767 Pathophysiology While the pathophysiology of EPS is unclear, EPS is very likely to be of multifactorial etiology The peritoneum normally consists of a single layer of mesothelial cells, submesothe[.]
39 Long-Term Outcome of Chronic Dialysis in Children Pathophysiology While the pathophysiology of EPS is unclear, EPS is very likely to be of multifactorial etiology The peritoneum normally consists of a single layer of mesothelial cells, submesothelial connective tissue, and arterioles [98] Mesothelial cells act as a barrier against all peritoneal injuries and play important roles in the transport of water and solutes, inflammation, and tissue repair Conventional peritoneal dialysis solutions are characterized by acid pH, high lactate concentration, high osmotic pressure, high glucose concentration, and glucose degradation products (GDPs) which are formed during high-temperature sterilization GDPs stimulate mesothelial cells to produce transforming growth factor-beta (TGF-β) and VEGFs [99] The profibrotic factor TGF-β induces epithelial-tomesenchymal transition of mesothelial cells, which further progresses to EPS through mediation by factors such as VEGF and plasminogen activator inhibitor [100–102] (Fig. 39.11) A “two-hit” theory has been proposed to explain the pathogenesis of EPS (Fig. 39.12) Prolonged exposure to bioincompatible dialysis solutions causes peritoneal mesothelial cells to detach and disappear, leading to peritoneal fibrosis and peritoneal hypertrophy In addition, hyalinizing vasculopathy occurs, and the thickened peritoneal capillary wall and the lumen narrowing change peritoneal permeability (first hit) Under those conditions, inflammatory stimuli such as bacterial peritonitis (second hit) result in the proliferation of peritoneal capillaries and an increase in peritoneal permeability This increases the penetration of large molecular substances such as fibrin and results in fibrin deposition on the peritoneal surfaces [75] Further degeneration and sclerosis of the fibrinous membrane subsequently results in compression of the intestine, leading to clinical manifestations The fibrinous membrane extends from the parietal peritoneum to the visceral peritoneum, sometimes with accumulation of ascitic fluid inside, which is readily detected by abdominal CT. Even mild inflammation may trigger capsular formation in patients with severe peritoneal dysfunction and morphologi- 767 cal changes Conversely, severe inflammation may induce EPS in patients with even mild peritoneal dysfunction and morphological changes Thus, even short-term PD patients may develop EPS if inflammation is severe Additionally, diffuse calcinosis between the capsule and the degenerated peritoneum may occur in patients with severe fibrosis or secondary hyperparathyroidism Incidence of EPS Based on various single-center and multicenter studies and national registry observational cohort studies involving adults, the prevalence of EPS is estimated to be between 0.4% and 8.9% (Table 39.12) On the other hand, there are only two reports of children, consisting of the Japanese multicenter study and the Italian registry of pediatric chronic dialysis These cohorts reported that the incidence of EPS after 5 years on PD in children was 6.6% and 21.1%, respectively [95, 103] EPS Development Can Be Predicted Previous studies involving many patients have suggested that the development of EPS may be associated with abnormalities of D/P Cr [104–106], mesothelial cell area [106], MMP-2 [90, 107], IL-6 [108], and CA125 in the PD effluent [91] Because the PET is an established method for assessing peritoneal permeability, it is recommended that the PET be performed on a regular basis, at least once per year, in patients on PD. Assessment of peritoneal function through the PET is noninvasive and highly objective, easy to perform, and economical Whereas the D/P Cr is not sufficiently conclusive to be able to predict the development of EPS based on a single assessment, it can be monitored for any change over time [104, 105] A continuously increasing D/P Cr, with results demonstrating at least 12 consecutive months of high D/P Cr, indicates progressive severe peritoneal deterioration, and discontinuation of PD should be considered in this situation Although mesothelial cell cytology has been demonstrated to correlate with the risk of EPS [106], it is not a very sensitive or specific predictor of EPS. The same is true for the afore- M Honda et al 768 Fig 39.11 Pathogenesis of encapsulating peritoneal sclerosis (EPS) Fig 39.12 Two-hit theory