Version May 2024
INTRODUCTION — Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis that is characterized by intraperitoneal inflammation and fibrosis, which at times results in the encasement of bowel loops. EPS causes ultrafiltration failure and bowel obstruction and is associated with significant morbidity and a high mortality.
This topic reviews EPS. Other, more common complications related to peritoneal dialysis are discussed elsewhere:
●(See "Microbiology and therapy of peritonitis in peritoneal dialysis".)
●(See "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis".)
●(See "Inadequate solute clearance in peritoneal dialysis".)
●(See "Peritoneal catheter exit-site and tunnel infections in peritoneal dialysis in adults".)
Factors that regulate solute and water transport across the peritoneal membrane are discussed separately. (See "Mechanisms of solute clearance and ultrafiltration in peritoneal dialysis".)
PATHOGENESIS — The pathogenesis of EPS is not well understood [1]. EPS is believed to be a result of inflammation in the peritoneum, which causes progressive peritoneal mesothelial cell loss, submesothelial fibrosis, and peritoneal capillary angiogenesis [2]. The inflammation is presumed to be due to the dialysis procedure itself and may be related to exposure to glucose or glucose degradation products and advanced glycosylation end products in peritoneal dialysis fluids. It has been proposed that by increasing the cytosolic NADH to NAD+ ratio, high glucose levels upregulate hypoxia-inducible factor 1, which stimulates a variety of proinflammatory and profibrotic pathways [3].
An increase in fibrinogenesis and in endothelial permeability causes exuberant fibrin deposition on the peritoneum [4]. Any process that increases inflammation, such as episodes of bacterial peritonitis, may cause increases in permeability and fibrin deposition [5].
Some have speculated that increased activity of the local renin-angiotensin system (RAS) in mesothelial cells may contribute to fibrin accumulation. Observational cohort data suggest that patients treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) (which inhibit the RAS) are less likely to have functional changes consistent with peritoneal fibrosis [6,7].
Repeated fibrin deposition causes formation of a dense capsule surrounding the small bowel, which may cause obstruction. Capsule formation and risk for adhesions and bowel encapsulation may be accelerated after peritoneal dialysis is discontinued. This is because fluid exchanges that are performed during peritoneal dialysis tend to wash away some of the excessive fibrin. When peritoneal dialysis is stopped, the inflammatory reaction and fibrin production continue, but fibrin is no longer washed away by peritoneal dialysis exchanges [4].
EPIDEMIOLOGY — EPS is rare. Among patients on peritoneal dialysis, the reported incidence varies between 0.7 and 13.6 per 1000 patient-years [8-14]. Limitations in study design and detection bias likely contribute to variability in reported individual risk. Many patients with EPS present after peritoneal dialysis has been discontinued (usually for repeated peritonitis episodes, ultrafiltration failure, or because patients receive kidney transplants); these patients are often not included in studies. There is no good screening test, which means that many patients with mild or early cases of EPS are not diagnosed. In addition, some patients who have mild peritoneal fibrosis may be misdiagnosed as having EPS. Not all instances of mild peritoneal fibrosis are true cases of EPS. Also, most studies do not account for competing risks of death. In a study of more than 17,000 patients on peritoneal dialysis, the estimated risk of EPS after five years fell by more than half when the competing risk of death was taken into account [15].
The risk also varies among centers and countries. This variability has been attributed to many factors such as genetic differences and differences in peritoneal dialysis protocols (prescribed volumes, peritoneal dialysis glucose concentration, use of biocompatible fluids, and time spent on peritoneal dialysis) [8].
The risk of EPS may be higher among transplant recipients who used to be on peritoneal dialysis compared with patients who are still on peritoneal dialysis and have not received a transplant [10,12-14]. In one retrospective study that identified 18 patients with EPS, 15 had a history of kidney transplantation [12].
The reasons for the transplantation-associated risk are not known. The increased risk may be related to the cessation of dialysis itself since, once the inflammation process has started, peritoneal lavage with peritoneal dialysis may limit fibrin accumulation and be protective. In addition, calcineurin inhibitors, which are a commonly used antirejection medication, are profibrotic and thus may worsen fibrin deposition. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)
However, among patients who have EPS, transplantation may increase survival, and EPS is not a contraindication to transplantation. (See 'Prognosis' below.)
