Genetic and clinical factors influence the baseline permeability of the peritoneal membrane

Gillerot, Gaëlle; Goffin, Éric; Michel, Catherine; Evenepoel, Pieter; Biesen, Wim Van; Tintillier, Michel; Stenvinkel, Peter; Heimbürger, Olof; Lindholm, Bengt; Nordfors, Louise; Robert, Annie; Devuyst, Olivier

doi:10.1111/j.1523-1755.2005.00357.x

Cited by 113 publications

(115 citation statements)

References 42 publications

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“…Dialysate IL-6 is considered a marker for local inflammation (18,22); however, different genetic backgrounds can influence IL-6 concentrations in serum and dialysate of individual patients at baseline (23). In the present analysis, a tendency for an increase with the duration of PD was found.…”

Section: Discussionsupporting

confidence: 62%

Early Diagnostic Markers for Encapsulating Peritoneal Sclerosis: A Case-Control Study

et al. 2010

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ObjectiveEncapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD). The aim of this study was to investigate whether dialysate levels of cancer antigen-125 (CA125), K+, interleukin (IL)-6, and vascular endothelial growth factor (VEGF) are early diagnostic markers of EPS. Therefore, we analyzed the time courses of the above described dialysate markers in EPS patients and controls.MethodsDialysate and serum samples of 11 EPS patients and 31 control patients, all treated with PD for at least 57 months, were longitudinally collected during standard peritoneal permeability analyses. CA125 and IL-6 were measured in dialysate only, K+and VEGF were measured in both dialysate and serum. CA125 and IL-6 are expressed as appearance rates (AR). The linear mixed model was used to analyze the time courses. Sensitivity and specificity were calculated based on the results of the last 2 time points.ResultsNo differences in the time courses of the different markers were present between the groups. For K+and VEGF attributed to local production, no differences between the groups were found. However, AR-CA125 was lower during the last 3 years prior to EPS ( p < 0.05) and AR-IL-6 tended to be higher 2 years prior to EPS ( p = 0.09). The combination of AR-CA125 < 33 U/min and AR-IL-6 > 350 pg/min had a sensitivity of 70% and a specificity of 89% for the development of EPS.ConclusionsCompared to controls, AR-CA125 showed lower values and AR-IL-6 tended to be higher during the last years prior to the diagnosis of EPS. The sensitivity and specificity of the combination of CA125 and IL-6 indicate their potential use for an early diagnosis of EPS.

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Section: Discussionsupporting

confidence: 62%

Early Diagnostic Markers for Encapsulating Peritoneal Sclerosis: A Case-Control Study

et al. 2010

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“…Increasing PSTR with time on PD is well established (2)(3)(4)(5) and from a theoretical perspective could be due to an increase in the anatomic membrane in contact with dialysate, an increase in the density of perfused capillaries (to include neoangiogenesis), or an increase in capillary perfusion rate or any combination of the above. There are good reasons to believe that the clinical variability in PSTR at the start of PD is in large part due to local membrane inflammation (16), and the strong relationship with Pcl at baseline observed in this study supports this because inflamed capillaries will be leaky. If this had been purely an anatomic coupling, this should have remained the case throughout the study; in fact, however, an increase in small-pore area with a relative decline in the large-pore area occurred.…”

Section: Discussionsupporting

confidence: 61%

“…First, given that both pore systems are located in the capillary vessel wall, there will probably be considerable anatomic coupling. Second, because intraperitoneal production of the proinflammatory cytokine IL-6 is correlated with, and is probably a key determinant of, PSTR (16), local inflammation would be expected to cause increased numbers of large pores per unit of capillary length. If the increase in PSTR occurring with time on treatment is a function of increasing intraperitoneal inflammation, then a parallel increase in Pcl would be anticipated.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Study of Small Solute Transport and Peritoneal Protein Clearance in Peritoneal Dialysis Patients

