-µm) sections for light microscopy were stained with 0.5% toluidine blue for morphologic assessments and were stained by using a modification of the periodic acid thiocarbohydrazide-silver proteinate-silver enhancement (PATCH-SP-SE) method to facilitate observation of small blood vessels and capillaries (21).
Sample Analyses
Samples were assessed by light microscopy, using a standardized method, by an experienced histopathologist who was unaware of patient characteristics and clinical details. Normal human parietal peritoneum (Figure 1) is composed of a sheet of flat mesothelial cells, separated by a basement membrane from a thin compact zone of mature fibrous tissue containing collagen and scattered elastin fibers. Deep to this is looser connective tissue containing widely spaced collagen fibers, occasional spindle-shaped fibroblast-like cells, scattered mononuclear phagocytes, mature lymphocytes, and adipose tissue. Small blood vessels, lymphatic vessels, and nerves are present in this loose connective tissue zone, and some extend into the compact zone.
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Early experience indicated that many of the biopsies exhibited vascular abnormalities, manifested by varying degrees of subendothelial hyalinization affecting predominantly venules and small veins but sometimes arterioles. The hyaline material was periodic acid-Schiff stain positive, and in florid cases led to distortion and narrowing of the vascular lumen or even complete luminal obliteration (in which cases the hyaline material was sometimes finely calcified). The degree of this "hyalinizing vasculopathy" was subjectively graded according to the criteria presented in Table 1, as illustrated in Figure 2, and data for the worst lesion in each biopsy were recorded.
The reproducibility of grading was evaluated by two observers using 40 samples that had been selected by a third member of the study group to include the entire spectrum of vasculopathy. Interobserver agreement was moderate for weighted analyses (
for agreement = 0.45) and good for unweighted analyses ( for agreement = 0.64).
Because a significant number of obliterated blood vessels were observed in preliminary analyses, it was clear that the use of specific endothelial cell markers would not accurately establish the number of blood vessels. The PATCH-SP-SE method was therefore used, which allowed the identification of all vessels on the basis of their basement membranes or (when obliterated) their mural hyalinization. The density of blood vessels (including obliterated vessels) in PATCH-SP-SE-stained sections oriented perpendicular to the peritoneal surface was thus quantified and expressed as vessel numbers per length (in millimeters) of surface peritoneum.
Statistical Analyses
Data are expressed as the median and interquartile range (IQR) (25 to 75%). Data were analyzed by using SPSS 10 for Macintosh (SPSS Inc., Chicago, IL). Because the data were not normally distributed, nonparametric analyses were performed throughout.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thickness of the Submesothelial Compact Zone
Figure 3 presents the thickness (median and IQR) of the submesothelial compact zone in the four groups of subjects (ranging from normal subjects to patients who had undergone PD for >8 yr). The median thickness ranged from 50 µm (IQR, 25 to 135 µm) in the normal group to 700 µm (IQR, 460 to 1060 µm) in the group that had undergone PD for >8 yr. The median thickness values were 140 µm (IQR, 60 to 220 µm) for the uremic group and 150 µm (IQR, 100 to 200 µm) for hemodialysis patients who underwent biopsies either during the insertion of a PD cannula or at transplantation.
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Further analysis of data for PD patients (Figure 4) demonstrated that the thickness of the submesothelial compact zone in group 4a (patients who underwent biopsies during transplantation or incidental surgery) was significantly less than that in group 4b (patients who underwent catheter-related surgery or exhibited membrane failure). The median thickness ranged from 180 µm (IQR, 100 to 270 µm) in the transplant group (n = 59) to 650 µm (IQR, 400 to 1100 µm) in the membrane failure group (n = 21). Mann-Whitney analysis demonstrated significant differences between the transplant group and the catheter problem group (P < 0.000), as well as between the incidental surgery group and the membrane failure group (P < 0.000). No difference could be demonstrated between the submesothelial compact zone thickness of the catheter problem group and that of the membrane failure group (P = 0.13).
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2 analysis of data for all biopsies (P < 0.0001) (Table 5). Of the patients with vasculopathy, 77 (84%) exhibited significant fibrosis and only 14 did not. Of those without vasculopathy, only 54 (44%) exhibited a similar degree of fibrosis.