EPS has been reported among patients not on peritoneal dialysis, but this entity is vanishingly rare [16].
RISK FACTORS — The two major risk factors for EPS are duration of time on peritoneal dialysis and severe, recurrent peritonitis. There are multiple other suggested risk factors.
●Time on peritoneal dialysis – The duration of time on peritoneal dialysis is the major risk factor for EPS [8-11,17-20]. In a prospective, multicenter study from 57 facilities in Japan, among a total of 1958 patients, the incidence of EPS was 0, 0.7, 2.1, 5.9, 5.8, and 17.2 percent for those who had undergone peritoneal dialysis for 3, 5, 8, 10, 15, and greater than 15 years, respectively [9]. Similar findings have been found in other studies as well [10,11,17,18]. In one Australian and New Zealand survey, the incidence of EPS was 0.3, 0.8, and 3.9 percent for patients on peritoneal dialysis for three, five, and eight years, respectively [11].
●Severe peritonitis – Multiple episodes of severe peritonitis (particularly with Staphylococcus aureus species, fungus, and Pseudomonas) are a risk factor [10-14,21]. In a study of 100 patients with EPS, 28 patients had one previous episode of peritonitis, 29 had two previous episodes, and 33 had three or more [21]. Only 10 patients did not have a history of peritonitis.
Repeated episodes of mild peritonitis do not appear to be a risk factor for EPS [11].
●Specific dialysate fluids – Higher dialysate glucose concentration, the use of acetate as a dialysate buffer, and bioincompatible dialysate may be risk factors. We do not believe there are sufficient data to suggest that icodextrin is a risk factor. (See "Peritoneal dialysis solutions".)
●Specific drugs – Beta blockers and calcineurin inhibitors may be risk factors [10-14].
●Decreased ultrafiltration and increased solute transport – A disproportionate decrease in ultrafiltration capacity compared with decline in solute transport (ie, uncoupling) may identify increased EPS risk [1]. In addition, decreased free-water transport alone and in combination with biomarkers may help predict EPS [22]. Larger studies are required to confirm these observations before they are introduced in routine clinical practice.
The utility of biomarkers in identifying patients at risk for EPS is unclear [1,8,22]. Inflammatory cytokines including interleukin (IL) 6, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein 1 (MCP-1), plasminogen activator inhibitor type 1, and others are mildly increased and cancer antigen 125 is decreased in patients who go on to develop clinical signs of EPS. However, there is marked variability in biomarker concentrations, and their predictive ability has not been demonstrated. Thus, they are not routinely checked in clinical practice.
PREVENTION — Reliable preventive measures have not been identified. Among all patients on peritoneal dialysis, possible preventive strategies include limiting use of high-glucose dialysate as much as possible and using biocompatible, or "neutral," peritoneal dialysis fluids. (See "Peritoneal dialysis solutions".)
Since the major risk factor is the duration of time on peritoneal dialysis (particularly after five or more years), some have advocated a time limit for peritoneal dialysis (see 'Risk factors' above). However, we do not set a time limit for peritoneal dialysis, since the vast majority of patients on peritoneal dialysis do not develop EPS, and the potential benefit of preemptively stopping peritoneal dialysis is offset by the risks associated with hemodialysis [8]. (See "Acute complications during hemodialysis".)
In addition, studies suggest that patients who may have already started to develop the inflammatory process (but which may not be clinically evident yet) worsen after peritoneal dialysis is discontinued [10].
Some clinicians rest the peritoneal membrane (ie, stop peritoneal dialysis and perform hemodialysis for a number of weeks to months) among patients who have one or more risk factors, such as those who have repeated episodes of severe peritonitis or who show decreases in ultrafiltration or increased solute transport. However, this practice is controversial since EPS may present or worsen after peritoneal dialysis is stopped [10]. If the decision is made to rest the membrane, then a short peritoneal dialysis dwell or lavage should be performed twice weekly just to flush the membrane and minimize possible adhesion formation. (See 'Treatment' below.)
