Characterization of hypersensitivity reactions to polysulfone hemodialysis membranes.

BACKGROUND: In recent years, cases have been reported in which unexpected systemic hypersensitivity reactions occurred in patients dialyzed with polysulfone- or polyethersulfone-biocompatible membranes in the absence of other risk factors. The pathomechanisms involved in these reactions are largely unknown. OBJECTIVE: To characterize hypersensitivity reactions to polysulfone hemodialysis using clinical and laboratory data and to identify biomarkers suitable for endotype identification and diagnosis. METHODS: We prospectively collected data from 29 patients with suspected hypersensitivity reactions to polysulfone hemodialysis membranes. Clinical laboratory parameters such as tryptase, blood cell counts, and complement levels were recorded. Acute samples were obtained from 18 cases for the ex vivo assessment of basophil activation by flow cytometry analysis of CD63, CD203, and FcεRI cell membrane expression. Serum cytokines and anaphylatoxin concentrations were evaluated in 16 cases by Luminex and cytometric bead array analysis. RESULTS: Tryptase was elevated during the acute reaction in 4 cases. Evidence of basophil activation was obtained in 10 patients. Complement activation was found in only 2 cases. However, C5a serum levels tended to increase during the acute reaction in those patients with hypoxemia. Significantly higher serum levels of interleukin-6 were observed during the acute reactions to polysulfone hemodialysis (P = .0103). CONCLUSION: Based on biomarker analysis, various endotypes were identified, including type I-like (with the involvement of mast cells or basophils), complement, and cytokine (interleukin-6) release-related reactions, with some patients showing mixed reactions. Further research is needed to unravel the exact mechanisms involved in the activation of these cellular and molecular pathways.

Preventing peritoneal membrane fibrosis in peritoneal dialysis patients.

Long-term peritoneal dialysis causes morphologic and functional changes in the peritoneal membrane. Although mesothelial-mesenchymal transition of peritoneal mesothelial cells is a key process leading to peritoneal fibrosis, and bioincompatible peritoneal dialysis solutions (glucose, glucose degradation products, and advanced glycation end products or a combination) are responsible for altering mesothelial cell function and proliferation, mechanisms underlying these processes remain largely unclear. Peritoneal fibrosis has 2 cooperative parts, the fibrosis process itself and the inflammation. The link between these 2 processes is frequently bidirectional, with each one inducing the other. This review outlines our current understanding about the definition and pathophysiology of peritoneal fibrosis, recent studies on key fibrogenic molecular machinery in peritoneal fibrosis, such as the role of transforming growth factor-ß/Smads, transforming growth factor-ß ß/Smad independent pathways, and noncoding RNAs. The diagnosis of peritoneal fibrosis, including effluent biomarkers and the histopathology of a peritoneal biopsy, which is the gold standard for demonstrating peritoneal fibrosis, is introduced in detail. Several interventions for peritoneal fibrosis based on biomarkers, cytology, histology, functional studies, and antagonists are presented in this review. Recent experimental trials in animal models, including pharmacology and gene therapy, which could offer novel insights into the treatment of peritoneal fibrosis in the near future, are also discussed in depth.

IL-17A is a novel player in dialysis-induced peritoneal damage.

The classical view of the immune system has changed by the discovery of novel T-helper (Th) subsets, including Th17 (IL-17A-producing cells). IL-17A participates in immune-mediated glomerulonephritis and more recently in inflammatory pathologies, including experimental renal injury. Peritoneal dialysis patients present chronic inflammation and Th1/Th2 imbalance, but the role of the Th17 response in peritoneal membrane damage has not been investigated. In peritoneal biopsies from dialyzed patients, IL-17A immunostaining was found mainly in inflammatory areas and was absent in the healthy peritoneum. IL-17A-expressing cells included lymphocytes (CD4+ and γδ), neutrophils, and mast cells. Elevated IL-17A effluent concentrations were found in long-term peritoneal dialysis patients. Studies in mice showed that repeated exposure to recombinant IL-17A caused peritoneal inflammation and fibrosis. Moreover, chronic exposure to dialysis fluids resulted in a peritoneal Th17 response, including elevated IL-17A gene and protein production, submesothelial cell infiltration of IL-17A-expressing cells, and upregulation of Th17 differentiation factors and cytokines. IL-17A neutralization diminished experimental peritoneal inflammation and fibrosis caused by chronic exposure to dialysis fluids in mice. Thus, IL-17A is a key player of peritoneum damage and it may be a good candidate for therapeutic intervention in peritoneal dialysis patients.