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Diabetes Mellitus and Vasculopathy
In view of the morphologic similarity between the observed vasculopathy in the peritoneal membrane and diabetic vasculopathy, the data were analyzed with respect to clinical diabetes mellitus. The number of samples obtained from diabetic patients was small (n = 28). Of the biopsies obtained from predialysis diabetic patients, four of 10 exhibited vasculopathy. In the nondiabetic predialysis group, 14 of 63 patients (22%) exhibited vasculopathy. Among diabetic PD patients, 39% (seven of 18 patients) exhibited vasculopathy. Of 112 nondiabetic PD patients, 66 (59%) exhibited vasculopathy.
Vessel Density
One hundred two biopsies were analyzed for vessel density per length of surface peritoneum. There were no significant differences in vessel density for any of the patient groups and, in particular, no significant change with the duration of PD (Figure 6A). When the samples were grouped according to the biopsy origin (Figure 6B), samples obtained from patients with membrane failure demonstrated significantly more vessels per length than did samples from normal individuals (P = 0.018) or from non-PD patients (P = 0.035). When samples were analyzed according to whether they demonstrated fibrosis (>150 µm), the biopsies with fibrosis exhibited significantly greater vessel density, compared with the samples without fibrosis (P = 0.01).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Predialysis uremic patients demonstrated a significantly thicker submesothelial compact zone, compared with that observed in parietal peritoneal membranes from normal individuals. The thickness was similar to that in biopsies obtained from patients who had undergone hemodialysis for varying periods before the initiation of PD. These findings indicate that uremia itself may induce changes in the peritoneal membranes of patients before they commence PD, which may represent changes related to chronic humoral inflammation (24).
The thickness of the compact zone in biopsy samples obtained from patients undergoing PD demonstrated a progressive significant increase in thickness with duration of PD. Our results are in contrast to those of a recent smaller series, in which the thickening of the submesothelial zone in PD patients (492 to 266 µm) was not different from that in uremic predialysis patients (492 ± 207 µm) (23).
The major limitation in the collection of peritoneal biopsy samples has been access to the peritoneum. Almost all previous studies have been limited to (1) biopsies obtained during catheter placement, (2) biopsies obtained during catheter removal, or (3) biopsies obtained during incidental laparotomy (applicable to hemodialysis and predialysis patients). Although this approach would result in the gradual acquisition of large numbers of biopsies, it would tend to skew the results away from "nonproblematic" peritoneal samples. We overcame this problem by collecting biopsies at the time of kidney transplantation (random collection).
When the data in this study were subdivided according to biopsy origin, submesothelial compact zone thickness was significantly greater among patients who had undergone surgery to treat PD-related problems or who had experienced membrane failure, compared with PD patients whose biopsies had been obtained at random. This finding was irrespective of therapy duration. We also examined the relationship between the duration of dialysis and membrane thickness in these same patient groups during the first 7 yr of dialysis. Patients whose biopsies were obtained at random demonstrated no correlation between thickness and the duration of dialysis. In contrast, among patients with a history of PD-related problems or membrane failure, there was a direct significant relationship between thickness and the duration of PD. This indicates that thickening of the membrane is not inevitable for all individuals undergoing PD.
A variety of vascular changes have been observed in the peritoneal membranes of patients undergoing PD, resembling changes observed in diabetic microvascular disease. These changes include reduplication of capillary basement membranes (25,26), expansion of extracellular matrix within the media of arterioles (27), and deposition of type IV collagen within the arterial wall (28). In addition, most of these changes are accompanied by the deposition of advanced glycosylation end products in the vessel wall (7,29,30). In this study, overt vasculopathy was present in 20% of the biopsies obtained from uremic non-PD patients. The proportion of patients with vasculopathy then increased with the duration of PD, so that, after 6 yr of therapy, 87% of biopsies exhibited evidence of vasculopathy. When the results were grouped according to biopsy origin, the severity of vasculopathy was significantly less in the random samples. Previous studies identified a link between the loss of ultrafiltration and the degree of vasculopathy and also proposed that the vascular changes might be related to the deposition of advanced glycosylation end products in the vessel wall (7).
