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Encapsulating peritoneal sclerosis

Encapsulating peritoneal sclerosis (EPS), also known as sclerosing encapsulating peritonitis, is a rare but severe clinical syndrome characterized by the thickening and fibrosis of the peritoneal membrane, which forms a fibro-collagenous cocoon encasing the small intestine and leading to recurrent bowel obstructions, malnutrition, and gastrointestinal dysfunction.^[1] It primarily affects patients undergoing long-term peritoneal dialysis (PD) for end-stage renal disease, though cases have been reported in association with other conditions such as intraperitoneal infections, abdominal surgeries, autoimmune disorders, and post-renal transplantation.^[2] The condition arises from chronic peritoneal injury, progressing through inflammatory, encapsulating, and obstructive stages, and remains a significant challenge despite advancements in dialysis technology.^[3] The etiology of EPS is multifactorial, with prolonged exposure to conventional PD fluids playing a central role; these fluids contain glucose degradation products, advanced glycation end-products, and acidic pH levels that trigger peritoneal inflammation, oxidative stress, and epithelial-to-mesenchymal transition in mesothelial cells, culminating in fibrosis and neo-membrane formation.^[1] Key risk factors include PD duration exceeding five years, severe or recurrent peritonitis, young age at PD initiation, and genetic predispositions, with a "two-hit" mechanism often proposed where initial peritoneal damage is exacerbated by a second insult such as PD withdrawal or transplantation.^[2] Epidemiologically, the incidence in PD patients ranges from 0.4% to 3.3% overall, rising sharply with treatment duration—up to 18.4% after five years and 22.2% after seven years in some cohorts—though rates have declined in regions like Japan from 2.5% (1999–2003) to 1.0% (2008–2012) following the adoption of neutral pH, biocompatible PD solutions.^[3] Non-PD-related cases are even rarer, often linked to beta-blocker use, tuberculosis, or malignancies.^[1] Clinically, EPS manifests in three phases: an early inflammatory stage with nonspecific symptoms such as fever, nausea, ascites, and ultrafiltration failure; an intermediate encapsulating phase marked by abdominal pain, distension, weight loss, and early satiety; and a late obstructive phase featuring overt bowel obstruction, malnutrition, and an abdominal mass in up to 50% of cases.^[2] Diagnosis relies on a combination of clinical history, laboratory findings (e.g., elevated C-reactive protein and hypoalbuminemia), and imaging; computed tomography (CT) is the modality of choice, demonstrating 100% sensitivity and 94% specificity for features like peritoneal thickening (>2 mm), calcification, loculated fluid, and bowel tethering to the posterior abdominal wall.^[1] In equivocal cases, laparoscopy or exploratory laparotomy may confirm the diagnosis by revealing the characteristic cocoon, while biomarkers like dialysate cancer antigen 125 levels can aid early detection during PD.^[3] Management of EPS is multidisciplinary and stage-dependent, beginning with immediate discontinuation of PD and transition to hemodialysis, alongside aggressive nutritional support via total parenteral nutrition to combat malnutrition.^[2] Medical therapies include corticosteroids (e.g., prednisolone at 0.5–1 mg/kg/day) to suppress inflammation, tamoxifen (10–40 mg/day) to inhibit fibrosis, and sometimes immunosuppressants like azathioprine or mTOR inhibitors; these approaches have shown response rates up to 60% in early stages.^[1] For advanced obstructive disease, surgical intervention—such as peritonectomy, enterolysis, and bowel resection—is often required, with postoperative mortality ranging from 19% to 34.5% but improving with experienced centers.^[2] Prognosis varies by timeliness of intervention, with overall mortality historically at 25–55% within the first year post-diagnosis, though recent data indicate reductions to 14.3% in Japan due to biocompatible solutions and earlier recognition.^[3]

Overview

Definition and Characteristics

Encapsulating peritoneal sclerosis (EPS) is a rare and serious syndrome characterized by chronic inflammation and progressive fibrosis of the peritoneum, resulting in the formation of a thick, fibrous membrane that encapsulates intra-abdominal organs, particularly the small intestine, and leads to functional impairment of bowel motility and absorption. This condition transforms the normally thin and flexible peritoneal lining into a rigid, inelastic structure, often described as a "cocoon" that encases loops of the small bowel, potentially progressing to total abdominal encasement in severe cases. Unlike simple peritoneal fibrosis, which may involve localized thickening without encapsulation, EPS features widespread sclerosis and adhesion formation that distinctly impair peritoneal function. The peritoneum, a serous membrane that lines the abdominal cavity and covers abdominal organs, plays a critical role in fluid exchange and ultrafiltration, particularly in patients undergoing peritoneal dialysis where it serves as a semipermeable barrier. In EPS, this membrane undergoes pathological remodeling, with excessive deposition of extracellular matrix components such as collagen, leading to peritoneal thickening and loss of its natural compliance. The sclerosis primarily affects the visceral peritoneum surrounding the small intestine, though it can extend to other structures like the colon and omentum, creating a fibrotic shell that restricts organ mobility and contributes to the syndrome's progressive nature. These anatomical changes underscore EPS as a distinct entity within peritoneal pathology, emphasizing its potential for irreversible structural alterations if not addressed early.