of pathogenesis of encapsulating peritoneal sclerosis (EPS) mentioned effluent markers To summarize, no measure is an independent, absolute diagnostic marker that can be used alone to detect peritoneal dysfunction or morphological change that may lead to EPS. It is recommended to make a comprehensive assessment based on the findings from multiple measures Risk Factors As stated above, numerous factors are likely involved in the development of EPS. Possible causal factors include PD duration, peritonitis, acetate dialysate, high-glucose dialysate, bioincompatible dialysate, chlorhexidine, and plasticizers [30, 109] Additionally, some 39 Long-Term Outcome of Chronic Dialysis in Children 769 Table 39.12 Relationship between long-term PD and EPS incidence EPS incidence (%) 6.6 12 21.1 10.8 19.4 0.5 3.3 0.7 2.1 5.9 5.8 17.2 8.8 0.8 3.9 20 100 15 38 0.6 2.3 1.2 18 75 67 9.4 22.2 10.8 23.3 25 PD duration 5 years or more 8 years or more 5 years or more 5 years or more 6 years or more 8 years or more 5–10 years 10 years or more 5 years 8 years 10 years 15 years 15 years or more 5–6 years 6 years or more 5 years or more 8 years or more 6 years or more 8 years or more 6 years or more 9 years or more 5 years 8 years 8 years or more 6–8 years 8–10 years 10–12 years 12–14 years 14 years or more 5 years or more 7 years or more 5 years or more 6 years or more 7 years or more Country Japan Adult or children Children Reference Hoshii S et al [95] Italy Australia Children Adult Vidal et al [103] Rigby RJ et al [160] Japan Adult Kawanishi et al [161] Japan Adult Kawanishi et al [123] Scotland Adult Brown et al [93] Australia and New Zealand Adult Johnson et al [96] Ireland Adult Phelan et al [162] USA Adult Bansal et al [163] Japan Adult Nakayama et al [116] Italy Adult Vizzardi et al [164] Scotland Adult Petrie et al [165] Iran Adult Alatab et al [166] EPS encapsulating peritoneal sclerosis, PD peritoneal dialysis patients might have a genetic predisposition to EPS [92, 109] than 5 years compared with 0.4% for those who had received PD for less than 5 years [103] The European Pediatric Dialysis Working Group PD Duration (EPDWG) reported that the median duration of The most important risk factor for EPS is long- PD was 5.9 (range, 1.6–10.2) years in patients term exposure to peritoneal dialysate The with EPS and 1.7 (range, 0.7–7.7) years in Japanese registry of pediatric peritoneal dialysis patients without EPS [94] patients reported that all patients with EPS had Many studies in adults have also shown that been on PD for 5 years or more [95] Additionally, the incidence of EPS increases as the PD duration the incidence of EPS was 6.6% after 5 years or becomes longer (Table 39.12) more of PD and 12% after 8 years or more of PD. The Italian Registry of Pediatric Chronic Composition of Dialysate Dialysis reported that the incidence of EPS was As a result of the reported association between 21.1% in patients who had received PD for more acetate-buffered dialysate and the development 770 of EPS [110], lactate-buffered dialysates are currently used in many PD patients Additionally, exposure to bioincompatible dialysate containing high concentrations of glucose and GDPs may be a risk factor [92] Icodextrin has also been shown to be associated with an increase in local inflammatory markers such as IL-6 [111, 112], and an association between the long-term use of icodextrin and the development of EPS has been reported [113] However, no differences in the prescription of icodextrin between patients with and without EPS have been reported [114] In fact, icodextrin has also been reported to be involved in the protection of mesothelial cells and peritoneal function [115] Thus, no conclusive evidence that icodextrin contributes to the development of EPS is available In contrast, neutral pH peritoneal dialysis solutions containing fewer GDPs are being used by an increasing percentage of PD patients globally (but not in the USA), and this has resulted in a reduction in EPS, based on an observational study [116] In patients using neutral pH dialysate, the incidence of EPS decreased to 1.0% with an incidence rate of 2.3/1000 patient-years, and clinical symptoms of EPS were often mild Studies with parietal peritoneal biopsy tissues have also provided evidence of a lower incidence of peritoneal vascular degeneration in the neutral pH dialysate group [117, 118] Peritonitis Severe peritonitis, especially when caused by Staphylococcus aureus, Pseudomonas, or fungi, might be a risk factor for EPS [93] It is unclear whether the frequency of