Significant Decreasing Incidence of Encapsulating Peritoneal Sclerosis in the Dutch Population of Peritoneal Dialysis Patients.

The Dutch Encapsulating Peritoneal Sclerosis (EPS) Registry was started in 2009. Cases were identified by contacting all Dutch nephrologists twice yearly. The predefined criteria for EPS allowed for inclusion of patients with diagnosed and suspected EPS. Cases registered between January 2009 and January 2015 were analyzed with follow-up until September 2015. Fifty-three EPS cases were identified, of which 28.3% were post-transplantation EPS cases. Fourteen patients were initially categorized as suspected EPS, of whom 13 developed EPS. A remarkable 6-fold decrease in the yearly incidence of EPS was observed, from 0.85% in 2009 to 0.14% in 2014. This decrease could not be explained by a decrease in the number of PD patients or average duration of PD treatment in this period. Two-year survival of EPS patients was 52%. The use of tamoxifen and surgical interventions increased significantly over the years. Tamoxifen-treated cases showed a trend to better patient survival and post-transplantation EPS had a significantly favorable outcome. In conclusion, the incidence of EPS has declined significantly in the Netherlands from 2009 to 2014.

Encapsulating peritoneal sclerosis is associated with T-cell activation.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an excessive fibrotic response of the peritoneum that may occur after long-term peritoneal dialysis (PD). The underlying pathophysiology is poorly understood, but involvement of peritoneal inflammatory T helper 1 cells may be pivotal. METHODS: Soluble interleukin-2 receptor alpha (sCD25) concentration was measured as a marker for T-cell activation in serum and ascites from EPS patients and various control patient groups. Peritoneal biopsies were stained for the presence of T cells, and T cells isolated from ascites of EPS patients were characterized in detail for differentiation status and cytokine expression. RESULTS: Serum sCD25 concentrations are significantly and specifically increased in EPS patients compared with haemodialysis, PD and predialysis patients. Peritoneal effluent of stable PD patients contains very low levels of sCD25, while sCD25 levels in ascites of EPS patients are high and indicative of local production. In the years preceding the diagnosis of EPS, the serum sCD25 concentrations increased while remaining at stable levels in control PD patients. The peritoneum and ascites of EPS patients showed a significant influx of T cells with relatively increased numbers of CD4(+) T cells. These T cells were fully differentiated and displayed a T helper 1 cell type with a pro-inflammatory cytokine profile. CONCLUSIONS: Increased serum sCD25 concentrations and peritoneal lymphocytosis in EPS patients indicate the involvement of activated T cells in the pathophysiology of excessive fibrosis.

CD4-Positive T Cells and M2 Macrophages Dominate the Peritoneal Infiltrate of Patients with Encapsulating Peritoneal Sclerosis.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Previously, it has been shown that infiltrating CD4-positive T cells and M2 macrophages are associated with several fibrotic conditions. Therefore, the characteristics of the peritoneal cell infiltrate in EPS may be of interest to understand EPS pathogenesis. In this study, we aim to elucidate the composition of the peritoneal cell infiltrate in EPS patients and relate the findings to clinical outcome. STUDY DESIGN, SETTING, AND PARTICIPANTS: We studied peritoneal membrane biopsies of 23 EPS patients and compared them to biopsies of 15 PD patients without EPS. The cellular infiltrate was characterized by immunohistochemistry to detect T cells (CD3-positive), CD4-positive (CD4+) and CD8-positive T cell subsets, B cells (CD20-positive), granulocytes (CD15-positive), macrophages (CD68-positive), M1 (CD80-positive), and M2 (CD163-positive) macrophages. Tissues were analysed using digital image analysis. Kaplan-Meier survival analysis was performed to investigate the survival in the different staining groups. RESULTS: The cellular infiltrate in EPS biopsies was dominated by mononuclear cells. For both CD3 and CD68, the median percentage of area stained was higher in biopsies of EPS as opposed to non-EPS patients (p<0.001). EPS biopsies showed a higher percentage of area stained for CD4 (1.29% (0.61-3.20)) compared to CD8 (0.71% (0.46-1.01), p = 0.04), while in the non-EPS group these cells were almost equally represented (respectively 0.28% (0.05-0.83) versus 0.22% (0.17-0.43), p = 0.97). The percentage of area stained for both CD80 and CD163 was higher in EPS than in non-EPS biopsies (p<0.001), with CD163+ cells being the most abundant phenotype. Virtually no CD20-positive and CD15-positive cells were present in biopsies of a subgroup of EPS patients. No relation was found between the composition of the mononuclear cell infiltrate and clinical outcome. CONCLUSIONS: A characteristic mononuclear cell infiltrate consisting of CD4+ and CD163+ cells dominates the peritoneum of EPS patients. These findings suggest a role for both CD4+ T cells and M2 macrophages in the pathogenesis of EPS.

