Encapsulating peritoneal sclerosis (EPS) is a lifethreatening

Peritoneal Dialysis International, Vol. 30, pp. 163 169 doi: 10.3747/pdi.2009.00022 0896-8608/10 $3.00 +.00 Copyright 2010 International Society for Peritoneal Dialysis ORIGINAL ARTICLES EARLY DIAGNOSTIC MARKERS FOR ENCAPSULATING PERITONEAL SCLEROSIS: A CASE-CONTROL STUDY Denise E. Sampimon, 1 Mario R. Korte, 2 Deirisa Lopes Barreto, 1 Anniek Vlijm, 1 Rudy de Waart, 3 Dirk G. Struijk, 1,4 and Raymond T. Krediet 1 Division of Nephrology, 1 Department of Medicine, Academic Medical Center, University of Amsterdam; Department of Internal Medicine, 2 Albert Schweitzer Hospital, Dordrecht; Department of Experimental Hepatology, 3 Academic Medical Center, University of Amsterdam; Dianet Foundation, 4 Amsterdam Utrecht, The Netherlands Objective: Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD). The aim of this study was to investigate whether dialysate levels of cancer antigen-125 (CA125), K +, interleukin (IL)-6, and vascular endothelial growth factor (VEGF) are early diagnostic markers of EPS. Therefore, we analyzed the time courses of the above described dialysate markers in EPS patients and controls. Methods: Dialysate and serum samples of 11 EPS patients and 31 control patients, all treated with PD for at least 57 months, were longitudinally collected during standard peritoneal permeability analyses. CA125 and IL-6 were measured in dialysate only, K + and VEGF were measured in both dialysate and serum. CA125 and IL-6 are expressed as appearance rates (AR). The linear mixed model was used to analyze the time courses. Sensitivity and specificity were calculated based on the results of the last 2 time points. Results: No differences in the time courses of the different markers were present between the groups. For K + and VEGF attributed to local production, no differences between the groups were found. However, AR-CA125 was lower during the last 3 years prior to EPS (p < 0.05) and AR-IL-6 tended to be higher 2 years prior to EPS (p = 0.09). The combination of AR-CA125 < 33 U/min and AR-IL-6 > 350 pg/min had a sensitivity of 70% and a specificity of 89% for the development of EPS. Correspondence to: D.E. Sampimon, Academic Medical Center, University of Amsterdam, Division of Nephrology, Department of Medicine, A01-114, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. d.e.sampimon@amc.uva.nl Received 3 February 2009; accepted 29 May 2009. Conclusions: Compared to controls, AR-CA125 showed lower values and AR-IL-6 tended to be higher during the last years prior to the diagnosis of EPS. The sensitivity and specificity of the combination of CA125 and IL-6 indicate their potential use for an early diagnosis of EPS. Perit Dial Int 2010; 30:163 169 epub ahead of print: 1 Feb 2010 www.pdiconnect.com doi: 10.3747/pdi.2009.00022 KEY WORDS: Encapsulating peritoneal sclerosis; interleukin-6; cancer antigen-125; biomarkers. Encapsulating peritoneal sclerosis (EPS) is a lifethreatening complication of long-term peritoneal dialysis (PD). No tests are available to make an early diagnosis of EPS. Typically, patients present with bowel obstruction, after which the diagnosis is made through either laparotomy or CT scanning (1 3). Ultrafiltration failure (UFF) is almost always present at the time of diagnosis of EPS but alone it is not diagnostic (4). Peritoneal solute transport is often fast but may decrease before the diagnosis is made (5). Peritoneal dialysate contains a number of substances that are produced or released locally in addition to their transport from the circulation (6). These include cancer antigen-125 (CA125) (7), potassium (8), cytokines (9), and growth factors (10). A marker of mesothelial cell mass, CA125 is a useful tool for measuring the integrity of the peritoneal membrane. A decrease in dialysate CA125 of patients that developed EPS has been found in 163

SAMPIMON et al. MARCH 2010 VOL. 30, NO. 2 PDI the past (11). Potassium is locally released in the dialysate through glucose-induced hypertonic cell shrinkage. A low K + release is present in long-term PD patients with UFF (12). Interleukin-6 (IL-6) is a local inflammation marker. Chronic PD may cause a chronic state of inflammation. In the second hit theory it is hypothesized that inflammation may induce EPS (13). Vascular endothelial growth factor (VEGF) is a marker for neoangiogenesis. Soluble VEGF is related to the mass transfer area coefficient of creatinine and reflects the number of perfused peritoneal microvessels (10), and EPS is often associated with a large vascular surface area (14). The aim of the present case control study was to analyze the time course of the above described