Historical Development

Encapsulating peritoneal sclerosis (EPS) was first recognized in the medical literature in the early 1980s as a rare complication of peritoneal dialysis (PD). The initial report came in 1980 from Gandhi et al., describing the condition in a patient undergoing intermittent PD, characterized by peritoneal thickening and bowel encapsulation. Subsequent cases emerged with the widespread adoption of continuous ambulatory PD (CAPD), including the first documented CAPD-associated instance in 1983 by Rottembourg et al. In Japan, where PD was introduced in 1982, the first case appeared in 1985, and early descriptions in Japanese literature referred to it as "sclerosing encapsulating peritonitis," often linked to long-term CAPD exposure. A pivotal 1996 report by the Japanese Sclerosing Encapsulating Peritonitis Study Group analyzed 62 cases among 6,923 CAPD patients from 1980 to 1994, highlighting an incidence of 0.9% and establishing case series that underscored its association with prolonged PD duration.^[4]^[5]^[6] The terminology for the condition evolved to reflect a deeper understanding of its pathological features. Early designations such as "sclerosing peritonitis" or "sclerosing encapsulating peritonitis" emphasized inflammatory and fibrotic aspects but were deemed imprecise for the encapsulating morphology observed. In 2000, the International Society for Peritoneal Dialysis (ISPD) formalized the term "encapsulating peritoneal sclerosis" in a position paper led by Kawaguchi et al., defining it as a syndrome involving progressive peritoneal membrane sclerosis leading to intestinal encapsulation and clinical manifestations like bowel obstruction. This shift aimed to standardize nomenclature, distinguishing it from simpler peritoneal sclerosis and facilitating global research and diagnosis.^[7]^[4] Key milestones in the 1980s and 1990s marked the growing recognition of EPS primarily in PD contexts. The 1980s saw initial case series confined to PD patients, with reports like those from Marigold et al. (1982) exploring potential links to beta-blocker use, though PD emerged as the dominant factor. By the 1990s, awareness expanded to include post-transplant presentations, with early cases noted shortly after kidney transplantation in PD patients, as documented in studies from the late 1990s, such as those analyzing bowel obstruction risks post-PD withdrawal. Japanese multicenter efforts, including the 1996 study group report, quantified risks and outcomes, revealing a mortality rate of around 40% and prompting calls for preventive strategies.^[4]^[6]^[8] In the 2010s, understanding advanced with recognition of non-PD etiologies and refined diagnostic criteria. Updates highlighted associations beyond PD, such as autoimmune diseases, sarcoidosis, and prior abdominal surgeries, broadening the etiological framework in reviews like those from Brown et al. (2017). Improved criteria, incorporating imaging and clinical features, were proposed by ISPD, aiding earlier detection. Historically, EPS posed challenges like frequent misdiagnosis as infectious peritonitis due to overlapping peritoneal inflammation and histological findings, contributing to its early reputation as a nearly fatal condition with mortality exceeding 30% in the 1990s. By the 2020s, perceptions shifted toward treatability, driven by interventions like biocompatible PD solutions introduced in the 2000s, which reduced incidence to about 1% in long-term cohorts, and multidisciplinary management improving survival rates.^[1]^[4]^[9]^[6]

Clinical Presentation

Signs and Symptoms

Encapsulating peritoneal sclerosis (EPS) primarily manifests through a range of gastrointestinal and systemic symptoms, often in patients undergoing long-term peritoneal dialysis. Common early symptoms include diffuse or crampy abdominal pain, nausea, vomiting, early satiety, and anorexia, which contribute to progressive malnutrition and significant weight loss. These nonspecific complaints typically arise due to peritoneal inflammation and initial bowel encapsulation, impairing normal digestive function.^[1]^[10] Gastrointestinal signs further encompass altered bowel habits such as constipation or diarrhea, alongside symptoms suggestive of partial obstruction, including abdominal distension and reduced bowel sounds on physical examination. In peritoneal dialysis patients, systemic features like ascites and low-grade fever may accompany these, reflecting ongoing peritoneal inflammation. Additionally, signs of ultrafiltration failure, such as fluid retention and edema, become evident as the peritoneal membrane's functionality declines.^[4]^[1] The disease often follows an insidious onset with vague, intermittent symptoms that evolve over months to years into more severe manifestations, such as intractable vomiting and acute bowel obstruction in advanced stages. In advanced stages, a palpable abdominal mass may be detected in up to 50% of cases. This progression underscores the need for early recognition, particularly in at-risk populations, to mitigate nutritional decline and obstructive complications.^[10]^[4]^[2]

Associated Complications

Encapsulating peritoneal sclerosis (EPS) frequently results in bowel-related complications due to the progressive encasement of intestinal loops by a thickened fibro-collagenous membrane, leading to partial or complete intestinal obstruction. This obstruction often progresses to ileus, characterized by impaired bowel motility and accumulation of intestinal contents, which can cause distension and severe functional impairment. In advanced cases, sustained obstruction heightens the risk of bowel ischemia from compromised vascular supply and potential perforation, which may precipitate peritonitis or sepsis if untreated.^[1]^[11] Nutritional and metabolic disturbances represent significant sequelae of EPS, arising primarily from chronic malabsorption secondary to recurrent bowel obstruction and reduced oral intake. Severe malnutrition is common, with many patients experiencing weight loss exceeding 10% in the preceding six months and requiring parenteral nutrition for support. Hypoalbuminemia frequently accompanies this, affecting the majority of cases at diagnosis and contributing to fluid imbalances and weakened immune function. Cachexia may develop as a result, marked by progressive muscle wasting and overall frailty that exacerbates the disease burden.^[12]^[1] Additional complications include recurrent ascites, often stemming from ongoing peritoneal inflammation and disrupted fluid dynamics within the abdominal cavity, sometimes manifesting as blood-tinged effusion. Bacterial overgrowth within obstructed bowel segments can promote translocation of pathogens across the intestinal wall into the peritoneum, intensifying inflammation, fibrosis, and the risk of systemic infection. In severe, untreated EPS, these processes may culminate in multi-organ failure, driven by sepsis, gut ischemia, and metabolic derangements, with mortality rates reaching 74% in such advanced presentations.^[4]^[1] Thromboembolic events, though rare, can occur in EPS patients, potentially linked to prolonged immobility secondary to bowel obstruction and associated discomfort, increasing the risk of venous thromboembolism such as pulmonary embolism.