Effect of self-administered intraperitoneal bemiparin on peritoneal transport and ultrafiltration capacity in peritoneal dialysis patients with membrane dysfunction. A randomized, multi-centre open clinical trial.

BACKGROUND: Progressive peritoneal membrane injury and dysfunction are feared repercussions of peritoneal dialysis (PD), and may compromise the long-term feasibility of this therapy. Different strategies have been attempted to prevent or reverse this complication with limited success. METHODS: We performed a randomized, open multi-centre trial, aimed at scrutinizing the efficacy of self-administered intraperitoneal (i.p.) bemiparin (BM) to modulate peritoneal membrane dysfunction. The main outcome variables were peritoneal creatinine transport and the ultrafiltration (UF) capacity, estimated during consecutive peritoneal equilibration tests. The trial included a control group who did not undergo intervention. The treatment phase lasted 16 weeks with a post-study follow-up of 8 weeks. RESULTS: Intraperitoneal BM did not significantly improve creatinine transport or the UF capacity, when the whole group was considered. However, we observed a time-limited improvement in the UF capacity for the subgroup of patients with overt UF failure, which was not observed in the control group. Intraperitoneal injection of BM did not carry an increased risk of peritoneal infection or major haemorrhagic complications. CONCLUSIONS: Our data do not support the systematic use of BM for management of peritoneal membrane dysfunction in PD patients. Further studies on the usefulness of this approach in patients with overt UF failure are warranted. Intraperitoneal administration of BM is safe in PD patients, provided regulated procedures are respected.

CCN2 (Cellular Communication Network Factor 2) Deletion Alters Vascular Integrity and Function Predisposing to Aneurysm Formation.

BACKGROUND: CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood. METHODS: Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible <i>Ccn2</i>-deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta. RESULTS: Ang II infusion in CCN2-silenced mice lead to 60% mortality within 10 days due to rapid development and rupture of aortic aneurysms, as evidenced by magnetic resonance imaging, echography, and histological examination. <i>Ccn2</i> deletion decreased systolic blood pressure and caused aortic structural and functional changes, including elastin layer disruption, smooth muscle cell alterations, augmented distensibility, and increased metalloproteinase activity, which were aggravated by Ang II administration. Gene ontology analysis of RNA sequencing data identified aldosterone biosynthesis as one of the most enriched terms in CCN2-deficient aortas. Consistently, treatment with the mineralocorticoid receptor antagonist spironolactone before and during Ang II infusion reduced aneurysm formation and mortality, underscoring the importance of the aldosterone pathway in Ang II-induced aorta pathology. CONCLUSIONS: CCN2 is critically involved in the functional and structural homeostasis of the aorta and in maintenance of its integrity under Ang II-induced stress, at least, in part, by disruption of the aldosterone pathway. Thus, this study opens new avenues to future studies in disorders associated to vascular pathologies.

Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study.

BACKGROUND: Chronic kidney disease (CKD) is increasing in patients older than 65 years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. HYPOTHESIS: PD should be offered to patients over 65 years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. OBJECTIVE: To describe PD treatment and outcomes in patients > 65 years, to compare their results with patients < 65 years and to identify areas with room for improvement in a real-life study. STUDY: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. RESULTS: We included 2,435 PD patients, 31.9% were older than 65 years; there was a difference of 25 years between both groups. Median follow up was 2.1 years. Older than 65 years group had more comorbidity: Diabetes (29.5% vs 17.2%; p < 0.001), previous CV events 34.5% vs 14.0%; p < 0.001), Charlson index (3.8 vs 3.0; p < 0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65 years group (0.65 vs 0.45 episodes/patient/year; p < 0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65 years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1 years). The main cause of PD withdrawal was transplant in group < 65 years (48.3%) and transfer to HD in group > 65 years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). Multivariate Cox regression analysis showed a relation (HR [95%CI]) between mortality and age > 65 years 2.4 [1.9-3.0]; DM 1.6 [1.3-2.1]; CV events 2.1 [1.7-2.7]. Multivariate Cox regression analysis identify a relation between technique failure and age > 65 years 1.5 [1.3-1.9]; DM 1.6 [1.3-1.9] and previous transplant 1.5 [1.2-2.0]. CONCLUSION: Patients older than 65 years fulfilled PD adequacy criteria during the follow up. We believe PD is a valid option for patients older 65 years. It is necessary to try to prevent infections and patient/caregiver fatigue, to avoid HD transfer for reasons not related to technique failure.