peritoneal membrane markers in patients that developed EPS and in long-term PD patients that did not progress to this complication. Our research question was whether any of the above mentioned dialysate markers could be used as an early diagnostic marker for EPS. PATIENTS AND METHODS PATIENTS All EPS patients diagnosed in our department between July 1995 and December 2008 and that underwent a peritoneal function test were selected for this study. The diagnosis of EPS was based on predefined criteria (1). These included clinical features such as bowel obstruction, ascites, and blood-stained dialysate in combination with UFF, confirmed by findings at radiology, laparotomy, or autopsy and reviewed by 2 experienced nephrologists. Between July 1995 and December 2008, 417 patients were treated with PD in our center; 63 were treated with PD for more than 57 months. Of these, 31 patients had dialysate samples available and did not develop EPS. Matching for PD duration, age, and gender was not possible due to the small available sample number. Therefore, we applied a restriction in PD duration, set on the shortest PD duration in the EPS group, with the intention of keeping PD duration equal between the groups. SAMPLES The dialysate and serum samples of EPS patients and controls were obtained during a standard peritoneal permeability analysis (SPA) (15). None of the patients had peritonitis at the time of the SPA or during the 6 preceding weeks. The presence of UFF was determined based on the recommendation of the International Society for Peritoneal Dialysis (16). Peritoneal dialysis patients undergo a SPA once per year to assess the functional condition of the peritoneum. The remaining dialysate and serum samples are frozen and stored after centrifugation. Therefore, several dialysate and serum samples from different time points, with an average interval of 1 year, were available for all patients. The average interval between the diagnosis of EPS and the time of the last available sample was 10 months. This allowed us to express the time points as years prior to the diagnosis of EPS, whereas time point zero was the time of the diagnosis of EPS. MARKERS Dialysate levels of CA125 were analyzed using an enzyme-labeled sandwich immunoassay (Roche Diagnostics, Almere, The Netherlands). Potassium was measured in dialysate and plasma with an ion-selective electrode (Roche Diagnostics) directly after the SPA. Interleukin-6 and VEGF were measured in dialysate using commercially available enzyme-linked immunosorbent assays (human IL-6 and human VEGF; R&D Systems, Minneapolis, MN, USA). Prior to the measurement of VEGF, the dialysate samples were concentrated 10 times through ultrafiltration using an ultra-15 centrifugal filter with a molecular cutoff point of 10 000 Da (Millipore, Molsheim, France). The concentration factor was defined as the albumin concentration in the concentrate divided by the albumin concentration in the original dialysate sample. Creatinine was measured using an enzymatic method on an automated analyzer (Hitachi H911; Boehringer, Mannheim, Germany). Albumin, immunoglobulin-g (IgG), and alpha-2-macroglobulin (A2M) were all measured by nephelometry (BN100; Behring, Marburg, Germany) with commercial antisera (Dakopatts, Glostrup, Denmark). Beta-2-microglobulin (B2M) was determined using a microparticle enzyme immunoassay with an IMX System (Abbott Diagnostics, North Chicago, IL, USA). CALCULATIONS AND STATISTICS Data are presented as median and range unless stated otherwise. In order to correct for peritoneal transport, the dialysate-to-plasma ratio (D/P) of K + was divided by D/P creatinine. Due to their size, diffusion of CA125 and IL-6 is negligible and only dialysate appearance rates (AR) were calculated to correct for the effect of the drained volume on their concentration. Peritoneal handling of the macromolecules B2M, VEGF, albumin, IgG, and A2M is expressed as dialysate-toserum ratio (D/S). A peritoneal transport line was computed for each patient based on the least squares regression analysis of the D/S ratios of B2M [molecular 164