Etiology

Primary Causes

Encapsulating peritoneal sclerosis (EPS) is predominantly caused by long-term peritoneal dialysis (PD), particularly in patients with end-stage renal disease, where chronic exposure to dialysate solutions leads to progressive peritoneal injury.^[1] The condition arises from repeated instillation of bioincompatible fluids that induce inflammation and structural changes in the peritoneal membrane.^[4] Glucose-based dialysates, commonly used for ultrafiltration, generate osmotic stress through high glucose concentrations, promoting mesothelial cell damage and subsequent fibrotic responses.^[4] Additionally, glucose degradation products in these solutions exacerbate bio-incompatibility by forming advanced glycation end products, which further impair peritoneal integrity.^[4] The risk of EPS development is notably amplified with prolonged PD duration, often exceeding several years.^[1] While PD remains the primary etiology, EPS can occur independently of dialysis in rarer instances, classified as primary or idiopathic cases where no clear precipitant is identified.^[13] Non-PD causes include post-abdominal surgery, such as colectomy, which introduces mechanical or chemical irritants to the peritoneum, triggering inflammatory cascades.^[13] Post-transplantation scenarios, particularly following kidney or liver transplants, are associated with EPS due to the profibrotic effects of immunosuppressive therapies like calcineurin inhibitors.^[1] Associations with autoimmune diseases, including systemic sclerosis, have also been reported, where underlying systemic inflammation contributes to peritoneal involvement.^[1] Historically, the beta-blocker practolol, now discontinued, was implicated in inducing peritoneal sclerosis through inhibition of mesothelial surfactant release, representing an early recognized pharmacological cause.^[14] In exceptional cases, peritoneal carcinomatosis may mimic EPS clinically and radiologically, though it stems from malignant dissemination rather than a primary sclerosing process.

Risk Factors

Encapsulating peritoneal sclerosis (EPS) primarily develops in patients undergoing long-term peritoneal dialysis (PD), with specific risk factors enhancing susceptibility within this population. Among PD-specific risks, extended duration of therapy exceeding 5-8 years significantly elevates the likelihood of EPS, as the cumulative exposure to dialysate promotes peritoneal membrane alterations. High peritoneal transport status, characterized by a dialysate-to-plasma creatinine ratio (D/P Cr) greater than 0.81, further increases vulnerability by accelerating solute absorption and fluid reabsorption issues. Additionally, acetate-buffered dialysates contribute through bioincompatibility, fostering inflammation and fibrosis compared to lactate-buffered alternatives.^[1] Patient-related non-modifiable factors include younger age at PD initiation, particularly under 40 years, which correlates with prolonged exposure potential and higher incidence rates independent of therapy duration. Genetic predispositions, such as polymorphisms in transforming growth factor-beta (TGF-β) genes, also play a role by enhancing fibrotic responses to peritoneal injury.^[15] Comorbid conditions heighten EPS risk through peritoneal damage; severe or recurrent peritonitis episodes, especially those caused by Staphylococcus aureus, promote persistent inflammation and membrane sclerosis. Loss of ultrafiltration capacity, defined as inadequate fluid removal despite hypertonic exchanges, serves as both a marker and contributor to progression toward EPS.^[1]^[16] Discontinuation of PD, such as after transfer to hemodialysis, represents a critical high-risk period for EPS manifestation, with up to 70-90% of cases diagnosed post-cessation due to unmitigated fibrotic processes.^[1]

Triggers

Discontinuation of peritoneal dialysis (PD) represents a major precipitating event for encapsulating peritoneal sclerosis (EPS) in susceptible patients, often leading to a rebound inflammatory response due to the abrupt withdrawal of dialysate flushing that previously cleared accumulated inflammatory mediators from the peritoneal cavity.^[1] This transition, typically to hemodialysis, carries the highest risk of EPS onset within 2 to 6 months post-transfer, with studies reporting that up to 70-90% of cases manifest after PD cessation, sometimes extending to several years but peaking early in this window.^[1]^[17] Infectious episodes, particularly severe or recurrent peritonitis, serve as acute triggers that accelerate peritoneal fibrosis and EPS development by intensifying local inflammation and promoting fibrogenic cytokine release.^[1] Common culprits include bacterial pathogens such as Staphylococcus aureus and Pseudomonas species, as well as fungal or mycobacterial infections like mucormycosis, which can provoke a disproportionate sclerosing response even in patients with prior PD exposure.^[1]^[18] Intra-abdominal infections beyond peritonitis, such as those complicating systemic inflammatory conditions, similarly exacerbate membrane thickening and encapsulation.^[9] Iatrogenic factors, including recent abdominal surgery or invasive peritoneal procedures, can disrupt the peritoneal surface and initiate acute inflammatory cascades that precipitate EPS in at-risk individuals.^[1] These interventions, such as laparotomy or catheter manipulations, may introduce mechanical trauma or foreign material, fostering adhesions and fibrosis, with case reports highlighting EPS emergence shortly after such events.^[19] Pharmacological exposures have been implicated as triggers, particularly in historical or non-PD contexts, where certain agents provoke peritoneal irritation leading to sclerosis. Older beta-blockers, such as practolol (withdrawn in the 1970s), timolol, and propranolol, are associated with EPS-like syndromes through direct mesothelial toxicity.^[20] In non-PD cases, iodinated contrast agents used in imaging studies have rarely been linked to peritoneal inflammation and subsequent encapsulation, likely via chemical irritation or hypersensitivity reactions.^[21]

