Encapsulating Peritoneal Sclerosis

Etiology

The etiology of encapsulating peritoneal sclerosis is not well studied. However, EPS is most commonly seen in patients on long-term peritoneal dialysis diagnosed with end-stage renal disease. During peritoneal dialysis, the dialysate typically contains glucose or glucose degradation products, which can induce inflammation in the peritoneum. This inflammation can increase endothelial permeability and fibrinogenesis, causing further damage to the peritoneum and leading to fibrin deposition.

Multiple fibrin depositions can form a dense fibrocollagenous capsule around parts of the small bowel. Peritoneal inflammation will continue to accumulate, leading to adhesion formation and worsening fibrosis. This can cause not only acute bowel obstruction but also malnutrition (see Image. Encapsulating Peritoneal Sclerosis). Risk factors in patients on peritoneal dialysis (PD) include duration of PD, cessation of PD, renal transplantation, peritonitis, young age, low pH, high glucose within dialysate, ultrafiltration failure, and exposure to chlorhexidine.[3]

Also, there are causes of EPS that are not directly related to peritoneal dialysis. Associations include autoimmune diseases, sarcoidosis, peritoneal and intra-abdominal malignancies, chronic peritoneal ascites, intraperitoneal chemotherapy, specific dialysate fluids such as acetate or bioincompatible dialysate, abdominal surgery, endometriosis, intraperitoneal infections (particularly Staphylococcus aureus, Pseudomonas, and Mycobacterium tuberculosis, as well as fungal species), calcineurin inhibitors, and beta-blocker administration. Proinflammatory states can predispose patients to EPS. Renal transplantation shows an increased risk of developing encapsulating peritoneal sclerosis, most commonly seen shortly after transplantation. There is a theory that this could be due to the profibrotic effects and immunosuppressive medication, such as calcineurin inhibitors, which may also be a result of the acute cessation of peritoneal dialysis.[3]

Epidemiology

The epidemiology of encapsulating peritoneal sclerosis has been studied in Scotland, Australia, New Zealand, and Japan. In contrast, there is very little data reporting the incidence of EPS in the United States. Most research available in the US has been conducted at single-center institutions. In a single center in New Haven, Connecticut, a retrospective observational cohort analysis of patients on peritoneal dialysis for 5 years or longer revealed an incidence of EPS of 18.4%. In this study, only 76 patients met the inclusion criteria, with 11 patients meeting the International Society for Peritoneal Dialysis criteria for the diagnosis of EPS.[4] 

At another US single-center institution, a retrospective study examined a 30-year-old peritoneal dialysis registry for the incidence of EPS. In this study, 676 patients met the inclusion criteria, and the incidence of EPS was 1.2%. The study also found that the incidence of EPS rose to 15% after 6 years and 38% after 9 years of peritoneal dialysis.[5]

Both US studies reveal not only how understudied EPS is, but the incidence of EPS increases for patients on peritoneal dialysis for at least 5 years or more. This finding is consistent with research in other countries, such as Scotland. Adult patients (n = 1238) who initiated peritoneal dialysis between 2000 and 2007 were identified by the Scottish Renal Registry. The incidence of EPS was 1.1% after 1 year, 3.4% after 3 years, 8.8% after 4 years, 9.4% after 5 years, and 22.2% after 7 years of staying on peritoneal dialysis.[6] 

In a study involving 13 years of data from 7618 patients in Australia and New Zealand, the incidence rate was 1.8 per 1000 patients. Respective cumulative incidences of EPS were 0.3% at 3 years, 0.8% at 5 years, and 3.9% at 8 years of dialysis. Results from a Japanese study revealed the incidence (and mortality rates) for EPS were 0% (0%) at 3 years, 0.7% (0%) at 5 years, 2.1% (8.3%) at 8 years, 5.9% (28.6%) at 10 years, 5.8% (61.5%) at 15 years, and 17.2% (100%) with 15 years or greater of peritoneal dialysis.[7] Studies from other countries reveal that the prevalence of EPS varies between 0.4% and 8.9%, but can reach as high as 22.2% after 7 years or more of peritoneal dialysis, as highlighted by the Scottish study.[8]