Histological and clinical findings in patients with post-transplantation and classical encapsulating peritoneal sclerosis: a European multicenter study.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) commonly presents after peritoneal dialysis has been stopped, either post-transplantation (PT-EPS) or after switching to hemodialysis (classical EPS, cEPS). The aim of the present study was to investigate whether PT-EPS and cEPS differ in morphology and clinical course. METHODS: In this European multicenter study we included fifty-six EPS patients, retrospectively paired-matched for peritoneal dialysis (PD) duration. Twenty-eight patients developed EPS after renal transplantation, whereas the other twenty-eight patients were classical EPS patients. Demographic data, PD details, and course of disease were documented. Peritoneal biopsies of all patients were investigated using histological criteria. RESULTS: Eighteen patients from the Netherlands and thirty-eight patients from Germany were included. Time on PD was 78(64-95) in the PT-EPS and 72(50-89) months in the cEPS group (p>0.05). There were no significant differences between the morphological findings of cEPS and PT-EPS. Podoplanin positive cells were a prominent feature in both groups, but with a similar distribution of the podoplanin patterns. Time between cessation of PD to the clinical diagnosis of EPS was significantly shorter in the PT-EPS group as compared to cEPS (4(2-9) months versus 23(7-24) months, p<0.001). Peritonitis rate was significantly higher in cEPS. CONCLUSIONS: In peritoneal biopsies PT-EPS and cEPS are not distinguishable by histomorphology and immunohistochemistry, which argues against different entities. The critical phase for PT-EPS is during the first year after transplantation and therefore earlier after PD cessation then in cEPS.

Localized encapsulating peritoneal sclerosis constricting the terminal ileum--an unusual appearance requiring surgical intervention.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD). It is characterized by encapsulation of the bowel, causing symptoms of intestinal obstruction. Exclusive involvement of parts of the bowel may occur and may be more common than previously thought. Our main objective was to investigate and report on patients with localized EPS. METHODS: Between July 2002 and December 2011, 9 of 17 EPS patients were referred to our department of surgery for a diagnostic laparotomy. Three of the 9 cases showed localized encapsulation of the small bowel and were selected for the purpose of this study. RESULTS: All 3 patients presented with an acute inflammatory state and symptoms of bowel obstruction. In 2 patients, EPS became clinically overt after kidney transplantation; the third patient was diagnosed while on hemodialysis. All shared a history of PD ranging from 31 to 101 months. In none of the patients was radiologic examination conclusive, although 2 showed peritoneal thickening and ascites. Each patient underwent laparotomy, confirming EPS. In all cases, a thickened peritoneal membrane became apparent, predominantly covering the ileocecal region of the intestine. In addition, a constrictive membrane at the level of the terminal ileum was noted. In 2 cases, the patients underwent enterolysis and dissection of the constricting fibrotic peritoneal membrane (peritonectomy) without bowel resection. The 3rd patient was managed with parenteral nutrition and tamoxifen. The postoperative course in 1 patient was complicated by infected ascites that resolved with antibiotic treatment. Eventually, all patients were doing well, with adequate oral intake and without the need for repeat surgery. CONCLUSIONS: Localized EPS may be more common than previously thought. It has a predilection for the level of the terminal ileum. We believe that an elective diagnostic laparotomy should be considered early, because this procedure offers both diagnostic opportunities and therapeutic options. Localized EPS cases may benefit most from enterolysis and peritonectomy.

Lower mortality and inflammation from post-transplantation encapsulating peritoneal sclerosis compared to the classical form.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) may occur after kidney transplantation (post-transplantation EPS) or may be diagnosed during or after peritoneal dialysis treatment (classical EPS). The aim of the present study was to investigate to what extent both EPS entities differ in clinical presentation, radiological findings, outcome, and the systemic inflammatory response, as measured by plasma C-reactive protein (CRP) levels both prior to and after EPS diagnosis. METHODS: We performed a retrospective analysis of 15 post-transplantation EPS and 19 classical EPS patients who were diagnosed at seven hospitals in the Netherlands between January 1, 2000, and January 1, 2011. RESULTS: There were no inter-group differences in age, duration of peritoneal dialysis, clinical presentation, or radiology findings at diagnosis. Post-transplantation patients had experienced a lower number of peritonitis episodes per patient-year (0.2 (0.0-0.4) vs. 0.7 (0.3-1.2), p = 0.01) with a longer interval between the last peritonitis and EPS diagnosis (18.1 (4.6-34.3) vs. 4.4 (0.89-13.78) months, p = 0.01). Post-transplantation EPS patients showed a remarkably lower mortality rate (40.0 vs. 84.2%, p < 0.05). In both groups a pattern of elevated CRP values was observed, increasing within the year before EPS diagnosis. In the post-transplantation group the median CRP level at diagnosis was lower (56.0 vs. 144.50 mg/l, p < 0.05) than in the classical EPS group. CONCLUSION: Post-transplantation EPS has a similar clinical presentation as classical EPS but with a lower systemic inflammatory response and better outcome.

Encapsulating peritoneal sclerosis: the state of affairs.

Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) with a 50% mortality rate. EPS is characterized by progressive and excessive fibrotic thickening of the peritoneum, leading to encapsulation of the bowels and intestinal obstruction. At present, EPS cannot be detected with certainty during its early stages; however, a progressive loss of ultrafiltration capacity often precedes its development. Studies that attempted to elucidate the pathogenesis of EPS have shown that the duration of exposure to PD fluids is the most important risk factor for EPS, and that young age and possibly the effects of peritonitis are additional contributory factors. The pathophysiology of EPS is probably best described as a multiple-hit process with a central role for transforming growth factor ß. A form of EPS that develops shortly after kidney transplantation has also been recognized as a distinct clinical entity, and may be a common form of EPS in countries with a high transplantation rate. Criteria have been developed to identify EPS by abdominal CT scan at the symptomatic stage, but further clinical research is needed to identify early EPS in asymptomatic patients, to clarify additional risk factors for EPS and to define optimal treatment strategies.

Risk factors associated with encapsulating peritoneal sclerosis in Dutch EPS study.

OBJECTIVE: Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with a multifactorial pathophysiology and possible increasing incidence. The aim of the present study was to evaluate the independent associations of PD duration, age, dialysis fluids, and kidney transplantation with EPS. METHODS: A multicenter case-control study was performed in the Netherlands from 1 January 1996 until 1 July 2007. The population comprised 63 patients with EPS and 126 control patients. Control patients were selected from the national registry and were matched for date of PD start. Associations were analyzed using a log linear regression model. Primary outcome was appearance of EPS. RESULTS: Compared with control patients, patients with EPS were younger at the start of PD (34.7 ± 15.4 years vs. 51.5 ± 14.7 years, p < 0.0001). The cumulative period on PD was longer in EPS patients than in control patients (78.7 ± 37.8 months vs. 32.8 ± 24 months, p < 0.0001), and the cumulative period on icodextrin was also longer in EPS patients (32.7 ± 23.3 months vs. 18.1 ± 15.7 months, p = 0.006). Compared with control patients, more EPS patients underwent kidney transplantation (47 vs. 59, p < 0.0001). With regard to the period after transplantation, the yearly probability of EPS increased in the year after transplantation to 7.5% from 1.75%. In multivariate regression analysis, cumulative PD duration, age at PD start, transplantation, time from last transplantation to EPS, calendar time, time on icodextrin, and ultrafiltration failure were independently associated with EPS. Transfer from PD to hemodialysis for reasons other than suspected EPS could not be identified as a risk factor for EPS. CONCLUSIONS: Duration of PD, age at PD start, kidney transplantation, time since last transplantation, ultrafiltration failure, and time on icodextrin were associated with a higher risk of EPS.

Tamoxifen is associated with lower mortality of encapsulating peritoneal sclerosis: results of the Dutch Multicentre EPS Study.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with an increasing incidence. There is no clear consensus on the treatment of EPS, but anecdotal reports indicate improvement in EPS patients treated with tamoxifen. At present, there is no evidence for the effect of tamoxifen treatment in EPS patients. This study investigates the effect of treatment with tamoxifen on survival in EPS patients. METHODS: This study is a retrospective analysis of survival in EPS patients as part of the Dutch multicentre EPS study in the period January 1996 to July 2007. Sixty-three patients with severe EPS were followed up until August 2008. Demographic, patient and PD-related variables of EPS patients were investigated. Patients treated with tamoxifen were compared to patients not treated with tamoxifen. Survival was analysed with multivariate Cox regression analysis. RESULTS: Twenty-four patients were treated with tamoxifen, and 39 were not treated with tamoxifen. The clinical and demographic characteristics were similar for the tamoxifen-treated and non-treated groups. The mortality rate was significantly lower in tamoxifen-treated patients compared to EPS patients not treated with tamoxifen (45.8% vs 74.4%, P=0.03). Survival in tamoxifen-treated patients, adjusted for calendar time, age, use of corticosteroids, presence of functioning transplantation, use of parental nutrition and centre influences was longer in comparison to not-treated patients (HR 0.39, P=0.056). CONCLUSIONS: Tamoxifen treatment in EPS patients is associated with lower mortality and shows a trend to an increased multivariate-adjusted survival. This supports additional use of tamoxifen to treat patients with severe EPS.

Early diagnostic markers for encapsulating peritoneal sclerosis: a case-control study.

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. 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.

Posttransplant encapsulating peritoneal sclerosis: a worrying new trend?

Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication in patients on peritoneal dialysis (PD). We describe a cluster of 13 EPS cases occurring in 2 university hospitals in The Netherlands. Most of these cases were diagnosed after recent kidney transplantation, when the patients developed severe symptoms of bowel obstruction. This accumulation raised the question as to whether other than known risk factors, such as duration of PD treatment, could be involved in the development or course of EPS after transplantation. According to various publications, EPS has been diagnosed often after withdrawal from PD, suggesting that cessation in itself may be a risk factor. In addition, transplantation-related management should be considered to play a role, including the use of the profibrotic calcineurin inhibitors and the trend to reduce the load of corticosteroids in treatment regimes. To identify risk factors, further multicenter studies are required, paying special attention to alterations in immunosuppressive treatment regimens as well as PD prescriptions, including PD fluid characteristics. Transfer from PD to hemodialysis should be under serious consideration in patients eligible for kidney transplantation as soon as there are indications of ultrafiltration failure.