The presence or absence of mesothelium on the surface of a peritoneal biopsy has often been taken to indicate underlying pathologic conditions (31). In view of the fragility of the mesothelial layer, we were meticulous in the development of our techniques, to minimize the possibility of trauma to the specimens. Thirty-six percent of the biopsies in this study were devoid of surface mesothelium. This finding was more common among the PD population (49%) than among patients who had never been exposed to PD (17%). Importantly, the absence of the mesothelium among PD patients was correlated with the presence of fibrosis, as well as with vasculopathy, although there were a number of specimens with fibrosis/vasculopathy and an intact mesothelium. It is therefore likely that submesothelial changes precede the loss of the mesothelium and that the loss of the mesothelium may be related to local ischemia. Interestingly, however, there was little evidence of cellular inflammation (acute or chronic) in any of the biopsies. In particular, there did not seem to be any evidence of chronic cellular inflammation in samples with fibrosis.
It is likely that peritoneal fibrosis is of multifactorial pathogenesis and that both inflammation and dialysis solution exposure contribute to it. Recent studies demonstrated that effluents from PD patients contained increased levels of latent transforming growth factor-ß1 and that these increases were related to increased local production, possibly from mesothelial cells, after glucose exposure (32). Transforming growth factor-ß1 has been identified as a key growth factor in the development of interstitial fibrosis in diabetic nephropathy (33). In our study, analysis of the relationship between vasculopathy and fibrosis demonstrated an overwhelming positive correlation between the two, suggesting a causal relationship. The results suggest that fibrosis is at least partly dependent on the presence of vasculopathy. The vasculopathy may lead to relative ischemia, exacerbating the development of fibrosis (34).
Among the small number of biopsies from diabetic patients, there did not seem to be an increased incidence of vasculopathy. This finding is supported by previous reports indicating that vascular changes in the gastrointestinal tract of diabetic patients are unusual (35). That observation suggests that vasculopathy among diabetic patients is organ related (35) and that the extent of the changes observed in the membranes of PD patients may be a unique development specifically driven by the process of PD and/or uremia.
Recent studies suggested that, in addition to the development of vasculopathy, changes in the vascular bed of the peritoneal membrane included the growth of new blood vessels or neoangiogenesis (9), which was thought to be particularly marked among patients described as having peritoneal sclerosis. The mechanism of such a change could be the increased deposition of advanced glycosylation end products in the membrane, resulting in increased release of vascular endothelial growth factor (36). This would, in turn, result in angiogenesis and increased vessel permeability. Much of the current data on angiogenesis, however, are derived from animal studies, in which there is rapid development of new blood vessels in the visceral peritoneum after exposure to glucose (37). Such results should be treated with caution when human structure-function relationships are being considered.
In this study, we used a variation of the periodic acid-Schiff staining technique to identify vessels. Because endothelial markers do not identify obliterated vessels or vessels with damaged endothelium, we used a technique that would identify and thus allow enumeration of all vessels on the basis of their basement membranes. An additional problem was how to analyze vessel numbers. Most studies have recorded numbers per high-power field (9,19,23). With the variability in membrane thickness (20 to 1200 µm), however, it would be impossible to make valid comparisons between specimens. We therefore elected to express vessel numbers per millimeter of peritoneal surface, which would take into account the total number of vessels irrespective of the thickness of the tissue. With this form of analysis, a significant increase in vessel number was observed only in biopsies obtained from patients with membrane failure and not in biopsies obtained at random. Furthermore, when samples with fibrosis were compared with those without fibrosis, the former samples exhibited a significantly greater number of vessels.
This study provides, for the first time, a comprehensive analysis of the morphologic changes that occur in the parietal peritoneal membranes of patients undergoing PD. It is, by necessity, cross-sectional, because a longitudinal study would be impractical with current biopsy methods. Nevertheless, our study clearly illustrates the wide variation in peritoneal morphologic features among patients and emphasizes the need to base conclusions on large sample numbers. It demonstrates that some of the changes predate PD and are present among uremic patients. It also demonstrates that, in the first 5 yr of dialysis, patients who do not experience problems with PD do not develop increased thickening of the submesothelial compact zone and do not develop significant vasculopathy. This study provides a sufficiently large cohort of samples to allow structure-function relationships to be established, as well as providing a repository of tissue for a variety of additional studies.
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Acknowledgments |
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and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 45: 890–896, 1994[Medline]
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, outliers; 
, extremes.