Pathophysiology

Disease Mechanism

Encapsulating peritoneal sclerosis (EPS) develops through a progressive sequence of peritoneal injury and remodeling, primarily triggered by long-term exposure to peritoneal dialysis (PD) fluids. The process begins with injury to mesothelial cells lining the peritoneum, induced by the hypertonicity and bioincompatibility of PD dialysate, which contains high glucose concentrations and leads to cellular stress and apoptosis. This initial damage results in denudation of the mesothelial layer, exposing underlying submesothelial connective tissue to the dialysate and promoting further pathological changes.^[22]^[14] Following denudation, an inflammatory cascade ensues, characterized by the recruitment of macrophages into the peritoneal cavity and the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). These mediators drive angiogenesis, increasing vascular permeability and the influx of additional inflammatory cells, while also activating fibroblasts in the submesothelial region. The heightened inflammatory environment fosters a shift toward a profibrotic state, where activated fibroblasts differentiate into myofibroblasts capable of excessive extracellular matrix (ECM) production.^[23]^[24] The fibrotic progression involves the deposition of ECM components, predominantly collagen types I and III, in the submesothelial space. However, histological studies indicate no significant differences in peritoneal membrane thickness between EPS and non-EPS patients; the distinguishing feature of EPS is the formation of a neo-membrane through fibrin exudation and adhesion, which progressively contracts due to myofibroblast-mediated remodeling, eventually encasing the small bowel and other abdominal organs in a cocoon-like structure that restricts intestinal motility. EPS evolves through distinct stages: an early phase of simple peritoneal sclerosis marked by membrane changes without encapsulation, progressing to the encapsulating phase where organ tethering occurs, leading to bowel obstruction and impaired peristalsis.^[25]^[6]

Molecular Pathways

The fibrogenic response in encapsulating peritoneal sclerosis (EPS) is primarily driven by the transforming growth factor-beta (TGF-β) pathway, which is upregulated in the peritoneal mesothelium and fibroblasts exposed to long-term peritoneal dialysis conditions. TGF-β1, the predominant isoform, binds to its type I and type II receptors, activating canonical Smad signaling where Smad2 and Smad3 are phosphorylated and form complexes with Smad4 to translocate to the nucleus, promoting transcription of genes involved in extracellular matrix (ECM) production such as collagen I and fibronectin. This leads to myofibroblast differentiation from peritoneal mesothelial cells via epithelial-to-mesenchymal transition (EMT), characterized by increased alpha-smooth muscle actin expression and excessive ECM deposition, contributing to peritoneal thickening. Non-canonical pathways, including crosstalk with JNK and ERK, further amplify this fibrotic cascade in TGF-β-induced EMT.^[26]^[27]^[28]^[29] Platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) play critical roles in promoting fibroblast proliferation and neovascularization, exacerbating peritoneal fibrosis in EPS. PDGF, particularly PDGF-B, stimulates the proliferation and migration of peritoneal fibroblasts through activation of PDGF receptors, leading to increased cellularity and collagen synthesis in the submesothelial layer. Concurrently, VEGF upregulation induces angiogenesis, with elevated peritoneal expression observed in EPS patients, fostering vascular proliferation that enhances solute transport dysfunction and contributes to membrane thickening. These growth factors often act in synergy with TGF-β to sustain the fibroproliferative environment.^[30]^[31]^[32]^[33] Advanced glycation end-products (AGEs), formed from glucose degradation products in conventional dialysates, induce oxidative stress and amplify fibrosis in EPS. AGEs accumulate in the peritoneal tissue of long-term dialysis patients, binding to the receptor for AGEs (RAGE) on mesothelial cells and macrophages, which triggers reactive oxygen species (ROS) production via NADPH oxidase activation and subsequent NF-κB pathway stimulation, promoting inflammatory cytokine release and fibrogenic gene expression. This oxidative milieu further upregulates TGF-β and PDGF, perpetuating ECM accumulation and peritoneal stiffening. The renin-angiotensin system (RAS) also contributes to fibrosis, with angiotensin II (Ang II) generated locally in the peritoneum activating AT1 receptors on fibroblasts, enhancing TGF-β expression and collagen deposition through ERK and Smad signaling. Acidic dialysates exacerbate RAS activation, linking it directly to progressive peritoneal sclerosis.^[34]^[35]^[36]^[37]^[38]^[39]^[40]^[41] Genetic polymorphisms modulate susceptibility and severity of EPS by influencing these pathways. Polymorphisms in genes related to inflammation, angiogenesis, and fibrosis may predispose individuals to exaggerated fibrogenic responses.^[14]^[42]^[43]