Pathophysiology

The pathophysiology of encapsulating peritoneal sclerosis is multifactorial and not fully understood. Long-term peritoneal dialysis is a significant risk factor, and patients who require treatment will experience adverse cellular changes to the peritoneal membrane due to exposure to bioincompatible peritoneal dialysis fluids. Approximately 50% to 80% of all patients on peritoneal dialysis will experience progressive sclerosis of the peritoneal membrane within 1 to 2 years of initiating treatment. The chemical composition of the solutions used in peritoneal dialysis causes oxidative stress, which damages the peritoneal membrane. The acidic pH, elevated osmolarity, and increased glucose concentration contribute to fibrosis, vasculopathy, and a decline in peritoneal ultrafiltration.[9]

Peritoneal dialysis solutions undergo heat sterilization processes, which eventually form glucose degradation products. Glucose degradation products and the increased glucose concentration are then exposed to the peritoneal membrane when the fluid is used in dialysis. Glucose degradation products then undergo another chemical reaction, forming irreversible reactive molecules known as advanced glycation end products. The advanced glycation end products slowly accumulate in the peritoneal membrane after multiple rounds of dialysis, which can cause peritoneal cell injury via several mechanisms. Advanced glycation end products can induce morphological changes in intracellular proteins and alter the existing structure of extracellular matrix components and receptors within peritoneal cells.

Lastly, advanced glycation end products can modify proteins, tightly binding to specific multi-ligand transmembrane receptors on endothelial cells and macrophages. This adverse binding can activate free radicals, pro-inflammatory cytokines, and growth factors, such as vascular endothelial growth factors, which can lead to abnormal transcription of DNA and subsequent apoptosis. This binding can further enhance the production of advanced glycation end products, potentially leading to additional damage.[10]

The increased glucose-oxidation metabolism is also how glycation end products and advanced glycation end products trigger the creation of reactive oxidative species. When the fluid, high in glucose concentration, enters the peritoneal cells, it increases glucose catabolism, leading to an overproduction of electron donors to compensate for the increased glucose uptake. Overproduction can eventually overwhelm the cell's capacity to neutralize reactive oxidative species, leading to a higher formation of these species. These reactive oxidative species lead to an increase in fibrinogenesis and endothelial permeability. Even peritoneal fluids that have a significant reduction in glucose degradation products and glucose, with a neutral pH, can exhibit the slow, progressive development of reactive oxidative species, which subsequently form fibrosis that later becomes sclerotic.[11]

Peritonitis can also be a major risk factor for EPS, particularly Staphylococcus aureus, Pseudomonas, Mycobacterium tuberculosis, and fungal infections. Inflammation that occurs in the setting of peritonitis can accelerate the peritoneal transformation process, leading to the formation of fibrosis. One study found that peritoneal inflammation was common after dialysis catheter removal for refractory bacterial peritonitis, and these patients had a 31% likelihood of developing EPS with a mortality rate of 36%.[12]

Histopathology

Podoplanin is a type-1 transmembrane sialomucin-like glycoprotein present on the endothelium of lymphatic vessels in both submesothelial fibrotic and mesothelial cells. Podoplanin can modulate inflammatory reactions by binding to chemokines and plays a potential role in the inflammatory process. Results from a study revealed that patients with EPS exhibited a diffuse infiltration of podoplanin-positive cells, which may serve as a suitable histopathological marker for EPS.[13]

History and Physical

The diagnosis of encapsulating peritoneal sclerosis can be made based on a constellation of symptoms and their timing. EPS typically develops in a step-wise fashion with an inflammatory, encapsulating, and ileus stage. EPS can begin with an inflammatory stage, during which patients may present with symptoms such as fever, anemia, hypoalbuminemia, nausea, diarrhea, and an elevation in C-reactive protein. This is associated with the genesis of bowel encapsulation. The physical exam can often be unremarkable during the encapsulating phase, as the fibrotic capsule can also be too premature to inhibit intestinal peristalsis. Over time, the fibrotic capsule becomes sclerotic and causes bowel obstruction-like symptoms, which leads to the ileus stage. Early symptoms in the ileus stage are nausea, vomiting, diarrhea, intermittent abdominal pain, anorexia, and loss of appetite.