The Effect of Nutritional Interventions on Long-Term Patient Survival in Advanced Chronic Kidney Disease.

Patients with end-stage kidney disease (ESKD) are at high risk of malnutrition and subsequent related mortality when starting dialysis. However, there have been few clinical studies on the effect of nutritional interventions on long-term patient survival. A 2-year longitudinal study was conducted from January 2012 to December 2016. A total of 186 patients with non-dialysis ESKD started the nutritional education program (NEP), and 169 completed it. A total of 128 patients participated in a NEP over 6 months (personalized diet, education and oral supplementation, if needed). The control group (n = 45) underwent no specific nutritional intervention. The hospitalization rate was significantly lower for the patients with NEP (13.7%) compared with the control patients (26.7%) (p = 0.004). The mortality odds ratio for the patients who did not receive NEP was 2.883 (95% CI 0.993-8.3365, p = 0.051). The multivariate analysis showed an independent association between mortality and age (OR, 1.103; 95% CI 1.041-1.169; p = 0.001) and between mortality and the female sex (OR, 3.332; 95% CI 1.054-10.535; p = 0.040) but not between mortality and those with NEP (p = 0.051). Individualized nutrition education has long-term positive effects on nutritional status, reduces hospital admissions and increases survival among patients with advanced CKD who are starting dialysis programs.

Cyclooxygenase-2 mediates dialysate-induced alterations of the peritoneal membrane.

During peritoneal dialysis (PD), exposure of the peritoneal membrane to nonphysiologic solutions causes inflammation, ultimately leading to altered structure and function. Myofibroblasts, one of the cell types that contribute to dysfunction of the peritoneal membrane, can originate from mesothelial cells (MCs) by epithelial-to-mesenchymal transition (EMT), a process that has been associated with an increased rate of peritoneal transport. Because cyclooxygenase-2 (COX-2) is induced by inflammation, we studied the role of COX-2 in the deterioration of the peritoneal membrane. We observed that nonepithelioid MCs found in peritoneal effluent expressed higher levels of COX-2 than epithelioid MCs. The mass transfer coefficient for creatinine correlated with MC phenotype and with COX-2 levels. Although COX-2 was upregulated during EMT of MCs in vitro, COX-2 inhibition did not prevent EMT. In a mouse model of PD, however, COX-2 inhibition with Celecoxib resulted in reduced fibrosis and in partial recovery of ultrafiltration, outcomes that were associated with a reduction of inflammatory cells. Furthermore, PD fluid with a low content of glucose degradation products did not induce EMT or COX-2; the peritoneal membranes of mice treated with this fluid showed less worsening than mice exposed to standard fluid. In conclusion, upregulation of COX-2 during EMT may mediate peritoneal inflammation, suggesting COX-2 inhibition as a potential strategy to ameliorate peritoneal deterioration in PD patients.

Previous comorbidity and lack of patient free choice of technique predict early mortality in peritoneal dialysis.

OBJECTIVE: To study the prognostic factors for mortality and hospital admission for patients on peritoneal dialysis (PD). METHOD: Biannual data on individual characteristics, clinical and analytical progress, treatment, and events were studied for a cohort of incident patients undergoing PD (2003-2006) in a reference area of 8.8 million people. RESULTS: 489 patients (age 53.58 years, 61.6% male) with 3-year follow-up were included. They presented at inclusion with Charlson Comorbidity Index (CCI) of 5.25; previous cardiovascular (CV) event, 23.7%; diabetes mellitus (DM), 19.1%; and hypertension (HT), 89.9%. Annual hospitalization rate per patient-year at risk was 0.6. The variables that predicted admission were CCI [odds ratio (OR) 1.14 per point], DM (OR 1.66), and previous CV event (OR 1.90). Anemia maintained significance when corrected for CCI: hemoglobin, 0.79 per 1 g/dL Hb; CCI, 1.15 per point. Annual mortality rate was 5.4%. Those that died were older (67.47 vs 52.78 years) and had a higher CCI (8.35 vs 5.0), a lower initial Hb (11.5 vs 12.2 g/dL), a higher hospital admission rate, a higher annual rate of peritonitis, more previous CV events (50.0% vs 22.1%), and higher prevalence of DM (38.5% vs 17.9%). Survival analysis identified the following prognostic factors: CCI [hazard ratio (HR) 1.51 per point], CV event (HR 2.85), DM (HR 2.52), age (HR 1.06 per year), and mandatory referral to PD (HR 6.54). The effect of CV events and DM persisted after correction for age, and that of choice of technique after correcting for CCI and/or age. CONCLUSIONS: The CCI is useful for risk estimation in PD patients. Previous CV event, DM, and age are the most relevant risk factors. Control of anemia has prognostic value for hospital admissions. Mandatory referral to PD is associated with higher mortality. The prognosis in PD depends on predialysis patient management.