Diagnosis

Diagnostic Methods

Diagnosis of encapsulating peritoneal sclerosis (EPS) typically involves a multimodal approach combining clinical evaluation, imaging studies, and, when necessary, invasive procedures to confirm peritoneal fibrosis and exclude mimics such as tuberculosis or malignancy. Suspicion arises in patients with a history of long-term peritoneal dialysis (PD) presenting with symptoms like abdominal pain, weight loss, or bowel obstruction, prompting further investigation.^[10] Computed tomography (CT) scanning serves as the gold standard for diagnosing EPS due to its high sensitivity (100%) and specificity (94%) when contrast-enhanced. Key CT findings include peritoneal thickening greater than 2 mm, calcifications, bowel tethering or dilation, loculated ascites, and the characteristic "cocoon sign" where small bowel loops are encapsulated within a fibrotic membrane. These features allow for non-invasive assessment, though early disease may yield normal results, and radiation exposure remains a limitation.^[44]^[10] Ultrasound provides a non-invasive initial evaluation, particularly useful for detecting ascites and loculations, but it is limited in visualizing sclerosis due to operator dependence and poor penetration in obese patients or without peritoneal fluid. It may show echogenic strands, membrane formation, or abnormal bowel motility, though reproducibility and specificity data are lacking.^[44] Magnetic resonance imaging (MRI) offers superior soft tissue contrast without radiation, revealing bowel distension, wall thickening, and lobulated ascites, with potential for early detection via cine-MRI assessing abdominal motion. However, its use is restricted by high cost, longer scan times, and risks of gadolinium in renal impairment, with evidence limited to case reports.^[44]^[10] Invasive confirmation via laparoscopy allows direct visualization of thickened, cocoon-like peritoneum and adhesions, often performed when imaging is equivocal or for therapeutic intervention. Peritoneal biopsy during laparoscopy or laparotomy confirms the diagnosis histologically by demonstrating submesothelial fibrosis, vasculopathy, and sclerosis, though it carries procedural risks and is typically reserved for advanced cases.^[10] The peritoneal equilibration test (PET) evaluates membrane function by measuring solute transport rates, with high transporter status indicating potential deterioration but lacking specificity for EPS, as not all high transporters develop the condition. It aids in functional assessment alongside imaging but does not replace anatomical evaluation.^[10] Clinical criteria for EPS diagnosis integrate PD history, persistent symptoms, and radiological evidence of encapsulation, requiring exclusion of infectious or neoplastic mimics through targeted testing. The International Society for Peritoneal Dialysis (ISPD) provides guidance on diagnosis through clinical and imaging features, though no single universal set of criteria exists, emphasizing multidisciplinary input.^[10]^[45]

Classification Systems

Encapsulating peritoneal sclerosis (EPS) is classified using frameworks that integrate clinical symptoms, peritoneal function, imaging, and histological findings to assess disease progression and inform management decisions. These systems emphasize early identification of preclinical changes to mitigate severe outcomes. A common phased classification, proposed by Nakamoto in 2005, categorizes EPS into four stages based on symptoms, inflammation, and peritoneal findings: Stage 1 (pre-EPS), involving ultrafiltration failure and increased peritoneal solute transport without overt symptoms, often detected via peritoneal equilibration testing; Stage 2 (inflammatory), with clinical symptoms like abdominal pain, nausea, and ascites from peritoneal inflammation; Stage 3 (encapsulating), marked by fibrotic membrane formation causing weight loss, early satiety, and partial bowel obstruction; and Stage 4 (chronic or obstructive), featuring persistent ileus, malnutrition, and severe encapsulation.^[46] A complementary clinical staging system, proposed by Kawanishi et al. in 2001, delineates four progressive stages to guide targeted therapies: Stage I (pre-symptomatic), characterized by subtle peritoneal changes without symptoms; Stage II (inflammatory), with emerging gastrointestinal issues like diarrhea and partial encapsulation; Stage III (encapsulating), involving membrane formation and moderate symptoms; and Stage IV (ileus), with complete encapsulation leading to obstruction and severe compromise. This framework highlights the transition from subclinical peritoneal alterations to life-threatening bowel compromise.^[47] Histological grading focuses on peritoneal biopsy features to differentiate EPS from simple sclerosis, as standardized by Korte et al. in 2012 using ordinal scales (absent, low grade, high grade) for key variables. Mild changes include partial mesothelial denudation and early interstitial fibrosis, while advanced grading reveals extensive sclerosis, podoplanin-positive vascular anomalies, and cocoon-like fibrous encapsulation of bowel loops, confirming diagnostic specificity for EPS.^[48] In the 2020s, updates to classification incorporate quantitative imaging scores, such as computed tomography-based systems evaluating peritoneal thickening (>2 mm), calcification, loculation, and bowel involvement for early risk stratification within peritoneal dialysis registries like those in Japan and Europe. These scores, as described in a 2023 study, enable predictive modeling of progression, with higher values correlating to severe EPS and poorer surgical outcomes.^[49]

Management

Prevention Strategies

Prevention of encapsulating peritoneal sclerosis (EPS) in patients undergoing peritoneal dialysis (PD) focuses on minimizing peritoneal membrane damage through vigilant monitoring and timely interventions. Regular peritoneal equilibration testing (PET) is recommended to detect early signs of membrane dysfunction, such as increased solute transport or ultrafiltration failure, which can signal impending fibrosis.^[50] Guidelines suggest performing PET annually or more frequently in long-term PD users. Some experts advocate considering discontinuation of PD after 5-8 years or upon evidence of deterioration to prevent progression to EPS.^[51] In high-risk cohorts, such as those with prolonged PD duration exceeding 8 years, planned transfer to hemodialysis has been associated with lower EPS incidence rates, dropping to around 1% in multidisciplinary programs.^[50] Infection control plays a pivotal role, as recurrent peritonitis is a major trigger for peritoneal inflammation leading to sclerosis. Antibiotic prophylaxis, including nasal mupirocin or oral antibiotics targeting Staphylococcus aureus, is advised to reduce peritonitis episodes in PD patients, particularly those at higher infection risk. The use of biocompatible dialysates, such as neutral-pH, low-glucose degradation product (GDP) solutions, further mitigates toxicity by preserving membrane integrity and reducing fibrosis; studies show these solutions correlate with significantly lower EPS rates compared to conventional acidic, high-GDP fluids.^[52]^[53] Patient selection and supportive measures are essential to avoid PD in vulnerable groups. PD should be cautioned against in young patients, who exhibit heightened susceptibility due to factors like prolonged exposure needs.^[51] Nutritional support, including monitoring and optimization of protein intake and micronutrients, helps maintain peritoneal membrane health and overall resilience against sclerotic changes.^[10] For long-term PD patients, screening protocols incorporate PET to identify early changes, with imaging such as CT considered if clinical suspicion arises, and ultrafiltration decline serving as a key trigger for modality switch.