CLINICAL FEATURES
History and physical — EPS is a slowly progressive, frequently asymptomatic disorder that occurs after many years on peritoneal dialysis (generally >5 years), often complicated by multiple episodes of severe peritonitis.
EPS develops in a stepwise fashion, and early (inflammatory) and late (ileus) stages have been identified.
●Early – Early signs and symptoms described by the patient are nonspecific and include anorexia, nausea, diarrhea, and intermittent abdominal pain.
The physical exam is often unrevealing in early stages, although, among patients who are still on peritoneal dialysis, blood-tinged dialysate/ascites may be observed on exchanges, especially after periods where the peritoneal dialysis cavity has been dry [1]. Patients who are still on peritoneal dialysis may develop progressive volume overload and lower ultrafiltration volumes, despite adjusting the peritoneal dialysis prescription to increase ultrafiltration.
●Late – More prominent clinical features occur in the late stage and result from ileus and/or peritoneal adhesions [23]. With encapsulation of the bowel, the patient develops symptoms of intermittent obstruction including severe cramping, abdominal pain, constipation, and vomiting. In a study of 111 patients with severe, late-stage EPS, the most commonly reported symptoms were abdominal pain and vomiting in 67 and 59 percent of patients, respectively [21]. By this stage, the exam may reveal an abdominal mass. Occasionally, bowel symptoms may occur in the absence of ultrafiltration failure (although careful review of the chart may show that the patient may have had the prescription adjusted to increase ultrafiltration).
At times after discontinuation of peritoneal dialysis (such as posttransplant), a patient is diagnosed with ascites but has no symptoms of an ileus or obstruction [21,24]. This may be a sign of early EPS. Such patients may be less likely to develop bowel adhesions because the ascetic fluid keeps the bowel walls from becoming adherent.
Laboratory findings — There are no routine laboratory findings that suggest EPS. The peritoneal dialysis fluid may show white blood cells (WBCs), but these are low in number and are generally nonspecific. Serial peritoneal equilibration tests may show a trend toward increased solute transport and decreased ultrafiltration, specifically with low free-water transport rates [25-27], probably due to interference of interstitial collagen-1 with the crystalloid osmotic gradient, rather than due to a vasculopathy [28]. However, these changes are not observed in all patients with EPS and are commonly observed in the absence of EPS, particularly among patients who have been on peritoneal dialysis for a number of years.
Radiographic findings — Computed tomography (CT) scan shows peritoneal calcification, bowel thickening, tethering, and dilatation [4,8,29]. Bowel tethering and peritoneal calcification are the most specific findings, although there are no radiographic abnormalities that are diagnostic in the absence of characteristic signs and symptoms [29]. A completely normal CT is unusual in late-stage disease but does not exclude early EPS.
DIAGNOSIS — The diagnosis is suspected in a patient who has been on peritoneal dialysis and who develops nonspecific gastrointestinal symptoms (such as abdominal pain, nausea, loss of appetite, constipation, diarrhea, vomiting) without obvious explanation, particularly in the setting of a progressive loss of ultrafiltration, resulting in fluid retention and edema.
A clue to the diagnosis may be found in the dialysis history. Sequential peritoneal equilibration testing (which is routinely performed to characterize membrane transport) may have demonstrated an initial increase from baseline in peritoneal solute transport followed by a decrease in solute transport [8,23]. The increase in peritoneal transport is often observed prior to onset of any gastrointestinal symptoms. (See "Peritoneal equilibration test" and "Management of hypervolemia in patients on peritoneal dialysis", section on 'Peritoneal equilibration test'.)
A presumptive diagnosis is generally made on the basis of clinical presentation and characteristic imaging (computed tomography [CT]) [8,30]. (See 'Radiographic findings' above.)
True confirmation of the diagnosis can only be made by laparotomy and/or laparoscopy, which demonstrates characteristic peritoneal thickening that encloses intestinal contents. However, laparotomy and/or laparoscopy are rarely done since they are invasive and associated with increased risk [30].
CT scanning is the key imaging technique for the diagnosis [8], although there are no radiographic abnormalities that are diagnostic in the absence of characteristic signs and symptoms [29]. (See 'Radiographic findings' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for EPS is broad and depends on the specific presentation. The differential for later stages of EPS include all causes of intermittent obstruction, particularly malignancy.