PDI MARCH 2010 VOL. 30, NO. 2 MARKERS PRIOR TO EPS weight (MW) 11800 Da], albumin (MW 69000 Da), IgG (MW 150000 Da), and A2M (MW 820000 Da) and their MWs, when both were plotted on a double logarithmic scale (17). By interpolation of the MW of VEGF (MW 34000 Da) in the regression equation, the expected D/S ratio was calculated assuming the dialysate concentration would be determined only by transport from the circulation. The concentration of VEGF attributed to local production was defined as the difference between measured and expected dialysate concentration. The linear mixed model was used to analyze the time courses of the various dialysate markers. This model is capable of handling datasets of patients with missing data. Because the linear mixed model approach takes information from different patient datasets, it uses information from datasets with full data to fit the datasets that have data points missing. In the present study we have patient datasets of three or more consecutive time points without missing values: CA125: EPS n = 7, control n = 16; K + : EPS n = 9, control n = 22; IL-6: EPS n = 4, control n = 14; and VEGF: EPS n = 3, control n = 5. These datasets are the basis for the group profiles. Most of the missing samples were missing at random. The dialysate samples could be absent due to previous studies not related to EPS or because they were lost during storage. A Mann Whitney U test was used to analyze the differences between cases and control at different time points. Sensitivity and specificity of all markers were calculated at 1 and 2 years prior to the diagnosis of EPS or prior to the discontinuation of PD in the control group. Cutoff values for these calculations were based on the literature. An AR-CA125 > 33 U/minute corresponds with CA125 dialysate concentrations of about 3 U/mL. Ho-dac-Pannekeet et al. (11) described a median CA125 of 4 U/mL in EPS patients. A D/P K + / D/P creatinine >1 means local release of K + from cells (8). An AR-IL-6 >350 pg/min corresponds to an IL-6 concentration of about 33 pg/ml, which is similar to values described in patients after 1 year of PD (18). A mean value of 15 ng/l for VEGF locally produced in the dialysate was reported by Zweers et al. (10). RESULTS PATIENTS TABLE 1 Characteristics of Patients with Encapsulating Peritoneal Sclerosis (EPS) and Their Time-Matched Controls Patient characteristics are listed in Table 1. We included 11 EPS patients and 31 controls. All EPS patients had specific features on the CT scan at the time of the diagnosis. These features include peritoneal thickening, peritoneal enhancement, peritoneal calcifications, adhesions of bowel loops, and signs of obstructions and/ or fluid loculation/septation. Patients that developed EPS were younger and the duration of PD treatment was longer. Reasons for discontinuation of PD treatment in EPS patients were UFF in 6, infection in 2, transplantation in 1, and EPS in 2. By 1 year after the diagnosis of EPS, 5 patients had died, 5 patients had transferred to hemodialysis, and 1 patient had received a functioning kidney graft. The cause of death in 4 of 5 EPS patients was related to EPS; 1 EPS patient died due to an aspiration pneumonia. Reasons for stopping PD treatment in controls were death in 12, infection in 3, transplantation in 7, and UFF in 4. The causes of death in the 12 control patients were myocardial/cerebral ischemia in 4, peritonitis in 4, septicemia in 1, voluntary discontinuation of dialysis in 1, and unknown in 2. Five control patients were censored at December 2008. None of the control patients developed EPS in the 3 years of follow-up. MARKERS EPS (n=11) Controls (n=31) Age (years) 35 (21 73) 53 a (32 87) Gender (M:F) 7:4 19:12 PD duration (months) 104 (57 149) 72 a (57 112) PD regime CAPD 4 17 APD 3 4 CAPD/APD 4 10 Net UF at last SPA (ml/4 hours) 121 ( 113 308) 494 b (73 920) Peritonitis episodes (total episodes since start of PD) 4 (0 15) 3 (0 11) Peritonitis incidence (episodes/year) 0.47 (0 2.61) 0.41 (0 1.66) PD = peritoneal dialysis; CAPD = continuous ambulatory PD; APD = automated PD; UF = ultrafiltration; SPA = standard permeability analysis. a p < 0.05. b p < 0.01. Data are presented as median and range. The time courses of the various dialysate markers are shown in Figures 1 4: AR-CA125 in Figure 1, D/P K + / D/P creatinine in Figure 2, AR-IL-6 in Figure 3, and dialysate concentration of locally produced VEGF in Figure 4. No significant difference was found for any of the 165

SAMPIMON et al. MARCH 2010 VOL. 30, NO. 2 PDI Figure 1 Linear mixed model estimations (mean and SEM) of the time course of the appearance rate (AR) of cancer antigen-125 (CA125) in the encapsulating peritoneal sclerosis (EPS) group (closed circles on solid line) and in the control group (closed squares on broken line). The number of patients at each time point is given below the horizontal axis. The time course was not different between the groups (p = 0.68). Statistically significant differences were found at time points 3, 2, and 1 years. *p < 0.05, Mann Whitney U test. Figure 3 Linear mixed model estimations (mean and SEM) of the time course of the appearance rate (AR) of interleukin (IL)-6 in the encapsulating peritoneal sclerosis (EPS) group (closed circles on solid line) and in the control group (closed squares on broken line). The number of patients at each time point is given below the horizontal axis. The time course was not different between the groups (p = 0.414). At 2 years, the AR of IL-6 tended to be higher. *p = 0.09, Mann Whitney U test. Figure 2 Linear mixed model estimations (mean and SEM) of the time course of dialysate-to-plasma ratio of potassium (D/P K + ) / D/P creatinine in the encapsulating peritoneal sclerosis (EPS) group (closed circles on solid line) and in the control group (closed squares on broken line). The number of patients at each time point is given below the horizontal axis. The time course was not different between the groups (p = 0.085). A statistically significant difference was found at time point 3. *p = 0.001, Mann Whitney U test. markers in the time courses but lower values for AR-CA125 in dialysate were found in the EPS patients compared to the controls at several time points. This Figure 4 Linear mixed model estimations (mean and SEM) of the time course of dialysate vascular endothelial growth factor (VEGF) attributed to local production in the encapsulating peritoneal sclerosis (EPS) group (closed circles on solid line) and in the control group (closed squares on broken line). The number of patients at each time point is given below the horizontal axis. The time course was not different between the groups (p = 0.97). group also showed a tendency for higher values of AR-IL-6 in dialysate. The absence of a difference in dialysate VEGF attributed to local production was confirmed by an analysis of dialysate VEGF only (data not shown). 166

PDI MARCH 2010 VOL. 30, NO. 2 MARKERS PRIOR TO EPS SENSITIVITY AND SPECIFICITY Sensitivity and specificity of the individual dialysate markers were calculated at time points 1 and 2 (Table 2). The combined sensitivity and specificity of AR-CA125 and AR-IL-6 was also calculated at these time points. This parameter had a sensitivity of 70% and a specificity of 89%. In patients with UFF, the combination of AR-CA125 < 33 U/min and AR-IL-6 > 350 pg/min had a sensitivity of 70% and a specificity of 100% for the development of EPS. DISCUSSION The current analysis showed that the combination of a dialysate AR-CA125 < 33 U/min and an AR-IL-6 > 350 pg/min is a useful tool for an early diagnosis of EPS in patients with UFF. The choice of biomarkers was based on results from previous investigations and their interpretation. Dialysate CA125 is a marker for mesothelial cell mass or turnover (7,19). It decreases with duration of PD (19). This is in accordance with the loss of mesothelium in PD, as found in the Peritoneal Biopsy Registry (20). Complete loss of mesothelium has been described in EPS (21). Our analysis showed lower values for dialysate CA125 at various time points in the pre-eps patients compared to the control group. This is in line with the alterations in peritoneal morphology. TABLE 2 Sensitivity and Specificity of Different Markers for the Development of Encapsulating Peritoneal Sclerosis (EPS) at One and Two Years Prior to Diagnosis of EPS Measure point 1 and 2 Sensitivity Specificity D/P K + / D/P creatinine >1 10/11 (91%) 8/29 (28%) AR-CA125 <33 U/min 7/10 (70%) 14/21 (66%) AR-IL-6 >350 pg/min 8/10 (80%) 10/20 (50%) VEGF >15 ng/l 6/9 (66%) 3/12 (25%) AR-CA125 <33 U/min and AR-IL-6 >350 pg/min 7/10 (70%) 17/19 (89%) AR-CA125 <33 U/min and AR-IL-6 >350 pg/min in UFF patients 7/10 (70%) 8/8 (100%) D/P = dialysate-to-plasma ratio; AR = appearance rate; CA125 = cancer antigen-125; IL-6 = interleukin-6; VEGF = vascular endothelial growth factor; UFF = ultrafiltration failure. The number before the slash refers to the number of positive findings; the number behind the slash refers to the number of analyzed samples. The percentage refers to sensitivity or specificity. Dialysate K + during a hypertonic 4-hour exchange is due partly to diffusion and convection and also to local release from cells (8). Hypertonic cell shrinkage causing K + efflux is the most likely mechanism. This phenomenon is especially present in patients during the first few years of PD, while it is absent in long-term patients with UFF. The amount of local release was not related to dialysate CA125 (12). Low values were found in both groups without an obvious trend, which may be caused by a lower number of cells or by impaired function of cellular K + channels. Dialysate IL-6 is considered a marker for local inflammation (18,22); however, different genetic backgrounds can influence IL-6 concentrations in serum and dialysate of individual patients at baseline (23). In the present analysis, a tendency for an increase