Treatment Approaches

Treatment of encapsulating peritoneal sclerosis (EPS) primarily involves a multidisciplinary approach, starting with conservative medical management to address inflammation and fibrosis, followed by nutritional optimization and surgical intervention for refractory cases. Medical therapy often begins with corticosteroids such as prednisone or prednisolone at doses of 0.5-1 mg/kg/day to reduce peritoneal inflammation and fibrin deposition, typically administered for several months with gradual tapering.^[1] Tamoxifen, an anti-fibrotic agent dosed at 10-40 mg/day for 2-6 months, is frequently combined with corticosteroids and has been associated with significantly lower mortality rates (45.8% versus 74.4% in untreated patients) based on the Dutch Multicentre EPS Study.^[1] Immunosuppressants like azathioprine or mycophenolate mofetil may be added in select cases to further modulate the immune response, though evidence is limited to small observational studies showing variable efficacy.^[54]^[4] Nutritional support is essential to counteract malnutrition and bowel obstruction, with total parenteral nutrition (TPN) recommended for patients with complete or near-complete intestinal obstruction to maintain caloric intake and improve outcomes prior to potential surgery.^[1] In cases of partial bowel patency, enteral feeding via nasogastric or gastrostomy tubes can be attempted if tolerated, emphasizing close monitoring to prevent complications like aspiration or further peritoneal irritation.^[54] For severe or progressive EPS unresponsive to medical therapy, surgical intervention through enterolysis— involving peritonectomy and adhesiolysis—is the definitive treatment to relieve bowel obstruction and excise sclerotic tissue, ideally performed 4-8 weeks after discontinuing peritoneal dialysis in expert centers to optimize recovery.^[1]^[4] Outcomes in specialized units demonstrate improved survival, with two-year rates reaching 73% when combined with perioperative medical management, though risks include bowel perforation, infection, and recurrence.^[55] Emerging therapies target specific molecular pathways, with mTOR inhibitors such as sirolimus showing promise in post-transplant EPS cases through antifibrotic effects; a literature review of 20 patients reported clinical improvement in 25%, particularly in those without ongoing renal disease.^[56] As of 2025, management continues to emphasize multidisciplinary care, with ongoing research into targeted antifibrotic therapies.^[20]

Prognosis and Epidemiology

Clinical Outcomes

Encapsulating peritoneal sclerosis (EPS) has historically been associated with high mortality rates ranging from 25% to 56%, particularly in early reports from the 1980s and 1990s, but outcomes have improved significantly with advances in early diagnosis and management, reaching around 30% 1-year mortality as of 2025.^[11] In a 2025 retrospective study of 35 patients, the one-year survival rate was 68.5%, with two-year and five-year rates at 55.6% and 26.3%, respectively, reflecting a notable reduction in early mortality compared to historical data.^[57] Mortality remains highest in the first year post-onset, often exceeding 30%, primarily due to complications like bowel obstruction and sepsis.^[10] Recovery rates for EPS vary by disease severity and treatment approach, with 50-70% of patients achieving remission through combined medical and surgical therapies.^[4] Bowel function recovery is reported in approximately 79% of milder stage II cases, dropping to 57% in stage III and 50% in stage IV, where full peritoneal encapsulation leads to poorer outcomes and higher recurrence risk.^[4] Surgical intervention, such as enterolysis, has been linked to improved long-term survival in meta-analyses, particularly in experienced centers.^[58] Key prognostic factors include early intervention within three months of symptom onset, which enhances survival by allowing timely cessation of peritoneal dialysis and initiation of alternative therapies.^[49] The absence of malnutrition at diagnosis is critical, as acute declines in nutritional status (e.g., albumin drop >0.3 g/dL) predict approximately twice the mortality risk (HR 2.01) due to compounded gastrointestinal complications.^[57] Post-treatment quality of life in EPS survivors is often compromised by persistent issues, including recurrent bowel obstruction in 10-20% of cases and intolerance to resuming peritoneal dialysis due to membrane fibrosis.^[59] These challenges contribute to ongoing nutritional deficits and reduced functional status, necessitating long-term multidisciplinary follow-up.^[1]

Incidence and Prevalence

Encapsulating peritoneal sclerosis (EPS) primarily affects patients undergoing long-term peritoneal dialysis (PD), with an overall incidence ranging from 0.5% to 3% among this population.^[4] The risk escalates significantly with prolonged PD duration, reaching 10% to 20% in patients on PD for more than 10 years, and up to 17.2% after 15 years or longer.^[1] In the general population, EPS is exceedingly rare, with an estimated incidence of less than 0.1%, as it is almost exclusively linked to PD exposure or other specific triggers.^[54] Prevalence varies by region, with higher rates reported in registries from Japan and the United Kingdom due to historically longer average PD durations and more comprehensive tracking; for instance, Japan's overall prevalence stands at approximately 2.3% to 2.5%, compared to lower figures in North America (around 1.2%).^[60]^[55] Recent data from 2025 indicates a continued decline in prevalence among PD patients, attributed to the widespread adoption of biocompatible PD solutions that mitigate peritoneal damage. A Japanese study identified around 700 EPS cases from 2012–2022, accounting for approximately 5% of PD-experienced patients.^[61] Non-PD-related cases, including idiopathic and post-surgical forms, account for less than 5% of total EPS occurrences and are more prevalent in tropical or subtropical regions.^[9] Demographically, EPS shows a predilection for males and individuals aged 20 to 50 years, particularly in idiopathic cases where the mean age is around 34.7 years with a 2:1 male-to-female ratio.^[9] Trends since the 2010s reflect a decreasing incidence globally, driven by improved PD practices such as earlier discontinuation in high-risk patients and the use of multi-disciplinary approaches, though underreporting persists in low-resource settings where diagnostic access is limited.^[9]^[62]