EPS should not be confused with the generally benign and subclinical peritoneal fibrosis that occurs in most patients on peritoneal dialysis. The latter condition is characterized by increased fibrous tissue, predominantly in the parietal peritoneum (discerned by biopsy) [31], and is without symptoms or radiographic changes and almost always without evidence of failure of ultrafiltration [32]. The peritoneal fibrosis in this setting may be induced by episodes of peritonitis (particularly if severe) or may simply be a consequence of a prolonged duration of peritoneal dialysis.
Changes in ultrafiltration and solute transport are neither specific nor sensitive for EPS. Such changes commonly occur in patients without EPS, and patients with EPS may present without them. (See 'History and physical' above.)
TREATMENT — Treatment primarily consists of medical therapy with tamoxifen and occasionally resting the peritoneum with a temporary switch to hemodialysis. Some patients require the cessation of peritoneal dialysis with a permanent switch to hemodialysis. All patients require close attention to nutritional status with supportive care as needed.
●Tamoxifen – We treat patients with tamoxifen. We give 10 mg three times daily for at least three months. We also give prednisone 40 mg daily for at least four months followed by a prednisone taper over an additional six to eight weeks [9,33-36].
In a number of case series and retrospective analyses, tamoxifen was associated with better survival [24,37,38]. In a retrospective analysis of a registry including 63 patients diagnosed with severe EPS between 1996 and 2007, tamoxifen was associated with lower mortality (46 versus 74 percent in patients not treated with tamoxifen) [24]. However, one study showed no difference in outcome between patients treated with tamoxifen versus those who were not [21].
Well-studied side effects of tamoxifen include venous thromboembolic events and increased risk of endometrial cancer and uterine malignancy. There are little data on side effects among patients with EPS. One report of four EPS patients treated with tamoxifen described two episodes of clotted hemodialysis access and a nonfatal pulmonary embolism [39]. (See "Managing the side effects of tamoxifen and aromatase inhibitors", section on 'Venous thromboembolism' and "Managing the side effects of tamoxifen and aromatase inhibitors", section on 'Uterine bleeding, hyperplasia, and cancer'.)
The additional benefit, if any, that is provided by prednisone is not clear [24].
●Resting the peritoneum – We rest the peritoneum in selected patients. This is based on our collective experience that resting the peritoneum may alleviate symptoms. Such patients must be maintained on hemodialysis via a temporary central venous catheter [40,41].
The selection of patients cannot be based on any laboratory parameter but rather on clinical judgment and depending on severity of symptoms and on the burden placed by hemodialysis. If peritoneal dialysis is stopped, the peritoneum should be flushed twice weekly to minimize adhesions. We typically instill 100 to 200 mL of 1.36 percent dialysate containing 3500 international units of heparin (which is allowed to dwell for 30 minutes and then drained) [40].
The duration of the rest is typically 4 to 12 weeks, depending on symptoms.
●Stopping peritoneal dialysis – We do not permanently stop peritoneal dialysis in all patients. The decision to stop peritoneal dialysis must be individualized and is only made after careful consideration of the risks and benefits of peritoneal dialysis versus hemodialysis. For some patients, the gastrointestinal symptoms associated with early EPS may be preferred to the complications of hemodialysis (including infectious and noninfectious complications of the hemodialysis access) as well as the lifestyle changes associated with initiating hemodialysis. (See "Dialysis modality and patient outcome", section on 'Selection of dialysis modality'.)
In addition, as noted above, the signs and symptoms of EPS such as small bowel obstruction and abdominal discomfort may worsen after stopping peritoneal dialysis, and there are no reliable indicators of which patients will worsen. (See 'Pathogenesis' above.)
If the decision is made to stop peritoneal dialysis, we remove the peritoneal dialysis catheter and place a tunneled catheter for hemodialysis. Some clinicians advocate keeping the peritoneal dialysis catheter in place and using it to lavage the peritoneum; however, there are no data to support this approach.
●Supportive care – Patients should be closely followed for evidence of developing malnutrition. We do not use total parenteral nutrition unless patients do not tolerate oral intake or have evidence of developing malnutrition. (See "Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis", section on 'Diagnosis of PEW'.)