Lambie

Davies

2014

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Peritoneal protein clearance (Pcl) is determined by both effective (small pores) membrane area and relative capillary leakiness (large pores). It is not known how these two components change with duration of peritoneal dialysis (PD) in the context of progressive membrane injury and differential attrition of patients with higher Pcl, which has been associated with increased mortality risk in several studies.Design, setting, participants, & measurements Patients treated continuously from 2000 to 2011 for a minimum of 4 years were selected from the longitudinal prospective Stoke PD Study. Pcl, membrane area (peritoneal solute transport rate [PSTR]), dialysis prescription, and residual renal function were measured every 6 months, along with comorbidity and peritonitis events. Multilevel multivariate analysis was used to determine associations with Pcl over time, taking into account within-subject correlations.Results From 280 incident patients, 335 datasets were analyzed from 49 patients receiving treatment for 4 years. Pcl correlated with PSTR at baseline (R=0.61; P,0.01), but over time there was progressive uncoupling of this relationship (year 4, R=0.28; P=0.05) with increasing PSTR (0.66-0.74; P,0.01) and stable Pcl (78.4-81.9 ml/d; P=0.7). Multivariate analysis found that age, PSTR, daily ultrafiltration, and sodium removal were significant predictors of Pcl when adjusted for sex, comorbidity, glucose exposure, and residual renal function. Peritonitis was associated with increased PSTR but a similar pattern of uncoupling. ConclusionThere is a progressive dissociation of the small-and large-pore pathways with time on PD, which would be in keeping with a switch from local inflammation early on to progressive fibrosis, combined with increased vascular surface area. Measuring longitudinal changes in Pcl may complement membrane function tests used to monitor progressive injury.

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“…Because transmission of genes is a random phenomenon, gene polymorphisms modulating IL-6 synthesis may represent an unbiased means for testing whether the link between IL-6 and CV outcomes in patients with CKD is causal (Mendelian randomization). The 2174 G/C single-nucleotide polymorphism is a functional variant located in the promoter region of the IL-6 gene that regulates the rate of IL-6 gene transcription (22)(23)(24)(25)(26)(27)(28) and therefore represents a reliable research tool for testing the nature (causal versus noncausal) of the link between IL-6 and CV outcomes in CKD. With this background in mind, we set out to confirm findings by Barreto et al (21) in a large observational study with a carefully characterized cohort of 755 patients with stages 2-5 CKD and to test whether this relationship may underlie a causal link by applying the Mendelian randomization approach (i.e., by stratifying the study population according to the functional 2174 G/C polymorphism in the IL-6 gene).…”

Section: Introductionmentioning

confidence: 99%

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Spoto

Mattace-Raso

Sijbrands

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives High serum IL-6 is a major risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patients with CKD, but it is still unknown whether the link between IL-6 and CVD in CKD is causal in nature.Design, setting, participants, & measurements In a cohort of 755 patients with stages 2-5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up6SD, 31610 months) and used the functional polymorphism (2174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal.Results In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P,0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the 2174 G/C polymorphism had higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95% CI, 1.15 to 4.00; P=0.02) as well as a 87% higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes. ConclusionsIn patients with stages 2-5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the 2174 G/C polymorphism in the IL-6 gene suggests that IL-6 may be causally involved in the high CV risk in this population.

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Genetic and clinical factors influence the baseline permeability of the peritoneal membrane

Abstract: These data (1) show that, together with clinical parameters, the functionally relevant -174G/C polymorphism of IL-6 contributes to the interpatient variability in small solute transport rate at the start of PD; and (2) substantiate the critical role played by IL-6 in the PM.

Cited by 113 publications

References 42 publications

Early Diagnostic Markers for Encapsulating Peritoneal Sclerosis: A Case-Control Study

Early Diagnostic Markers for Encapsulating Peritoneal Sclerosis: A Case-Control Study

Longitudinal Study of Small Solute Transport and Peritoneal Protein Clearance in Peritoneal Dialysis Patients

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

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