Denise E. Sampimon

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 β. 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.

Biological markers in the peritoneal dialysate effluent: are they useful.

A review is given on biomarkers in peritoneal effluent. It comprises methods to distinguish between diffusion and local production. This is followed by examples of various biomarkers. Their potential use is discussed in 4 situations: inherent fast transporters, longitudinal follow-up of patients, biocompatibility testing of new dialysis solutions, and their potential use in the detection of patients who are likely to develop encapsulating peritoneal sclerosis.

The −174G/C variant of IL6 as risk factor for mortality and technique failure in a large cohort of peritoneal dialysis patients

BACKGROUND Functional variants in the IL6 gene, in particular the -174G/C polymorphism (rs1800795), affect the mortality risk in dialysis patients. Peritoneal dialysis (PD) patients harbouring the C allele of the -174G/C polymorphism of IL6 showed faster peritoneal transport. The aim of this study was to investigate this IL6 variant as risk factor for mortality and technique failure in a large cohort of Caucasian PD patients. METHODS A Dutch multicentre cohort of 398 incident PD patients (NECOSAD) was analysed. Survival analysis was performed for death and technique failure with a maximum follow-up of 5 years. A combined PD cohort from Amsterdam (Academic Medical Center, N = 71) and Brussels (Université catholique de Louvain Medical School, N = 102) was used for independent replication. RESULTS In NECOSAD, 105 patients died on dialysis [incidence rate 10.3/100 person-years (py)], and 138 patients experienced technique failure (16.2/100 py), with peritonitis as important cause. Patients with the C/C genotype had a 71% increased mortality risk compared to patients with the G/G genotype (95% confidence interval 0.98-2.98); this effect was mainly a long-term effect: a 2.7-fold increased mortality risk was found in patients having survived 2 years since the start on dialysis, and a 1.7-fold increased risk for the combined end point (mortality or technique failure). In the combined replication cohort, no increased risks were found in patients with the C/C genotype. CONCLUSIONS The C/C genotype of the -174G/C polymorphism was associated with an increased mortality risk in 398 Dutch incident PD patients. The existence of substantial differences between the two academic replication cohorts and the discovery cohort from NECOSAD and the limited power of these cohorts prevented an independent replication of the NECOSAD findings.

Encapsulating Peritoneal Sclerosis in a Peritoneal Dialysis Patient Using Biocompatible Fluids Only: Is Alport Syndrome a Risk Factor?

A 30-year-old Caucasian male known to have Alport syndrome presented acutely in 2002 with end-stage kidney failure and tertiary hyperparathyroidism. A parathyroidectomy was performed and automated peritoneal dialysis (PD) was initiated. The dialysis prescription consisted of a 7.5% icodextrin-based solution (Extraneal; Baxter Healthcare, IRL-Dublin, Ireland) for the long dwell and 1.1% amino acidbased solution (Nutrineal, Baxter) and lactate/bicarbonate solution (Physioneal, Baxter) for the short dwells. Five episodes of peritonitis occurred during follow-up, caused by either coagulase-negative staphylococci (n = 2) or Staphylococcus aureus (n = 3). All episodes were successfully treated with antibiotics. It appeared difficult to keep the calcium × phosphorus product below target and the patient developed calcifications in his hands and feet. After 6 years of PD a diagnosis was made of encapsulating peritoneal sclerosis (EPS). The diagnosis was based on abdominal complaints, especially bowel obstruction, ultrafiltration failure, a low effluent calcium antigen-125 and a computed tomographic (CT) scan compatible with EPS (1). The CT scan showed peritoneal thickening, calcifications, adhesions, and fluid loculations/septation. The patient was transferred to hemodialysis. After removal of the Tenckhoff catheter he developed massive ascites. Encapsulating peritoneal sclerosis is a severe complication of long-term PD. Long-term exposure to conventional dialysis solutions is an important risk factor for EPS (2). The pathological role of dialysis solutions may be due to the large amounts of glucose and glucose degradation products (GDPs), which enhance the formation of advanced glycosylation end products. More biocompatible solutions are now available. These solutions have a physiological pH and contain low amounts of GDPs (3).To our knowledge no patient has yet been described who developed EPS while being treated with biocompatible fluids exclusively. Alport syndrome is a rare disorder of collagen IV, which is present in basement membranes throughout the body (4). Whether Alport syndrome affects the basement membranes of peritoneal tissue and vessels is unknown. EPS is associated with an increase in interstitial and endothelial collagen IV deposits (5). We hypothesized that Alport syndrome could affect the peritoneum because interstitial collagen IV synthesis in the peritoneum may be disturbed. Our research question was, Does Alport syndrome predispose to the development of EPS in PD patients?

Experimental Peritoneal Sclerosis Models Should Not Be Based on Chlorhexidine Gluconate Anymore

Background/Aims: Currently available rodent models of peritoneal sclerosis are not based on clinically relevant factors: renal failure in combination with exposure to bioincompatible fluids. Our aim was to develop a chronic peritoneal infusion model of peritoneal sclerosis in rats with renal failure. Methods: Male Wistar rats underwent a catheter implantation and a 70% nephrectomy. They were randomly divided into three peritoneal infusion groups: chlorhexidine gluconate/ethanol (CGE) + Dianeal (Baxter Healthcare, Castlebar, Ireland), CGE + buffer (Physioneal without glucose; Baxter, Nivelles, Belgium) and Dianeal alone. After 8 weeks a peritoneal permeability test was performed and omental tissue was obtained for morphometrics. Results: The CGE + Dianeal group (n = 6) and CGE + buffer (n = 6) group showed high peritoneal clearances of small solutes and proteins, ultrafiltration failure, impaired free water transport, severe fibrosis and high vessel counts, but the groups did not differ significantly. The Dianeal group (n = 6) showed significantly lower clearances of small solutes and proteins, normal ultrafiltration and sodium sieving, and significantly lower fibrosis scores and vessel counts. Conclusions: Abnormalities seen in peritoneal sclerosis can be induced in a peritoneal infusion model in rats with renal failure. However, the addition of a bioincompatible dialysis solution had no contributing role, probably because the effects were overruled by those of CGE.

No need for an "expiry date" in chronic peritoneal dialysis to prevent encapsulating peritoneal sclerosis: comments from around the world.

Following the publication of our editorial [1], we encouraged a number of our colleagues to communicate and express their views on the pathogenesis and future prevention of this serious complication of chronic peritoneal dialysis and their views on our position regarding its management. Their letters give a great insight into current views and future directions in the prevention, detection and management of this serious complication. The two reports from China assert that this is a rare complication among their patients, contrary to reports from Japan. If these Chinese findings are supported by longer and prospective studies, we will have to revise our current views on the pathogenesis of this condition, which will lead to new approaches to its prevention.