with the duration of PD was found. This would be in accordance with the inflammatory changes described in some EPS patients (24). It is unknown whether different genetic backgrounds influence IL-6 levels in long-term PD patients and patients that develop EPS. Soluble VEGF in dialysate is derived partly from diffusion and partly by local production (10). Locally produced VEGF is related to the mass transfer area coefficient of creatinine (10), which reflects the surface area of peritoneal microvessels (14,25). Patients with EPS have fast solute transport rates and an increased number of vessels. Furthermore, VEGF is likely to be important in neoangiogenesis in an EPS rat model (26). No high dialysate concentration of locally produced VEGF was found in the present analysis. We speculate that, in humans, neoangiogenesis may occur in an earlier stage than fibrosis during the development of EPS. The results of our analysis support a role of endothelial-to-mesenchymal transition in the development of EPS. In this process, mesothelial cells acquire fibroblastlike characteristics (27). Transforming growth factor-beta (TGF-β) is an important inducer of endothelial-to-mesenchymal transition. During the first year of continuous ambulatory PD (CAPD), this process was associated with low dialysate values of CA125 and relatively high ratios of IL-6/CA125 and VEGF/CA125 (28). However, without the correction for CA125, these associations were absent. It should be appreciated that relationships present during the first year of PD do not necessarily apply in longterm patients. For various reasons some biomarkers were not analyzed. Dialysate TGF-β was not analyzed because we previously found that it was present in a non-active form and the results were not related to the duration of PD or any other parameter (10). Similarly, dialysate hydroxyproline was not informative (29). Tumor necrosis factor-alpha was 167

SAMPIMON et al. MARCH 2010 VOL. 30, NO. 2 PDI not analyzed because it is locally produced only during acute peritonitis (17). Fibrinolytic proteins were not measured because no citrate or EDTA plasma was collected. However, these are potentially interesting markers because local peritoneal production has been shown for tissue plasminogen activator inhibitor type 1 antigen (30). Methods for the measurement of collagen IV and alpha-smooth muscle actin are not commercially available. C-reactive protein (CRP) was not analyzed in this study because it was not routinely determined in the past. A Japanese study showed that CRP levels are not different among EPS patients and controls (31). The sensitivity and specificity of the combination of dialysate CA125 and IL-6 in patients with UFF suggest that it is possible to identify patients at risk for clinically established EPS. This is important because preventive interventions to reduce morbidity and mortality might be more effective at this stage than after the establishment of the diagnosis. Apart from discontinuation of PD, such interventions could include peritoneal resting (32), steroids and immunosuppressives (33,34) or mycophenolate mofetil (35), and also tamoxifen (36). These interventions could potentially be monitored by dialysate CA125 and IL-6 but this would require further studies. A potential weakness of the present study is the difference in PD duration between the two groups. The cumulative period on PD is probably the most important risk factor for the development of EPS (37). Despite the fact that the shortest duration of PD in the control group was 57 months, which is similar to the observed shortest duration in the EPS group, the median overall duration of PD was different. Nevertheless, 6 of 11 EPS patients had PD duration that overlapped with the control group. The EPS patients were also younger. This may be relevant for the development of EPS because it was also found in a different EPS cohort (1). Another shortcoming might be that not all analyses could be done in all patients because of the limited number of available serum and dialysate samples. However, the number of samples in the EPS group averaged 8 and was never smaller than 5. Glucose exposure was not calculated in the EPS or the control group. This was because half the patients were treated with CAPD and the other half were treated with automated PD. These two dialysis modalities are difficult to compare because, in automated PD, more but shorter dwells are employed. However, in a previously published analysis, we reported that CAPD patients with EPS had a greater exposure to glucose and its degradation products than time-matched controls (1). 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