●Surgical interventions – Patients with EPS are at risk for acute obstruction due to adhesions. The acute management of such patients is similar to other patients with mechanical small bowel obstruction. (See "Management of small bowel obstruction in adults".)
Surgery for relief of chronic symptoms is not commonly performed, because of the risk for worsening adhesions and unrecognized perforations [30,42]. Two reports have been published from one center that described a benefit of total enterolysis in EPS patients with severe anorexia and weight loss [9,43]. In a retrospective study of 50 patients with EPS who underwent enterolysis, 46 patients (94 percent) had complete relief from bowel obstructive symptoms, with an average follow-up period of 35 months [43]. Two patients died, and two continued to have mild subacute symptoms.
Surgery for treatment of chronic symptoms should only be considered in a center with experience in the care of patients with EPS.
●Other therapies – A variety of immunosuppressive agents have been used to treat EPS, either alone or in combination with glucocorticoids. These agents include mycophenolate mofetil, mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus, and azathioprine [44]. However, the evidence to support the use of these medications for the treatment of EPS is limited to case reports.
PROGNOSIS — Historically, the reported mortality associated with EPS was very high, ranging from 35 to 50 percent in some series [8,9,30,42]. In an analysis of data from a Dutch registry of 53 cases from 2009 to 2015, the one- and two-year survival were 67 and 52 percent, respectively [37].
Transplantation may confer a survival benefit among those who have EPS. Two retrospective studies have suggested an association of transplantation with better survival among patients with EPS [21,24]. Supportive care (nutritional supplementation), treatment with tamoxifen, and use of glucocorticoids may have contributed to the improved survival.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)
SUMMARY AND RECOMMENDATIONS
●Overview – Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis that is characterized by intraperitoneal inflammation and fibrosis and results in the encasement of bowel loops. (See 'Introduction' above and 'Pathogenesis' above.)
●Risk factors – The major risk factors for EPS are duration of time on peritoneal dialysis and episodes of severe peritonitis. Other possible risk factors include higher dialysate glucose concentration, the use of acetate as a dialysate buffer, the use of drugs such as beta blockers, and transplantation. (See 'Risk factors' above.)
●Prevention – Possible preventive strategies include limiting use of high-glucose dialysate and using biocompatible, or "neutral," peritoneal dialysis fluids. We do not set a time limit for peritoneal dialysis, since most patients on peritoneal dialysis do not develop EPS, and the potential benefit of stopping peritoneal dialysis is offset by the risks associated with hemodialysis. EPS may also worsen when peritoneal dialysis is stopped. (See 'Prevention' above.)
●Clinical features – Early signs and symptoms include anorexia, nausea, diarrhea, and intermittent abdominal pain. With encapsulation of the bowel, the patient develops severe cramping, abdominal pain, constipation, and vomiting due to obstruction. In later stages, the exam may reveal an abdominal mass. There are no routine laboratory findings that suggest EPS. (See 'Clinical features' above.)
●Diagnosis – The diagnosis is usually made on the basis of presentation and computed tomography (CT) imaging. A suggestive clinical history includes gastrointestinal symptoms without obvious cause, particularly in the setting of progressive ultrafiltration failure resulting in fluid overload. Sequential peritoneal equilibration testing that shows an increase followed by a decrease in solute transport prior to the onset of gastrointestinal symptoms strongly supports the diagnosis but is not a specific nor sensitive finding. True confirmation of the diagnosis can only be made by laparotomy and/or laparoscopy, but these are rarely done. (See 'Diagnosis' above.)
●Treatment – For most patients on peritoneal dialysis with EPS, we suggest treatment with tamoxifen and prednisone (Grade 2C). A preferred regimen is daily tamoxifen (10 mg three times daily) for at least three months, with prednisone (40 mg daily) for at least four months, followed by a prednisone taper over an additional six to eight weeks. The decision to stop peritoneal dialysis must be individualized and is only made after careful consideration of the risks and benefits of peritoneal dialysis versus hemodialysis. (See 'Treatment' above.)
●Prognosis – The reported mortality associated with EPS is very high. (See 'Prognosis' above.)
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