peritonitis is a risk factor for EPS [94, 103] It has been reported that patients with severe peritonitis episodes developed progressive EPS after switching from PD to HD [119], whereas mild recurrent peritonitis was not a risk factor for EPS [96] While peritonitis may be strongly associated with the development of EPS [120], the degree of association differs between patients on short-term PD and those on long-term PD. Patients on PD for as long as 5 years or more are more likely to develop EPS when peritonitis occurs [30, 121, 122] M Honda et al Discontinuation of PD EPS has also been reported to occur after renal transplantation or after switching from PD to HD [123–126] Post-transplantation EPS has occurred mostly within 1 year of transplant, presumably because of the profibrotic effects of calcineurin inhibitors (CNIs) [124, 126] CNIs, especially tacrolimus, increase TGF-β mRNA expression and extracellular matrix production [126, 127] A steroid reduction protocol might also increase the risk of EPS by reducing the anti-inflammatory effects of steroids [128] However, mammalian target of rapamycin inhibitors may reduce angiogenesis and fibrosis [129, 130] In Japan, EPS has often occurred after switching from PD to HD, with a reported incidence of 69% in adults [96] and 29% in children [30, 95] Discontinuation of PD might result in an increase in inflammatory mediators and the intraperitoneal fibrin concentration, and there have been conflicting reports about the benefits of peritoneal lavage after discontinuing PD. Some studies have reported that the lavage prevented EPS [106, 131], whereas others pointed out that the lavage might increase the risk of EPS [92] Drugs Besides the abovementioned CNIs, treatment with β-blockers has been reported to be a risk factor for EPS [132] An association between the use of chlorhexidine to sterilize tubing connections for PD and development of EPS has also been reported [133] Diagnosis of EPS The diagnosis of EPS is based on a combination of structural (e.g., CT scan appearance) and functional features (intermittent, subacute bowel obstruction) [134] Clinical Diagnosis EPS develops gradually and progresses slowly [135] The pre-EPS clinical picture is characterized by UF failure and mild ascites In early EPS, findings that are suggestive of a systemic inflammatory response are sometimes noted Late EPS is characterized by symptoms of intestinal obstruc- 39 Long-Term Outcome of Chronic Dialysis in Children tion that are caused by the encapsulating peritoneum Digestive symptoms including abdominal pain, nausea, vomiting, constipation, and diarrhea, which are symptoms of small intestinal obstruction, are noted Finally, symptoms of complete intestinal obstruction may occur, including abdominal mass, low-grade fever, hemorrhagic effluent, anorexia, weight loss, and malnutrition Increased CRP [95, 103], as well as failure of UF (or decrease in UF), and increased peritoneal permeability are noted It has been reported that EPS occurred in 50% of patients who continued PD after a decrease in UF [136], and the EPDWG reported that failure of UF was observed in 90% or more of children with EPS [94] However, these changes in membrane function are also observed in many patients on chronic PD without EPS Radiological Diagnosis Radiographic examinations which are often conducted to diagnose EPS include ultrasonography and CT. Ultrasonography reveals the formation of a mass in the intestinal tract, with a thickened peritoneum, and CT reveals peritoneal thickening and encapsulation, which are findings of intestinal obstruction, in addition to peritoneal calcification (Fig. 39.13) [137–139] However, because these imaging findings are infrequently seen in the early stages of this disorder, neither ultrasonography nor CT is suitable for screening Pathological Diagnosis Peritoneal biopsy is recommended for children who have been on PD for 8 years or more with failure of UF and/or peritoneal calcification on CT [140] If biopsy reveals a loss of mesothelial cells, thickened submesothelial connective tissue, denatured collagen fibers, and/or a markedly thickened microvascular wall with vascular lumen narrowing (Fig. 39.14), a diagnosis of peritoneal sclerosis is made [75], and PD should be discontinued; this approach protected all of six reported pediatric PD patients diagnosed with peritoneal sclerosis from EPS [140] Peritoneal biopsy is helpful and practical in diagnosing EPS as mentioned above, but is not recommended to be performed on a routine basis because it is highly invasive 771 