Effects of cinacalcet on gastrointestinal hormone release in patients with secondary hyperparathyroidism undergoing dialysis.

UNLABELLED: Objective. Our aim has been evaluating the influence of an acute dose of cinacalcet on the gastrointestinal hormonal responses to a test meal in uraemic patients with secondary hyperparathyroidism undergoing peritoneal dialysis (PD) or haemodialysis (HD). METHODS: Twenty patients (11 PD, 9 HD) on cinacalcet treatment (30-120 mg/day) were studied. Twelve patients (1 PD, 11 HD) who never received cinacalcet were studied as control group. Each patient received a test meal with blood samples at 0, 2 and 4 h. At 0 time, patients in the cinacalcet group received their usual oral dose of this calcimimetic. Plasma concentrations of intact parathyroid hormone (PTH), vasoactive intestinal peptide (VIP), ghrelin, substance P, serotonin, cholecystokinin (CCK) and gastrin were quantified at 0, 2 and 4 h. RESULTS: No significant differences in baseline concentrations of serum VIP, ghrelin, substance P, serotonine, CCK and gastrin were found between controls and cinacalcet-treated patients. In comparison with the control group, cinacalcet administration was followed by a significant decrease in VIP concentration at 4 h and a significant increase in substance P at 4 h. However, the areas under the curves of all studied gut hormones were similar in both groups. CONCLUSION: An acute dose of cinacalcet exerts minimal influence on gut hormone responses to a mixed meal in dialysis patients on chronic therapy with this drug. The small but significant differences between control subjects and patients on cinacalcet in VIP and substance P levels at 4 h should be investigated in symptomatic patients.

Peritoneal dialysis in the comprehensive management of end-stage renal disease patients with liver cirrhosis and ascites: practical aspects and review of the literature.

The treatment of cirrhotic patients with ascites and end-stage renal disease is complex, due mainly to decreased effective arterial volume and hemodynamic instability. Peritoneal dialysis as a continuous therapy represents an alternative to hemodialysis-related intolerance. We report on our experience and that of others with cirrhotic patients with ascites treated by peritoneal dialysis. Hemodynamic tolerance was excellent in all patients and solute and water peritoneal transport increased to above the normal range in almost all cases. Morbidity and mortality were related principally to liver disease and other comorbidities. Peritoneal protein losses, initially high, decreased over time, maintaining serum albumin within the low normal range. The incidence of peritonitis was similar or slightly higher than usual in these patients, with peculiar etiology. The experiences with peritoneal dialysis suggest consideration of this treatment as the first choice for cirrhotic patients with ascites and that need to start dialysis.

Characterization of epithelial-to-mesenchymal transition of mesothelial cells in a mouse model of chronic peritoneal exposure to high glucose dialysate.

Animal models of peritoneal dialysis fluid (PDF) exposure are key tools in the study of mechanisms involved in alterations of the peritoneal membrane and in the design of therapies. We recently developed a mouse model of chronic peritoneal exposure to high glucose dialysate. Herein, we make a sequential analysis of the effects of glucose-based PDF on mouse peritoneal membrane and on mesothelium. We demonstrate that chronic exposure to PDF induces thickness and fibrosis of the peritoneal membrane in a time-dependent manner. We also show that mesothelial cells progressively detach and lose cytokeratin expression. In addition, we demonstrate that some mesothelial cells invade the submesothelial space, where they appear as cytokeratin- and alpha-smooth muscle actin-positive cells. These findings demonstrate that epithelial-to-mesenchymal transition (EMT) of mesothelial cells takes place in mouse peritoneum exposed to PDF, validating this model for the study of effects of drugs on the EMT process as a therapy for peritoneal deterioration.

Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. METHODS: Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. RESULTS: Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. CONCLUSIONS: Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.

Peritoneal Membrane Preservation.

Peritoneal dialysis (PD) is a successfully used method for renal replacement therapy. However, long-term PD may be associated with peritoneal fibrosis and ultrafiltration failure. The key factors linked to their appearance are repeated episodes of inflammation associated with peritonitis and long-term exposure to bioincompatible PD fluids. Different strategies have been proposed to preserve the peritoneal membrane. This article reviews the functional and structural alterations related to PD and strategies whereby we may prevent them to preserve the peritoneal membrane. The use of new, more biocompatible, PD solutions is promising, although further morphologic studies in patients using these solutions are needed. Blockade of the renin-angiotensin-aldosterone system appears to be efficacious and strongly should be considered. Other agents have been proven in experimental studies, but most of them have not yet been tested appropriately in human beings.

Ex vivo analysis of dialysis effluent-derived mesothelial cells as an approach to unveiling the mechanism of peritoneal membrane failure.

During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids, which causes progressive fibrosis and angiogenesis and, ultimately, ultrafiltration failure. In addition, repeated episodes of peritonitis or hemoperitoneum may accelerate all these processes. Fibrosis has been classically considered the main cause of peritoneal membrane functional decline. However, in parallel with fibrosis, the peritoneum also displays increases in capillary number (angiogenesis) and vasculopathy in response to PD. Nowadays, there is emerging evidence pointing to peritoneal microvasculature as the main factor responsible for increased solute transport and ultrafiltration failure. However, the pathophysiologic mechanism(s) involved in starting and maintaining peritoneal fibrosis and angiogenesis remain(s) elusive. Peritoneal stromal fibroblasts have been considered (for many years) the cell type mainly involved in structural and functional alterations of the peritoneum; whereas mesothelial cells have been considered mere victims of peritoneal injury caused by PD. Recently, ex vivo cultures of effluent-derived mesothelial cells, in conjunction with immunohistochemical analysis of peritoneal biopsies from PD patients, have identified mesothelial cells as culprits, at least in part, in peritoneal membrane deterioration. This review discusses recent findings that suggest new peritoneal myofibroblastic cells may arise from local conversion of mesothelial cells by epithelial-to-mesenchymal transition during the repair responses that take place in PD. The transdifferentiated mesothelial cells may retain a permanent mesenchymal state, as long as initiating stimuli persist, and contribute to PD-induced fibrosis and angiogenesis, and hence to membrane failure. Future therapeutic interventions could be designated in order to prevent or reverse epithelial-to-mesenchymal transition of mesothelial cells, or its pernicious effects.

Serum albumin levels, an additional factor implicated in hyperparathyroidism outcome in peritoneal dialysis: a prospective study with paired bone biopsies.

Renal osteodystrophy encompasses several histologic subtypes, all of which can undergo change over time. In peritoneal dialysis (PD) patients, we studied bone histology and the factors influencing any changes over 1 year In 44 PD patients, we collected two paired bone biopsies (at baseline and after 12 months) and biochemical and treatment data (at baseline and every 3 months). Of the 44 original patients, 24 completed the study. Of these 24 patients, 19 were initially diagnosed with adynamic bone lesion (ABL). After 1 year, 12 still had ABL; the other 7 had changed to high turnover bone lesion (HTBL). Another 5 patients were initially diagnosed with HTBL. Among these, 4 still had HTBL at 1 year; 1 had changed to ABL. In patients who changed to HTBL from ABL, serum albumin had increased to 4.2 +/- 0.3 g/dL at month 12 from 3.7 +/- 0.4 g/dL at baseline (p < 0.05). In patients who still had ABL, serum albumin did not change. Additionally, the percentage increase in serum albumin over the study was higher in HTBL patients than in ABL patients (0.1408 +/- 0.139 g/dL vs. -0.0076 +/- 0.113 g/dL, p = 0.009). A lower likelihood of diabetes (p = 0.033) and a higher serum albumin [area under the curve: 0.822; 95% confidence interval (CI): 0.651 to 0.993] identified a HTBL diagnosis at 12 months. Older age increased the probability of changing to ABL (OR: 1.2935; 95% CI: 1.03 to 1.67; p= 0.02). Bone lesions can change over time, and this change is associated with age, diabetes, and serum albumin. A change to HTBL was associated with improvement in serum albumin. Protein status is possibly a factor influencing bone lesion outcome.

