New Strategy for Encapsulating Peritoneal Sclerosis from the Perspective of Hormone Receptor Expression in Peritoneal Tissue

Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term continuous peritoneal dialysis (PD) therapy, with a high morbidity and a mortality of approximately 50% (1). In EPS, an intestinal obstruction syndrome, peritoneal deterioration and intraperitoneal inflammation lead to intestinal adhesions, which are covered with a fibrin capsule and which cause bowel obstruction, resulting in severe malnutrition (2).

Recently, several investigations using animal models have shed light on the pathogenesis of EPS. Based on the findings, advances in clinical research have identified several strategies for the prevention and treatment of EPS. In humans, surgical procedures and initiation of general immunosuppressive agents (such as glucocorticoids or mycophenolate mofetil) or antifibrotic agents (such as colchicine or tamoxifen) have been applied in clinical settings (3). However, the causes of EPS are not yet fully understood, and no effective therapy for preventing and treating EPS has been established.

In this issue of Peritoneal Dialysis International, Braun et al. demonstrate the pattern of hormone receptors in human peritoneum from control, uremic, PD, and EPS cohorts. Interestingly, the authors found that expression of vitamin D receptor (VDR) is more common in EPS than in PD patients. In addition, Braun and colleagues investigated estrogen receptor (ER, which is the tamoxifen receptor), matrix metalloproteinase 9 (MMP9), and transforming growth factor β1 (TGFβ1) in the context of a potential role in tamoxifen therapy. They found that there was almost no expression of ER in peritoneal tissue in any group, that MMP9 expression was minimal and TGFβ1 expression was moderate in all groups, and that the expression pattern was nonspecific. Finally, the authors concluded that vitamin D, angiotensin converting-enzyme inhibitors, or angiotensin II receptor blockers might, via the vitamin D/angiotensin II pathway, be suitable interventions to preserve the integrity of the peritoneal membrane (4). Based on the results of their investigation of ER, MMP9, and TGFβ1, these authors concluded that, to improve the understanding of tamoxifen's mechanism of action, further study is required.

Tamoxifen is a selective ER modulator and, as such, a nonsteroidal estrogen antagonist in many tissues. Tamoxifen has been used for fibrosing syndromes such as retroperitoneal fibrosis, desmoid tumors, and fibrosing mediastinitis. To date, only individual case reports and small case series on the use of tamoxifen in EPS have been published (5); however, the way in which tamoxifen acts in EPS remains unclear. In the study by Braun and colleagues, the finding of almost no ER expression in the peritoneal tissue of EPS patients indicates that an ER-independent pathway is involved in the fibrosis- inhibiting effect of tamoxifen. To date, reports have shown that inhibition of TGFβ expression is an ER- independent mechanism of fibrosis inhibition (6) and that, in a rat model of peritoneal fibrosis, tamoxifen can inhibit fibrosis by inhibiting expression of connective tissue growth factor (7). The foregoing findings indicate that the detailed fibrosis-inhibiting mechanism of tamoxifen in peritoneal fibrosis remains unclear and that further study is needed.

An extremely important finding of the Braun et al. study is that, among the various hormone receptors, VDR was expressed more commonly in EPS patients than in PD patients. Recent studies have demonstrated that 1,25(OH)₂D₃–VDR has multiple physiologic and pathologic roles that extend beyond the regulation of mineral metabolism, including regulation of renal and cardiovascular functions. In addition, VDR activation induced suppression of several renin–angiotensin system components and inhibited fibrosis through decreased TGFβ expression, upregulation of hepatocyte growth factor, and inhibition of nuclear factor κB activation in the kidney (8). Based on the Braun et al. results, expectations are therefore high that, in peritoneal fibrosis, a VDR agonist would have a similar peritoneal fibrosis–inhibiting effect via a similar mechanism.

Because EPS has a poor prognosis, multimodal therapy is required. A new finding from the study by Braun and colleagues concerns diversity in the expression of various hormone receptors in PD and EPS patients. Although almost no ER expression was observed in the EPS patients, ER expression in peritoneal fibroblasts has previously been reported (9). Therefore, the possibility that proliferation of ER-positive fibroblasts, with a resultant progression of peritoneal fibrosis in the fibrotic state preceding EPS, leads to onset of EPS cannot be ruled out. In future, it will be important to investigate ER expression in the peritoneum of PD patients in various pathologic states.

Despite the high expectations for vitamin D preparations as a treatment strategy for increased VDR expression in EPS patients, there is little evidence for its efficacy, and investigations using experimental models and clinical studies are needed. To date, evidence of a direct link between expression of hormone receptors in peritoneal tissue and treatment effect is insufficient. Recently, however, several biological markers in PD effluents (such as interleukin 6 and cancer antigen 125) were reported to be useful in predicting the development of EPS (10). Through study of the combination of these markers in PD effluents and of the expression patterns of hormone receptors in peritoneal tissue, tailor-made treatments for EPS may become possible.