Complication Of Long-term Peritoneal Dialysis Research Articles

A protective role of nintedanib in peritoneal fibrosis through H19-EZH2-KLF2 axis via impeding mesothelial-to-mesenchymal transition.

Peritoneal fibrosis (PF), a common complication of long-term peritoneal dialysis, accounts for peritoneal ultrafiltration failure to develop into increased mortality. Nintedanib has previously been shown to protect against multi-organ fibrosis, including PF. Unfortunately, the precise molecular mechanism underlying nintedanib in the pathogenesis of PF remains elusive. The mouse model of PF was generated by chlorhexidine gluconate (CG) injection with or without nintedanib administration, either with the simulation for the cell model of PF by constructing high-glucose (HG)-treated human peritoneal mesothelial cells (HPMCs). HE and Masson staining were applied to assess the histopathological changes of peritoneum and collagen deposition. FISH, RT-qPCR, western blot and immunofluorescence were employed to examine distribution or expression of targeted genes. Cell viability was detected using CCK-8 assay. Cell morphology was observed under a microscope. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays were applied to validate the H19-EZH2-KLF2 regulatory axis. Aberrantly overexpressed H19 was observed in both the mouse and cell model of PF, of which knockdown significantly blocked HG-induced mesothelial-to-mesenchymal transition (MMT) of HPMCs. Moreover, loss of H19 further strengthened nintedanib-mediated suppressive effects against MMT process in a mouse model of PF. Mechanistically, H19 could epigenetically repressed KLF2 via recruiting EZH2. Furthermore, TGF-β/Smad pathway was inactivated by nintedanib through mediating H19/KLF2 axis. In summary, nintedanib disrupts MMT process through regulating H19/EZH2/KLF2 axis and TGF-β/Smad pathway, which laid the experimental foundation for nintedanib in the treatment of PF.

The probiotic Lactobacillus casei Zhang-mediated correction of gut dysbiosis ameliorates peritoneal fibrosis by suppressing macrophage-related inflammation via the butyrate/PPAR-γ/NF-κB pathway.

Peritoneal fibrosis is a complication of long-term peritoneal dialysis (PD) that restricts its clinical application for the treatment of end-stage renal disease. Lactobacillus casei Zhang (LCZ), a probiotic strain isolated from traditional fermented koumiss, exhibits health benefits such as anti-inflammatory and antioxidative effects, improvement of insulin resistance and mitigation of renal injury. However, whether LCZ can prevent peritoneal fibrosis remains unknown. Here, we assessed the effects of LCZ in a mouse model of PD-induced peritoneal fibrosis. Our results showed that the administration of LCZ significantly ameliorated peritoneal fibrosis in experimental mice. Macrophage infiltration, inflammatory M1 polarization and inflammatory cytokines in peritoneal dialysis effluents were effectively reduced by LCZ. Meanwhile, LCZ corrected gut dysbiosis and enriched beneficial bacteria that produce short-chain fatty acids, specifically Dubosiella, Lachnospiraceae, Parvibacter, and Butyricicoccus. Correspondingly, the local butyrate level in peritoneal dialysis effluents was significantly elevated by LCZ. Mechanistically, we found activation of PPARγ and inhibition of the NF-κB pathway in LCZ-treated mice, an observation that was replicated in a butyrate-treated macrophage cell line. In conclusion, our study suggests that LCZ is beneficial for preventing PD-induced peritoneal fibrosis through modulating the gut microbiota, enhancing butyrate production, activating PPARγ, and suppressing NF-κB-mediated inflammation.

Differentially Expressed microRNAs in Peritoneal Dialysis Effluent-Derived Exosomes from the Patients with Ultrafiltration Failure.

Background Ultrafiltration failure remains one of the most severe complications of long-term peritoneal dialysis (PD), which results in death. This study aimed to characterize the circulating exosomal microRNA (miRNA) profiles associated with ultrafiltration failure and explore its underlying mechanisms. Methods Exosomes were isolated from the peritoneal dialysis effluent (PDE) of patients with ultrafiltration failure or success using the ultracentrifugation method, and then transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot were used for exosome characterization. After that, the isolated exosomes were sent for small RNA sequencing, and eight differentially expressed miRNAs (DE-miRNAs) were chosen for RT-qPCR validation. Results TEM, NTA, and western blot revealed that exosomes were successfully isolated. After sequencing, 70 DE-miRNAs involved in ultrafiltration were identified, including 41 upregulated ones and 29 downregulated ones. Functional analyses revealed that these DE-miRNAs were significantly enriched in pathways of cancer, ubiquitin-mediated proteolysis, axon orientation, and the Rap1 and Ras signaling pathways. In addition, the consistency rate of RT-qPCR and sequencing results was 75%, which indicated the relatively high reliability of the sequencing data. Conclusions Our findings implied that these DE-miRNAs may be potential biomarkers of ultrafiltration failure, which would help us to discover novel therapeutic targets/pathways for ultrafiltration failure in patients with end-stage renal disease.