References

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Encapsulating peritoneal sclerosis (EPS), a condition with a high mortality rate, is a serious complication of peritoneal dialysis (PD).
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The utilization of the peritoneal cavity for dialysis creates the opportunity for alterations in the function and structure of the peritoneal membrane.
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Encapsulating peritoneal sclerosis (EPS) is a debilitating condition characterized by a fibrocollagenous membrane encasing the small intestine.Introduction · Diagnosis · Immunosuppression
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Jan 4, 2015 · A number of rodent models of EPS have been developed using chronic chemical irritation to induce peritoneal sclerosis and bowel encapsulation ( ...
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Encapsulating Peritoneal Sclerosis: Pathophysiology and Current ...
Nov 16, 2019 · Early reports suggested that a beta blocker, such as practolol, induces peritoneal sclerosis via inhibition of peritoneal surfactant release ...3.1. Pathophysiology · 4. Diagnosis Of Eps · 5. Treatment Of Eps
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Long-term peritoneal dialysis and encapsulating peritoneal sclerosis ...
Encapsulating peritoneal sclerosis (EPS) is the most serious complication of long-term peritoneal dialysis (PD), with a mortality rate that exceeds 30%.
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Mucormycosis—A Possible Trigger Pathogen for Encapsulating ...
Encapsulating peritoneal sclerosis is a rare cause of intestinal obstruction that is characterized by a thick grayish-white fibrotic membrane encasing the small ...
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Surgical management of Encapsulating Peritoneal Sclerosis (EPS ...
Aug 26, 2021 · Encapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD).
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Unraveling the enigma of sclerosing encapsulating peritonitis
Jun 18, 2025 · Successful treatment of encapsulating peritoneal sclerosis with immunosuppressive therapy. Am J Kidney Dis 2008;51:e7–10. ArticlePubMed; 87 ...
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Encapsulating peritoneal sclerosis | Nephrology Dialysis ...
Encapsulating peritoneal sclerosis. Nephrology ... ENCAPSULATING PERITONEAL SCLEROSIS. Deirisa ... Previous exposition to gadolinium-based contrast agents ...So019 · So020 · So021
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https://pubmed.ncbi.nlm.nih.gov/22785109/
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Transforming growth factor β-induced peritoneal fibrosis is ... - PubMed
Background: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal ... TGFβ type 1 receptor and SMAD signaling pathways ...
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A Crosstalk between the Smad and JNK Signaling in the TGF-β ...
These data indicate a crosstalk between the JNK1 and Samd3 pathways during the TGF-β1-induced EMT and fibrotic process in RPMCs.
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[PDF] Peritoneal Dialysis -Associated Fibrosis: Emerging Mechanisms and ...
Aug 22, 2025 · TGF-β1 induces EMT transition primarily through the. SMAD2/3 pathway, as well as non-canonical pathways including. RAS/RAF/MEK/ERK, PI3K/AKT/ ...
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Preventing peritoneal membrane fibrosis in peritoneal dialysis patients
Jun 7, 2016 · Smad7 inhibits Smad2/3 phosphorylation by blocking their access to TGF-b receptors or translocation to the nucleus. The non-Smad signaling, ...<|separator|>
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Extracellular Vesicles of Patients on Peritoneal Dialysis Inhibit the ...
Mar 29, 2024 · PDE-EVs penetrated into the peritoneal mesothelial cells and fibroblasts and reduced their PDE- or PDGF-B-induced proliferation. Furthermore ...
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Patients with Encapsulating Peritoneal Sclerosis Have Increased ...
Peritoneal expression of CCN2, TGFβ1, and VEGF are significantly increased in EPS patients. In early stages of peritoneal fibrosis, only CCN2 expression is ...Missing: PDGF | Show results with:PDGF
[33]
Morphologic changes of peritoneum and expression of VEGF in ...
We hypothesized that vascular proliferation may occur in long-term peritoneal dialysis and VEGF may be a key factor in this process. In this study, we examined ...Missing: PDGF | Show results with:PDGF
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[PDF] A Review on Major Pathways Leading to Peritoneal Fibrosis in ...
Nov 22, 2022 · Together, these cytokines promote fibroblast proliferation and collagen synthesis and eventually lead to peritoneal fibrosis. For that reason, ...
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Accumulation of advanced glycation end products and beta 2 ...
Accumulation of advanced glycation end products and beta 2-microglobulin in fibrotic thickening of the peritoneum in long-term peritoneal dialysis patients.
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Pathophysiological Mechanisms of Peritoneal Fibrosis and ... - MDPI
High levels of glucose in peritoneal dialysate were reported to cause progressive deposition of advanced glycation end products (AGEs) in the peritoneum. Strong ...3.1. Angiogenesis... · 4.6. Anti-Fibrogenic Factors · 6.1. Peritoneal Pathological...
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A review of research progress on mechanisms of peritoneal fibrosis ...
Sep 24, 2023 · The accumulation of glucose degradation products (GDPs) in the peritoneum triggers the formation of excessive advanced glycation end products ( ...
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Long-term exposure to new peritoneal dialysis solutions: Effects on ...
Standard PDF induced accmulation of advanced glycation end products (AGEs) and up-regulation of the receptor for AGE (RAGE). AGEs accmulation was absent and ...
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Role of the renin-angiotensin system in the pathogenesis ... - PubMed
Acidic dialysis solution induces activation of the peritoneal renin-angiotensin system and progression of peritoneal fibrosis. For the peritoneum undergoing ...
