Peritoneal inflammation precedes encapsulating peritoneal sclerosis: results from the GLOBAL Fluid Study

Lambie, Mark R.; Chess, James; Summers, Angela; Williams, Paul F.; Topley, Nicholas; Davies, Simon

doi:10.1093/ndt/gfv440

Cited by 50 publications

(39 citation statements)

References 26 publications

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“…Previous studies have suggested that a number of proteins, primarily inflammatory biomarkers (IL-6, TNF-α, MCP-1, CCL-15, PAI-1), were slightly increased in the PDE of patients who subsequently developed EPS (10,49,(64)(65) , but were not identified by our proteomics approach. Previous studies used a targeted ELISA based approach, which h a s h i g h s e n s i t i v i t y a n d s u b s e q u e n t l y resolution.…”

Section: Discussionmentioning

confidence: 60%

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A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent

Zavvos

Buxton

Evans

et al. 2017

Kidney International

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Encapsulating peritoneal sclerosis (EPS) is a potentially devastating complication of peritoneal dialysis (PD). Diagnosis is often delayed due to the lack of effective and accurate diagnostic tools. We therefore examined peritoneal effluent for potential biomarkers that could predict or confirm the diagnosis of EPS and would be valuable in stratifying at-risk patients and driving appropriate interventions. Using prospectively collected samples from the Global Fluid Study and a cohort of Greek PD patients, we utilized 2D SDSPAGE/ MS and iTRAQ to identify changes in the peritoneal effluent proteome from patients diagnosed with EPS and controls matched for treatment exposure. We employed a combinatorial peptide ligand library to compress the dynamic range of protein concentrations to aid identification of low-abundance proteins. In patients with stable membrane function, fibrinogen γ-chain and heparan sulphate proteoglycan core protein progressively increased over time on PD. In patients who developed EPS, collagen-α1(I), γ-actin and Complement factors B and I were elevated up to five years prior to diagnosis. Orosomucoid-1 and a2-HS-glycoprotein chain-B were elevated about one year before diagnosis, while apolipoprotein A-IV and α1-antitrypsin were decreased compared to controls. Dynamic range compression resulted in an increased number of proteins detected with improved resolution of protein spots, compared to the full fluid proteome. Intelectin-1, dermatopontin, gelsolin, and retinol binding protein-4 were elevated in proteome-mined samples from patients with EPS compared to patients that had just commenced peritoneal dialysis. Thus, prospective analysis of peritoneal effluent uncovered proteins indicative of inflammatory and pro-fibrotic injury worthy of further evaluation as diagnostic/prognostic markers.

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Section: Discussionmentioning

confidence: 60%

“…Therefore, lower levels of 1-PI and apo A-IV may indicate an active inflammatory process which might contribute to EPS development (49) . The latter is further supported by the observed increases in Complement factor expression (43) .…”

Section: Discussionmentioning

confidence: 99%

A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent

Zavvos

Buxton

Evans

et al. 2017

Kidney International

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“…51,52 Furthermore, recent data from the GLOBAL Study showed that patients who developed encapsulating peritoneal sclerosis had earlier higher dialysate levels of IL-6 during PD. 53 These two scenarios would fit well into the concept that, depending on a pathophysiologic context, IL-6 can either be crucial for host defense or promote chronic disease. 28 Here, we show that dialysate IL-6 and sIL-6R can act together through the trans-signaling pathway controlled by the STAT3-SP4 axis to upregulate mesothelial VEGF production during peritonitis.…”

Section: Discussionmentioning

confidence: 74%

IL-6 Trans–Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane

Catar

Witowski

Zhu

et al. 2016

JASN

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Vascular endothelial growth factor (VEGF) is implicated in the peritoneal membrane remodeling that limits ultrafiltration in patients on peritoneal dialysis (PD). Although the exact mechanism of VEGF induction in PD is unclear, VEGF concentrations in drained dialysate correlate with IL-6 levels, suggesting a link between these cytokines. Human peritoneal mesothelial cells (HPMCs), the main source of IL-6 and VEGF in the peritoneum, do not bear the cognate IL-6 receptor and are thus unable to respond to classic IL-6 receptor signaling. Here, we investigated whether VEGF release by HPMCs is controlled by IL-6 in combination with its soluble receptor (IL-6 trans-signaling). Although treatment with either IL-6 or soluble IL-6 receptor (sIL-6R) alone had no effect on VEGF production, stimulation of HPMCs with IL-6 in combination with sIL-6R promoted VEGF expression and secretion through a transcriptional mechanism involving STAT3 and SP4. Conditioned medium from HPMCs cultured with IL-6 and sIL-6R promoted angiogenic endothelial tube formation, which could be blocked by silencing SP4. , induction of peritoneal inflammation in wild-type and IL-6-deficient mice showed IL-6 involvement in the control of and expression and new vessel formation, confirming the role of IL-6 trans-signaling in these processes. Taken together, these findings identify a novel mechanism linking IL-6 trans-signaling and angiogenesis in the peritoneal membrane.

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“…Therefore, our transcriptome data relate the functional results obtained with the streamlined assay to molecular mechanisms underlying enhanced response to TLR-stimulation. Unlike elevated basal levels of peritoneal IL-6 in PD patients, which predispose to membrane transformation 37, 38 , increased response to bacterial stimuli would more likely reduce peritonitis rates. However, further large scale trials are required to elucidate whether findings obtained in the settings of sepsis and other disorders can be translated to PD.…”

Section: Discussionmentioning

confidence: 99%

Functional and Transcriptomic Characterization of Peritoneal Immune-Modulation by Addition of Alanyl-Glutamine to Dialysis Fluid

Kuster

Becker

Gluexam

et al. 2017

Sci Rep

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Peritonitis remains a major cause of morbidity and mortality during chronic peritoneal dialysis (PD). Glucose-based PD fluids reduce immunological defenses in the peritoneal cavity. Low concentrations of peritoneal extracellular glutamine during PD may contribute to this immune deficit. For these reasons we have developed a clinical assay to measure the function of the immune-competent cells in PD effluent from PD patients. We then applied this assay to test the impact on peritoneal immune-competence of PD fluid supplementation with alanyl-glutamine (AlaGln) in 6 patients in an open-label, randomized, crossover pilot trial (EudraCT 2012-004004-36), and related the functional results to transcriptome changes in PD effluent cells. Ex-vivo stimulation of PD effluent peritoneal cells increased release of interleukin (IL) 6 and tumor necrosis factor (TNF) α. Both IL-6 and TNF-α were lower at 1 h than at 4 h of the peritoneal equilibration test but the reductions in cytokine release were attenuated in AlaGln-supplemented samples. AlaGln-supplemented samples exhibited priming of IL-6-related pathways and downregulation of TNF-α upstream elements. Results from measurement of cytokine release and transcriptome analysis in this pilot clinical study support the conclusion that suppression of PD effluent cell immune function in human subjects by standard PD fluid is attenuated by AlaGln supplementation.

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Peritoneal inflammation precedes encapsulating peritoneal sclerosis: results from the GLOBAL Fluid Study

Cited by 50 publications

References 26 publications

A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent

A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent

IL-6 Trans–Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane

Functional and Transcriptomic Characterization of Peritoneal Immune-Modulation by Addition of Alanyl-Glutamine to Dialysis Fluid

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