Use of paclitaxel carried in solid lipid nanoparticles to prevent peritoneal fibrosis in rats.

Progressive fibrous thickening of peritoneal membrane (PM) is a major complication of long-term peritoneal dialysis. TGF-β/SMAD pathway activation, inflammation and neoangiogenesis have an important role in PM changes induced by peritoneal dialysis. Here, we investigated the effects of paclitaxel (PTX) carried in lipid core nanoparticles (LDE) on the development of peritoneal fibrosis (PF) in rats. To induce PF, 21 male Wistar rats (300-350g) were injected with chlorhexidine gluconate for 15 consecutive days and randomly assigned to three groups: 1)PF, n = 5: no treatment; 2)LDE, n = 8: treated with LDE only, 3/3 days during 15 days; 3)LDE-PTX, n = 8: treated with PTX (4mg/kg) associated with LDE, 3/3 days during 15 days. A Control group without PF induction (n = 5) was designed, received saline solution, 3/3 days. Peritoneum function tests were performed, and anterior abdominal wall samples of the PM were collected for analyses of peritoneal thickness, immunohistochemitry, and gene expression. LDE-PTX treatment preserved the membrane function, maintaining the ultrafiltration rate and mass transfer of glucose at normal levels. LDE-PTX also prevented PM thickening induced by chlorhexidine gluconate injections. LDE-PTX treatment reduced the number of myofibroblasts infiltrating PM and inhibited the cell proliferation. Gene expression of fibronectin, FSP-1, VEGF, TGF-β, and SMAD3 were reduced by LDE-PTX. LDE-PTX was effective to prevent development of PF and preserve the PM filtration capacity in this rat model, with clear-cut actions on pro-fibrotic mechanisms. Thus, LDE-PTX can be candidate for future clinical trials as adjuvant to peritoneal dialysis to prevent PF development, since this preparation is devoid of toxicity as shown previously.

Risk factors for Encapsulating Peritoneal Sclerosis in patients undergoing peritoneal dialysis: A meta-analysis.

Encapsulating Peritoneal Sclerosis (EPS) is the most serious complication of long-term peritoneal dialysis (PD), which considerably reduces the patient's quality of life, leading to patients discontinuing PD. Considering these negative effects, it is necessary to systematically review and determine the risk factors of EPS. The PubMed, Embase, Web of Science, Cochrane Library, and China Biology Medicine (CBM) were searched from their inception to January 1st, 2022, and the bibliographies from the citations of relevant articles were manually searched. The ROBINS-I (Risk of Bias in Non-randomized studies of Interventions) tool was used to evaluate the risk of bias of included studies. Ten studies involving 12595 participants were included in this meta-analysis. The results revealed that a younger age at PD onset (MD = -7.70, 95% CI, -11.53~-3.86), a higher transporter (MD = 0.13, 95% CI, 0.09~0.18), a longer PD duration (SMD = 1.15, 95% CI, 0.68~1.61), a longer peritonitis duration (MD = 12.66, 95% CI, 3.85~21.47), and history of glomerulonephritis (OR = 1.42, 95% CI, 1.02~1.97) were significant risk factors for EPS. However, sex, use of icodextrin, the number of peritonitis episodes, and history of multicystic kidney disease did not affect the risk of EPS. This review provides a scientific basis for further understanding the etiology of PD-related EPS and improving prevention strategies. More high-quality studies are necessary to validate this paper's findings.

Mitochonic acid-5 ameliorates chlorhexidine gluconate-induced peritoneal fibrosis in mice.

Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis, attributable to inflammation and mitochondrial dysfunction. Mitochonic acid-5 (MA-5), an indole-3-acetic acid derivative, improves mitochondrial dysfunction and has therapeutic potential against various diseases including kidney diseases. However, whether MA-5 is effective against peritoneal fibrosis remains unclear. Therefore, we investigated the effect of MA-5 using a peritoneal fibrosis mouse model. Peritoneal fibrosis was induced in C57BL/6 mice via intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 3weeks. MA-5 was administered daily by oral gavage. The mice were divided into control, MA-5, CG, and CG + MA-5 groups. Following treatment, immunohistochemical analyses were performed. Fibrotic thickening of the parietal peritoneum induced by CG was substantially attenuated by MA-5. The number of α-smooth muscle actin-positive myofibroblasts, transforming growth factor β-positive cells, F4/80-positive macrophages, monocyte chemotactic protein 1-positive cells, and 4-hydroxy-2-nonenal-positive cells was considerably decreased. In addition, reduced ATP5a1-positive and uncoupling protein 2-positive cells in the CG group were notably increased by MA-5. MA-5 may ameliorate peritoneal fibrosis by suppressing macrophage infiltration and oxidative stress, thus restoring mitochondrial function. Overall, MA-5 has therapeutic potential against peritoneal fibrosis.

Clinical improvement of encapsulating peritoneal sclerosis after challenging course and 6\xa0months of total parenteral nutrition in child with nephronophthisis: a case report

BackgroundEncapsulating peritoneal sclerosis is a rare but potentially lethal complication of long-term peritoneal dialysis that is associated with significant morbidity and mortality. The occurrence of encapsulating peritoneal sclerosis varies worldwide, but is increased in patients maintained on peritoneal dialysis for 5–8 years. The etiology of encapsulating peritoneal sclerosis remains unidentified, and a high index of clinical suspicion is required for diagnosis.Case presentationWe report a 5-year-old Saudi female with end-stage renal disease secondary to nephronophthisis type 2. She underwent peritoneal dialysis for 30 months, with four episodes of peritonitis. She presented with clinical signs of peritonitis. Three days later, she developed septic shock, which required pediatric intensive care unit admission. The peritoneal dialysis catheter was removed because of refractory peritonitis. Her course was complicated by small bowel perforation, and severe adhesions were revealed on abdominal ultrasound and computed tomography, consistent with a diagnosis of EPS. This finding was later confirmed by diagnostic laparotomy performed twice and complicated by recurrent abdominal wall fistula. She received total parenteral nutrition for 6 months and several courses of antibiotics. The patient received supportive treatment including nutritional optimization and treatment for infection. No other treatments, such as immunosuppression, were administered to avoid risk of infection. Following a complicated hospital course, the patient restarted oral intake after 6 months of total parenteral nutrition dependency. Her abdominal fistula resolved completely, and she was maintained on hemodialysis for few years before she received a kidney transplant.ConclusionWhen treating patients using peritoneal dialysis, it is important to consider encapsulating peritoneal sclerosis with refractory peritonitis, which is not always easy to identify, particularly if the patient has been maintained on peritoneal dialysis for less than 3 years. Early identification of encapsulating peritoneal sclerosis and appropriate conservative treatment, including nutritional optimization and treatment of infections, are essential to achieve a better prognosis.

MO713ENCAPSULATING PERITONEAL SCLEROSIS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of long-term peritoneal dialysis (PD). Causative factors are the chronic exposure to bioincompatible PD and peritonitis episodes. Pro-inflammatory state and oxidative stress associated with chronic uremia may further accelerate these pathomechanisms. Clinical symptoms are, essentially, signs of intestinal obstruction. Treatments commonly used are corticosteroids, tamoxifen, immunosuppressants like azathioprine, mycophenolate mofetil (MMF), or mTOR inhibitors which has fibrinolytic properties and may help with reducing inflammation. In the last ten years, the incidence of SEP in kidney transplant recipients has increased, but few cases have been reported. Given the rare nature of this pathology, we decided to publish the cases of two EPS happening after kidney transplantation (KT). Case report We report the cases of two male patients aged 46 and 25 with a history of chronic renal failure, who benefited of continuous ambulatory peritoneal dialysis (CAPD) for three years. The first patient was switched to haemodialysis (HD) for sub-dialysis, with one episode of peritonitis and one episode of catheter infection. The second patient had three episodes of peritonitis complicated by asymptomatic EPS, hence its transfer to HD. Our two patients presented, at 30 and 40 days post KT, an episode of acute intestinal obstruction with abdominal scans fitting with a mechanical bowel obstruction on an encapsulating peritonitis without signs of complication. Both patients were on corticosteroid therapy (15 and 17.5 mg/day) combined with MMF and Calcineurin inhibitors (CNIs) (Tacrolimus). Medical measures were not effecient. Surgical treatment was then considered. During the operation, a classical picture of EPS was found characterized by a thin cocoon-like sclerotic membrane encasing the small bowel. A complete resection of the encapsulating sclerotic membrane and total adhesiolysis were performed, with an immediate improvement on the clinical level. No recurrence was noted for both patients at 5 and 24 months respectively. Conclusion The specificities of our patients compared to the reported cases were the short duration of the PD and the relatively young age. In fact, some studies demonstrated an increased incidence of EPS in younger patients. In addition, this complication has declared itself despite corticosteroid therapy. Some case reports have demonstrated an increase in the incidence of SEP in kidney transplant patients, suggesting the possible implication of CNIs which have a profibrotic effect and may promote peritoneal matrix accumulation.