The physical exam can also be unremarkable; however, some patients on peritoneal dialysis have reported blood-tinged ascites or dialysis fluid during the procedure, especially after periods when the peritoneal dialysis cavity has been dry. Ineffective ultrafiltration and transition from low to a high transporter status may also be a sign of EPS.[14][15] Late symptoms in the ileus stage can progress to severe abdominal pain, intractable vomiting, malnutrition, constipation, and weight loss. At this stage of symptom progression, the physical examination may reveal an abdominal mass with tenderness upon light and deep palpation, hypoactive bowel sounds, and potentially abdominal rigidity. The timing of symptoms is also important, as most patients (70% to 90%) will be diagnosed with EPS after terminating peritoneal dialysis, which can develop as late as 5 years later.[16]

Evaluation

Currently, there are no laboratory tests for encapsulating peritoneal sclerosis; therefore, radiographic imaging is recommended to confirm the diagnosis. Computed tomography (CT) is the definitive imaging modality of choice for EPS, with one study affirming 100% sensitivity and 94% specificity for diagnosing EPS. CT imaging would reveal peritoneal enhancement, thickening, and calcifications; bowel tethering, thickening, and dilatation; and fluid septation/loculation (see Image. Abdomen/Pelvis Encapsulating Peritoneal Sclerosis, Computed Tomography).[17] However, the results of other studies suggest that early EPS may not exhibit changes beyond ascites, and a high clinical suspicion is necessary.[14][15] 

EPS can be diagnosed with clinical signs of intestinal obstruction, with radiological imaging of bowel encapsulation. However, it is essential to note that other imaging modalities, such as abdominal radiography, can be used to diagnose EPS. This is because abdominal radiography lacks the same level of sensitivity and specificity. Still, air-fluid levels, signs of bowel dilation, and peritoneal calcifications can be used to suspect EPS in the setting of intestinal obstruction.

Notably, x-ray films can have a normal presentation despite having EPS. The most sensitive and specific method to confirm EPS can be achieved through a laparoscopy or laparotomy procedure, which allows for visualization of the peritoneal thickening that encloses the bowel. But due to the invasive nature and the elevated risks of surgery, this is rarely done to diagnose EPS.[18]

Treatment / Management

Initial treatment of EPS begins with considering the cessation of peritoneal dialysis to halt further derangements to the peritoneal membrane. Not every patient can benefit from stopping peritoneal dialysis; therefore, this decision must carefully weigh the benefits and risks, as hemodialysis is typically the next step for most patients. Hemodialysis carries a different set of complications and risks when compared to peritoneal dialysis, in addition to lifestyle changes. Notably, because many cases of EPS are diagnosed years after stopping peritoneal dialysis, there is the potential for symptoms to worsen even after discontinuing.[3] 

Regardless, if the decision to cease peritoneal dialysis is made, the standard of care would be to switch from peritoneal dialysis to hemodialysis and remove the peritoneal dialysis catheter. To decrease the risk of abdominal adhesions, the peritoneum should be flushed twice a week with 100 to 200 mL of 1.36% dialysate with 3500 international units of heparin. Bowel rest should be maintained for 4 to 12 weeks, depending on the severity of the symptoms present.[19]

Medical management of EPS includes the use of corticosteroids or tamoxifen. Steroids act by decreasing inflammation and the development of fibrin deposition. In treating the early stages of EPS, steroids have been proven to be an effective medication. Still, the effect tends to decrease in the later stages when fibrosis is significant, and bowel obstruction occurs. For these earlier stages, prednisolone dosing is 0.5 to 1.0 mg/kg/day or a pulse dose of 500 to 1000 mg of methylprednisolone for 2 to 3 days.[20] 

Treatment should be continued for at least 1 year with a steroid taper. If using prednisolone, the taper should be 0.5 to 1.0 mg/kg daily for the first month, 0.25 to 0.5 mg at 2 to 3 months, and then 10 mg at 6 months. C-reactive protein should be monitored, and a dramatic rise should raise the suspicion of inflammation due to bacterial peritonitis or intestinal obstruction. Tamoxifen can be an alternative treatment and may be considered the first choice, considering the well-documented adverse effects of steroids. Despite this, tamoxifen is typically given in combination with steroids. Tamoxifen is administered in doses of 10 to 40 mg/day for at least 2 to 6 months.[21]