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Role of the Renin–angiotensin System in the Pathogenesis of ...
Oct 29, 2020 · In rats treated with pH 3.5 dialysis solution, necropsy findings revealed features identical to those of encapsulating peritoneal sclerosis (EPS) ...
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The effects of renin-angiotensin system inhibition on ... - PubMed
Background: Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome associated with symptoms of ileus and irreversible sclerosis of both visceral ...
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High glucose dialysate-induced peritoneal fibrosis
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ACE I/D polymorphism is associated with mortality in a cohort study ...
The DD genotype identifies dialysis patients at an increased risk for mortality.Missing: MMPs EPS
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Matrix metalloproteinase (MMP-9 and MMP-2) gene polymorphisms ...
Apr 6, 2010 · MMP-2 (gelatinase A) predominantly degrades fibronectin and laminin, whereas MMP-9 (gelatinase B) degrades collagen Types IV and V [7]. In the ...
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Encapsulating peritoneal sclerosis—a rare but devastating ...
Encapsulating peritoneal sclerosis (EPS) is a devastating but, fortunately, rare complication of long-term peritoneal dialysis.
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Genetic Polymorphisms and Peritoneal Membrane Function. - Abstract
Nov 13, 2014 · Encapsulating peritoneal sclerosis is a complication of PD therapy that manifests as progressive, massive fibrosis and cocooning of the intra- ...
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Imaging in encapsulating peritoneal sclerosis - PMC - NIH
Jun 17, 2011 · In this review, we provide an overview of all imaging modalities that have been used overtime to diagnose EPS as a late complication of PD.
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ISPD recommendations for the evaluation of peritoneal membrane ...
Feb 10, 2021 · This tool is used to measure the peritoneal function soon after the start of dialysis. The goal is to understand how well the peritoneal membrane works.
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[PDF] Encapsulating Peritoneal Sclerosis (EPS) - ISPD
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Histological Criteria for Encapsulating Peritoneal Sclerosis - NIH
Nov 7, 2012 · Variables were classified as either binary (present or absent) or ordinal. The ordinal variables were discriminated as absent, low grade, ...
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Prediction of surgical outcomes in severe encapsulating peritoneal ...
Encapsulating peritoneal sclerosis (EPS) is a rare and potential lethal complication of peritoneal dialysis characterized by bowel obstruction. Surgical ...
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https://doi.org/10.1186/s12882-017-0741-0
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https://rarediseases.org/rare-diseases/encapsulating-peritoneal-sclerosis/
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https://pubmed.ncbi.nlm.nih.gov/27425661/
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Encapsulating Peritoneal Sclerosis - Symptoms, Causes, Treatment
Jan 7, 2025 · In EPS, the lining around the bowels also known as the ... Sclerosing encapsulating peritonitis: Review. Sultan Qaboos Univ Med ...<|control11|><|separator|>
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[PDF] Encapsulating peritoneal sclerosis treatment service (adults)
Following this treatment regime, the two-year survival rate was 73% whereas it was only 48% in those not treated. Another Japanese review article (Kawaguchi et ...
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mTOR inhibitors for management of encapsulating peritoneal sclerosis
Jul 17, 2016 · Background: Encapsulating peritoneal sclerosis (EPS) is an infrequent, serious complication of peritoneal dialysis (PD). EPS may develop after ...
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Clinical improvement of encapsulating peritoneal sclerosis after ...
Jul 13, 2021 · Encapsulating peritoneal sclerosis is a rare but potentially lethal complication of long-term peritoneal dialysis that is associated with significant morbidity ...Missing: epidermidis | Show results with:epidermidis
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Encapsulating peritoneal sclerosis outcomes: a retrospective study ...
Sep 1, 2025 · Peritoneal dialysis (PD) is a cost-effective treatment option for end-stage kidney disease, offering advantages in terms of flexibility and ...
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Effect of surgery for encapsulating peritoneal sclerosis on mortality ...
May 25, 2025 · Surgical treatment was associated with reduced mortality in patients with encapsulating peritoneal sclerosis compared with nonsurgical treatment ...
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Encapsulating peritoneal sclerosis: incidence, predictors, and ...
Encapsulating peritoneal sclerosis is a complication of peritoneal dialysis characterized by persistent, intermittent, or recurrent adhesive bowel ...Missing: terminology | Show results with:terminology
[64]
Outcomes of the surgical management of encapsulating peritoneal ...
Dec 31, 2019 · Encapsulating peritoneal sclerosis (EPS) is a rare but near-fatal complication of peritoneal dialysis (PD). Despite the high mortality rate ...Missing: intolerance | Show results with:intolerance
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[PDF] Encapsulating peritoneal sclerosis in peritoneal dialysis. A review ...
Encapsulating peritoneal sclerosis in peritoneal dialysis. A review and European initiative for approaching a serious and rare disease. RESUMEN.<|control11|><|separator|>
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Encapsulating Peritoneal Sclerosis in the Era of a Multi-Disciplinary ...
Aug 6, 2025 · This strategy includes planned PD discontinuation for high-risk patients and the introduction of biocompatible solutions. This study examined ...<|control11|><|separator|>