SIRT1-modified human umbilical cord mesenchymal stem cells ameliorate experimental peritoneal fibrosis by inhibiting the TGF-\u03b2/Smad3 pathway

IntroductionPeritoneal fibrosis is a serious complication of long-term peritoneal dialysis (PD). Combination therapies are emerging as a promising treatment for tissue damage. Here, we investigated the therapeutic potential of SIRT1-modified human umbilical cord mesenchymal stem cells (hUCMSCs) for peritoneal fibrosis.MethodsSIRT1 was overexpressed in hUCMSCs to establish SIRT1-modified hUCMSCs. Co-culture and transplantation experiments were performed in TGF-β-stimulated Met-5A cells and peritoneal damage rodent model to assess the therapeutic potential of SIRT1-modified hUCMSCs for peritoneal fibrosis through qPCR, Western blot, and peritoneal function analyses.ResultsSIRT1-modified hUCMSC administration had more potent anti-fibrosis ability than hUCMSCs, which significantly inhibited the expression of fibrotic genes and suppressed EMT process, increased ultrafiltration volume, and restored homeostasis of bioincompatible factors in dialysis solution. Mechanistically, SIRT1-modified hUCMSCs attenuated peritoneal fibrosis through reducing peritoneal inflammation and inhibiting the TGF-β/Smad3 pathway in peritoneal omentum tissues.ConclusionSIRT1-modified hUCMSCs might work as a promising therapeutic strategy for the treatment of peritoneal dialysis-induced peritoneal damage and fibrosis.

Adipose-Derived Mesenchymal Stem Cells Modulate Fibrosis and Inflammation in the Peritoneal Fibrosis Model Developed in Uremic Rats.

Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting the peritoneal membrane (PM) function. Adipose tissue-derived mesenchymal stem cells (ASC) display immunomodulatory effects and may represent a strategy to block PF. The aim of this study was to analyze the effect of ASC in an experimental PF model developed in uremic rats. To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and chronic kidney disease (CKD), was developed in Wistar rats. Rats were fed with a 0.75% adenine-containing diet, for 30 days, to induce CKD with uremia. PF was induced with intraperitoneal injections of chlorhexidine gluconate (CG) from day 15 to 30. 1 × 106 ASC were intravenously injected at days 15 and 21. Rats were divided into 5 groups: control, normal rats; CKD, rats receiving adenine diet; PF, rats receiving CG; CKD+PF, CKD rats with PF; CKD+PF+ASC, uremic rats with PF treated with ASC. PF was assessed by Masson trichrome staining. Inflammation- and fibrosis-associated factors were assessed by immunohistochemistry, multiplex analysis, and qPCR. When compared with the control and CKD groups, GC administration induced a striking increase in PM thickness and inflammation in the PF and CKD+PF groups. The development of PF was blocked by ASC treatment. Further, the upregulation of profibrotic factors (TGF-β, fibronectin, and collagen) and the increased myofibroblast expression observed in the CKD+PF group were significantly ameliorated by ASC. Beyond the antifibrotic effect, ASC showed an anti-inflammatory effect avoiding leucocyte infiltration and the overexpression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the PM induced by GC. ASC were effective in preventing the development of PF in the experimental model of CKD+PF, probably due to their immunomodulatory properties. These results suggest that ASC may represent a potential strategy for treating long-term PD-associated fibrosis.