Treatment The International Society for Peritoneal Dialysis (ISPD) position paper on EPS recommends that treatment of EPS includes discontinuation of PD, nutritional support, and surgical therapy [134] However, there are no consensus guidelines on the management of EPS Corticosteroids are used in Japan as the first treatment option after the onset of EPS [141, 142] Corticosteroids may act by inhibiting inflammation to prevent ascites and fibrin deposition Treatment should be initiated immediately after EPS onset; dose reduction following a good response is also important Additionally, the necessity for prolonged high-dose steroid therapy for patients with a continuously increasing CRP has been reported [143] However, reports about the efficacy of corticosteroids are insufficient, so there is currently no consensus on the use of this therapy Tamoxifen, a selective estrogen receptor modulator [144], is widely used in Europe for the treatment of EPS. Tamoxifen may prevent peritoneal dysfunction and morphological changes by inhibiting profibrotic factor gene expression, inhibiting mesothelial stromal cell transformation, and promoting denatured collagen removal [145, 146] Treatment with tamoxifen has resulted in resolution of EPS-related symptoms [147], and an EPS registry study in the Netherlands reported a significant improvement in the survival rate in the tamoxifen group [148] EPS treatment guidelines published in the Netherlands in 2011 contain recommendations for the use of steroids and tamoxifen and the timing of surgery [143] However, because drug therapies have been evaluated only in case series or in small case-control studies, no definite conclusions can currently be drawn about the clinical efficacy of these therapies In the United Kingdom (UK), the National Institute for Health and Care Excellence Guideline [149] stated that drug therapy should be used at the discretion of individual physicians because there is no conclusive evidence regarding its utility Surgery While surgical treatment was initially contraindicated for EPS [150], favorable results of intesti- M Honda et al 772 a b Fig 39.13 (a) CT scan findings of EPS. Thickened bowel wall (arrow) and loculation of ascitic fluid (star) (b) CT scan findings of the peritoneum with calcifications (*) Fig 39.14 Peritoneal biopsy of EPS nal adhesiolysis have been reported in Japan [151–153] Surgical treatment is required for patients with an acute abdomen resulting from complete intestinal obstruction, intestinal perforation, or intra-abdominal hemorrhage, as well as those with no response to drug therapy Surgical treatment administered by an experienced team should be considered for complete EPS as soon as possible after a reduction in inflammation has been accomplished Based on reports in Japan [152], the UK [154], Germany [155], and the Netherlands [156], the mortality rate for surgery ranges from 32% to 35%, which is better than the results associated with conservative therapy (39– 56%) [96, 97] Nutritional Support Malnutrition is of great concern in patients with severe EPS, and nutritional support is extremely important for these patients Adequate enteral or parenteral nutritional support restores the nutritional status in many patients [157, 158] Nutritional support should be initiated early to prevent malnutrition and ideally to decrease mortality risk Outcome Based on a report in adults, the mortality rate of EPS is as high as 25–56%, and many PD patients have died within 2 years of the diagnosis of EPS The pediatric registries have reported mortality rates of 13–27% [94, 95, 159], which are lower compared with those in adults, but the reason for this is unknown Normal intestinal function has been reported after recovery from EPS [94], showing that early diagnosis and appropriate management are extremely important for the patient’s prognosis Prevention Currently, there are no recommended strategies to prevent EPS. Kawaguchi et al recommended ... Ultrasonography reveals the formation of a mass in the intestinal tract, with a thickened peritoneum, and CT reveals peritoneal thickening and encapsulation, which are findings of intestinal obstruction,... [140] If biopsy reveals a loss of mesothelial cells, thickened submesothelial connective tissue, denatured collagen fibers, and/or a markedly thickened microvascular wall with vascular lumen narrowing... died within 2 years of the diagnosis of EPS The pediatric registries have reported mortality rates of 13–27% [94, 95, 159], which are lower compared with those in adults, but the reason for this