Surgical interventions become the treatment choice when patients are at risk of obstruction due to fibrotic adhesions.[22] A peritonectomy involves the lysis of adhesions and total ablation of sclerotic tissue in the abdomen. Surgery should only be considered in chronic individuals who fail medical and conservative management and in patients with acute symptoms of bowel obstruction. The risks of surgery include perforation of the intestines, sepsis, bleeding, fistula formation, and death. There is also a risk of recurrence of adhesions and symptoms. Despite this, suturing the intestine to itself to prevent recurrence has been proposed, and considering medical management with steroids or tamoxifen might decrease the risk.[23](A1)

Nutrition and hydration should be optimized in patients with EPS. Patients who elect to treat with surgery are at high risk of refeeding syndrome, so aggressive nutritional support should be a vital aspect of the management plan for these patients in the pre- and postoperative period. In research conducted in the United Kingdom, patients who underwent surgery reportedly experienced improved surgical outcomes when total parenteral nutrition was used in preoperative management. Importantly, total parenteral nutrition is not the mainstay treatment for all patients, as chronic EPS patients can benefit from close monitoring and increased oral intake.[24]

Differential Diagnosis

One important disease that can be mistaken for encapsulating peritoneal sclerosis is peritoneal encapsulation. This is also a rare disease in which a thin accessory peritoneal membrane can surround various parts of the small bowel. Peritoneal encapsulation forms an accessory peritoneal sac, which is typically asymptomatic and incidentally diagnosed; however, it can also cause symptoms of small bowel obstruction. This peritoneal sac differs from EPS, as peritoneal encapsulation is a congenital malformation, not one that develops from chronic inflammation.[25] Because many symptoms of EPS can be nonspecific gastrointestinal complaints, the differential diagnosis can be extensive, including small bowel obstruction, gastroparesis, irritable bowel syndrome, pancreatic adenocarcinoma, peptic ulcer disease, pancreatitis, Crohn disease, retroperitoneal fibrosis, tumors, malignancy, hernias, and peritonitis.[26]

Prognosis

Results from a Taiwanese study reviewed data from 3 Taiwanese medical centers and categorized patients into mild/moderate or severe encapsulating peritoneal sclerosis. Severe EPS included signs and symptoms of intractable obstruction, gut ischemia, sepsis, and those that needed surgical intervention. They found that the overall mortality rate of EPS was 35% and 74% in patients in the severe EPS group.[27] Results from a single-center Japanese retrospective observational study spanning nearly 15 years demonstrated Kaplan–Meier estimated survival rates at 1, 2, 3, 5, and 8 years after EPS diagnosis at 91%, 83%, 77%, 66%, and 53%, respectively.[28] Encapsulating peritoneal sclerosis carries high morbidity and a mortality rate that can approach as high as 50% within 12 months of diagnosis.[14][15] 

Complications

The risk of developing complications from EPS is strongly and positively correlated with the duration of peritoneal dialysis treatment. Complications can arise from medical treatment and surgical intervention. Untreated EPS is associated with high morbidity and mortality, primarily secondary to recurrent bowel obstructions resulting in intestinal failure, malnutrition, and sepsis.[29] Worsening complications include bowel ischemia, perforation, and death. Tamoxifen has been associated with a higher risk of endometrial adenocarcinoma, uterine sarcoma, pulmonary embolism, and stroke in female patients.[30] 

Prednisone has been reported to have adverse effects of tertiary adrenal insufficiency, hypertension, sodium retention, decreased serum potassium, fluid retention, psychiatric disturbances, cushingoid features, and hyperglycemia. From a surgical perspective, complications include excessive bleeding, inadvertent bowel injury, abscess formation, surgical site infection, perforation of intestinal contents, deep vein thrombosis, atelectasis, and sepsis.[31] Many of these complications occur in the postoperative period. Thus, prophylactic management should include deep vein thrombosis prophylaxis, preoperative antibiotics, insertion/removal of Foley catheters, incentive spirometry, and slowly escalating the diet as tolerated.[32]