A Successful Treatment of Encapsulating Peritoneal Sclerosis in an Adolescent Boy on Long-term Peritoneal Dialysis: A Case Report

Encapsulating peritoneal sclerosis (EPS) is a rare life-threatening complication associated with peritoneal dialysis (PD). EPS is characterized by progressive fibrosis and sclerosis of the peritoneum, with the formation of a membrane and tethering of loops of the small intestine resulting in intestinal obstruction. It is very rare in children. We present a case of a 16-year-old adolescent boy who developed EPS seven years after being placed on continuous ambulatory peritoneal dialysis (CAPD) complicated by several episodes of bacterial peritonitis. The diagnosis was based on clinical, radiological, intraoperative and histopathological findings. The patient was successfully treated with surgical enterolysis. During a 7-year follow-up, there have been no further episodes of small bowel obstruction documented. He still continues to be on regular hemodialysis and is awaiting a deceased donor kidney transplant. EPS is a long-term complication of peritoneal dialysis and is typically seen in adults. Rare cases may be seen in the pediatric population and require an appropriate surgical approach that is effective and lifesaving for these patients.

Encapsulating Peritoneal Sclerosis: Pathophysiology and Current Treatment Options.

Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of long-term peritoneal dialysis (PD), which may even occur after patients have switched to hemodialysis (HD) or undergone kidney transplantation. The incidence of EPS varies across the globe and increases with PD vintage. Causative factors are the chronic exposure to bioincompatible PD solutions, which cause long-term modifications of the peritoneum, a high peritoneal transporter status involving high glucose concentrations, peritonitis episodes, and smoldering peritoneal inflammation. Additional potential causes are predisposing genetic factors and some medications. Clinical symptoms comprise signs of intestinal obstruction and a high peritoneal transporter status with incipient ultrafiltration failure. In radiological, macro-, and microscopic studies, a massively fibrotic and calcified peritoneum enclosed the intestine and parietal wall in such cases. Empirical treatments commonly used are corticosteroids and tamoxifen, which has fibrinolytic properties. Immunosuppressants like azathioprine, mycophenolate mofetil, or mTOR inhibitors may also help with reducing inflammation, fibrin deposition, and collagen synthesis and maturation. In animal studies, N-acetylcysteine, colchicine, rosiglitazone, thalidomide, and renin-angiotensin system (RAS) inhibitors yielded promising results. Surgical treatment has mainly been performed in severe cases of intestinal obstruction, with varying results. Mortality rates are still 25–55% in adults and about 14% in children. To reduce the incidence of EPS and improve the outcome of this devastating complication of chronic PD, vigorous consideration of the risk factors, early diagnosis, and timely discontinuation of PD and therapeutic interventions are mandatory, even though these are merely based on empirical evidence.

Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis

BackgroundPeritoneal fibrosis (PF) remains a serious complication of long-term peritoneal dialysis (PD). The goal of this study was to investigate the anti-fibrotic effects of curcumin on the PF response to PD and its’ mechanism.MethodsMale Sprague–Dawley rats were infused with 20 mL of 4.25% glucose-based standard PD fluid for 8 consecutive weeks to establish PF model and then divided into five groups: Control, received sham operation and 0.9% physiological saline; PD, received 4.25% standard PD fluid; Curcumin, PD rats injected intraperitoeally with curcumin for 8 weeks at doses of 10, 20 or 40 mg/kg. Masson’s staining was performed to evaluate the extent of PF. Peritoneal Equilibration Test (PET) was conducted to assess ultrafiltration volume (UFV) and mass transfer of glucose (MTG), quantitative RT-PCR, and immunohistochemistry or western blotting were performed to measure the expression levels of inflammation and fibrosis-associated factors. We also detected the TGF-β1 in peritoneal fluid by ELISA.ResultsCompared with the control group, the PD rats showed decreased UFV (2.54 ± 0.48 to 9.87 ± 0.78 mL, p < 0.05] and increased MTG (18.99 ± 0.86 to 10.85 ± 0.65 mmol/kg, p < 0.05) as well as obvious fibroproliferative response, with markedly increased peritoneal thickness (178.33 ± 4.42 to 25.26 ± 0.32um, p < 0.05) and higher expression of a-SMA, collagen I and TGF-β1. Treatment with curcumin significantly increased UFV, reduced MTG and peritoneal thickness of PD rats. The elevated TGF-β1 in peritoneal fluid of PD rats was significantly decreased by curcumin. It attenuated the increase in protein and mRNA of TGF-β1, α-SMA and collagen I in peritoneum of PD rats. The mRNA expressions of TAK1, JNK and p38, as well as the protein expressions of p-TAK1, p-JNK and p-p38 in peritoneum of PD rats were reduced by curcumin.ConclusionsPresent results demonstrate that curcumin showed a protective effect on PD-related PF and suggest an implication of TAK1, p38 and JNK pathway in mediating the benefical effects of curcumin.

MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-β1 (TGF-β1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.

Tamoxifen and bone morphogenic protein-7 modulate fibrosis and inflammation in the peritoneal fibrosis model developed in uremic rats

BackgroundPeritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats.MethodsTo mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 μg/Kg, IP). Animals were followed up for 30 days.ResultsCG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFβ/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression.ConclusionsIn conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process.

Evaluation of Candida peritonitis with underlying peritoneal fibrosis and efficacy of micafungin in murine models of intra-abdominal candidiasis

Candida peritonitis is a crucial disease, however the optimal antifungal therapy regimen has not been clearly defined. Peritoneal fibrosis (PF) can be caused by abdominal surgery, intra-abdominal infection, and malignant diseases, and is also widely recognized as a crucial complication of long-term peritoneal dialysis. However, the influence of PF on Candida peritonitis prognosis remains unknown. Here, we evaluated the severity of Candida peritonitis within the context of PF and the efficacy of micafungin using mice. A PF mouse model was generated by intraperitoneally administering chlorhexidine gluconate. Candida peritonitis, induced by intraperitoneal inoculation of Candida albicans, was treated with a 7-day consecutive subcutaneous administration of micafungin. Candida infection caused a higher mortality rate in the PF mice compared with the control mice on day 7. Proliferative Candida invasion into the peritoneum and intra-abdominal organs was confirmed pathologically only in the PF mice. However, all mice in both groups treated with micafungin survived until day 20. Micafungin treatment tends to suppress inflammatory cytokines in the plasma 12 h after infection in both groups. Our results suggest that PF enhances early mortality in Candida peritonitis. Prompt initiation and sufficient doses of micafungin had good efficacy for Candida peritonitis, irrespective of the underlying PF.

CXCR4-Receptor-Targeted Liposomes for the Treatment of Peritoneal Fibrosis.

Peritoneal fibrosis (PF) is a common complication of long-term peritoneal dialysis (PD). It is considered as the main reason for dialysis inadequacy and PD withdrawal. Transforming growth factor beta (TGF-β) regulates the expression of stromal cell-derived factor 1 (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) on human peritoneal mesothelial cells (HPMCs), resulting in an increased migratory potential of HPMCs and extracellular matrix (ECM) deposition in the scar tissue and eventually fibrosis. Because SDF-1α/CXCR4 activation has a vital role in the pathogenesis of PF, codelivery of a CXCR4-receptor targeting agent with an antifibrotic agent in a single nanocarrier can be a promising strategy for treating PF. Here, for the first time, AMD3100 (AMD), a CXCR4-receptor antagonist, was coformulated with sulfotanshinone IIA sodium (STS IIA) into a liposome (STS-AMD-Lips) to develop a CXCR4 receptor targeting form of combination therapy for PF. CXCR4 targeting increased the ability of liposomes to target fibrotic peritoneal mesothelial cells overexpressing CXCR4 and facilitated the ability of STS IIA treatment at the fibrotic site. The liposome had an average diameter of 103 nm with encapsulated efficiencies of above 50%. The in vivo studies confirmed the reversal of PD solution-induced epithelial-to-mesenchymal transition by STS-AMD-Lips in HPMCs. The in vivo studies also revealed the precise biodistribution of the liposomes to peritoneum. Significant reduction of the morphological lesions and decreased level of ECM proteins were observed in rats treated with STS-AMD-Lips, proving that the liposomal nanocarrier has excellent ability to reverse PF. It has been concluded that the STS-AMD-Lips exhibit specific peritoneal targeting ability and could be used to improve STS-AMD combination delivery for the treatment of PF.

Surgical Treatment for Encapsulating Peritoneal Sclerosis: 24 Years' Experience.

Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis. The mortality rate for EPS is high, primarily due to complications related to bowel obstruction. Surgery was previously contraindicated; however, surgical enterolysis is performed for patients in whom bowel obstruction fails to improve. This was a retrospective observational study of patients with EPS who received surgical intervention at a single center between November 1993 and October 2017. The severity of intestine damage was characterized by grade-3 peritoneal calcification on abdominal computed tomography (CT) scan and degeneration of the small intestinal wall in surgery. Two-hundred and forty-three patients with EPS opted for surgery. Among them, 58 had recurrence and required re-surgery; a total of 318 EPS surgeries were performed. Death was related to EPS in 61 patients (25.1%), of whom 15 died postoperatively. Sixty-seven patients (27.6%) died from other causes. The actuarial survival rates at 1, 2, 3, 5, and 8 years after EPS diagnosis were 91%, 83%, 77%, 66%, and 53% respectively. The 50% actuarial survival points after EPS diagnosis and surgery were 104 months and 85 months, respectively. Peritoneal calcification and small intestinal wall degeneration grading showed significant association with the mortality curve for EPS-related death. Excellent outcomes for EPS are achieved with surgery. The degree of peritoneal deterioration affected the clinical outcomes. Currently, EPS is no longer recognized as a fatal complication.

Surgical treatment of post-transplant encapsulating peritoneal sclerosis: A single-center experience.

Encapsulating peritoneal sclerosis (EPS) related to peritoneal dialysis (PD) has a vague etiology and high mortality. In this study, our aim was to determine treatment options for EPS cases. A total of 169 patients underwent kidney transplantation from January 2008 to January 2018 and 119 patients from a cadaveric and 50 patients from a living donor. Twenty-one patients were undergoing PD before the transplantation. The mean PD time was 6.9 (IQR 3-14) years. Four patients received surgical treatment for EPS that occurred after the transplant. After the surgical treatment, 2 patients died because of sepsis. Two patients were discharged without complications, but 1 had late-term EPS recurrence. EPS is a rare but serious complication of long-term PD. It has a high mortality and morbidity rate. Long-term PD is the most significant factor for triggering EPS. Nutritional support and surgical intervention is the next step if medical treatment fails. Resistant cases should be treated surgically without much delay before the condition deteriorates. It can be especially devastating for patients with a long-term PD history to have EPS after a successful transplant. Because EPS is a challenging condition, its management should be done in experienced clinics to decrease its mortality and morbidity rates.

HIF1A and VEGF regulate each other by competing endogenous RNA mechanism and involve in the pathogenesis of peritoneal fibrosis

BackgroundPeritoneal fibrosis is a major intractable complication of long-term peritoneal dialysis, and would eventually lead to peritoneal ultrafiltration failure and the termination of peritoneal dialysis. Hypoxia-inducible factor 1-alpha (HIF1A) has been reported to regulate vascular endothelial growth factor (VEGF) and involves in peritoneal fibrosis, but the exact molecular regulation mechanism remains unknown. MethodsHIF1A and VEGF protein levels were measured in 42 peritoneal patients using enzyme linked immunosorbent assay. Bioinformatics, reverse transcription-polymerase chain reaction, correlation analysis, RNA interference, gene over-expression and luciferase assays were performed to clarify the competing endogenous RNA (ceRNA) regulation between HIF1A and VEGF. ResultsBoth HIF1A and VEGF levels were elevated in the peritoneal effluent of peritoneal dialysis patients with ultrafiltration problems, and were positively correlated with each other at protein level and mRNA level. Bioinformatics analysis identified 8 common targeted miRNAs for HIF1A and VEGF, including miR-17-5p, 20a, 20b, 93, 106a, 106b, 199a-5p and 203. MiR-17-5p was proved to be present in patients’ peritoneal effluent and selected for further studies. HIF1A mRNA and VEGF mRNA could regulate each other, and miR-17-5p was required in the regulations. Down/up regulation of HIF1A mRNA and VEGF mRNA resulted in up/down regulation of miR-17-5p. Furthermore, down/up regulation of miR-17-5p was associated with up/down regulation of HIF1A mRNA and VEGF mRNA. Luciferase assay indicated that HIF1A and VEGF regulated each other through 3′UTR. ConclusionHIF1A and VEGF could regulate each other in peritoneal mesothelial cell in the mediation of miR-17-5p and 3′UTR, indicating HIF1A and VEGF might regulate each other through competing endogenous RNA mechanism in the development of peritoneal fibrosis.