Fibroblast Growth Factor 21 (FGF-21) in Peritoneal Dialysis Patients: Natural History and Metabolic Implications.

BACKGROUND: Human fibroblast growth factor 21 (FGF-21) is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD) patients suffer potential interference with FGF-21 status with as yet unknown repercussions. OBJECTIVES: The aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time. METHODS: We studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy. RESULTS: Plasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685) at baseline; 582 pg/ml (60.5-949) at first year and 647 pg/ml (120.5-1116.6) at third year) (p<0.01). We found a positive correlation between time on dialysis and FGF-21 levels (p<0.001), and also, those patients with residual renal function (RRF) had significantly lower levels of FGF-21 than those without RRF (ρ -0.484, p<0.05). Lastly, there was also a significant association between FGF-21 levels and peritoneal protein losses (PPL), independent of the time on dialysis (ρ 0.410, p<0.05). CONCLUSION: Our study shows that FGF-21 plasma levels in incident PD patients significantly increase during the first 3 years. This increment is dependent on or is associated with RRF and PPL (higher levels in patients with lower RRF and higher PPL). FGF-21 might be an important endocrine agent in PD patients and could act as hormonal signaling to maintain glucose homeostasis and prevent potential insulin resistance. These preliminary results suggest that FGF-21 might play a protective role as against the development of insulin resistance over time in patients undergoing a continuous glucose load.

Mesenchymal conversion of mesothelial cells as a mechanism responsible for high solute transport rate in peritoneal dialysis: role of vascular endothelial growth factor.

BACKGROUND: During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids that cause epithelial-to-mesenchymal transition of mesothelial cells, fibrosis, and angiogenesis. Ultrafiltration failure is associated with high transport rates and increased vascular surface, indicating the implication of vascular endothelial growth factor (VEGF). Sources of VEGF in vivo in PD patients remain unclear. We analyzed the correlation between epithelial-to-mesenchymal transition of mesothelial cells and both VEGF level and peritoneal functional decline. METHODS: Effluent mesothelial cells were isolated from 37 PD patients and analyzed for mesenchymal conversion. Mass transfer coefficient for creatinine (Cr-MTC) was used to evaluate peritoneal function. VEGF concentration was measured by using standard procedures. Peritoneal biopsy specimens from 12 PD patients and 6 controls were analyzed immunohistochemically for VEGF and cytokeratin expression. RESULTS: Nonepithelioid mesothelial cells from effluent produced a greater amount of VEGF ex vivo than epithelial-like mesothelial cells (P < 0.001). Patients whose drainage contained nonepithelioid mesothelial cells had greater serum VEGF levels than those with epithelial-like mesothelial cells in their effluent (P < 0.01). VEGF production ex vivo by effluent mesothelial cells correlated with serum VEGF level (r = 0.6; P < 0.01). In addition, Cr-MTC correlated with VEGF levels in culture (r = 0.8; P < 0.001) and serum (r = 0.35; P < 0.05). Cr-MTC also was associated with mesothelial cell phenotype. VEGF expression in stromal cells, retaining mesothelial markers, was observed in peritoneal biopsy specimens from high-transporter patients. CONCLUSION: These results suggest that mesothelial cells that have undergone epithelial-to-mesenchymal transition are the main source of VEGF in PD patients and therefore may be responsible for a high peritoneal transport rate.

Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products.

Peritoneal dialysis (PD) is a well-established therapy for end-stage renal failure, but its efficiency is limited by recurrent peritonitis. As PD solutions impair local inflammatory responses within the peritoneal cavity, we have analyzed their influence on the in vitro maturation of human monocyte-derived dendritic cells (MDDC). Evaluation of MDDC maturation parameters [expression of adhesion and costimulatory molecules, receptor-mediated endocytosis, allogeneic T cell activation, production of tumor necrosis factor alpha, interleukin (IL)-6 and IL-12 p70, and nuclear factor (NF)-kappaB activation] revealed that currently used PD solutions differentially inhibit the lipopolysaccharide (LPS)-induced maturation of MDDC, an inhibition that correlated with their ability to impair the LPS-stimulated NF-kappaB activation. Evaluation of PD components revealed that sodium lactate and glucose-degradation products impaired the acquisition of maturation parameters and NF-kappaB activation in a dose-dependent manner. Moreover, PD solutions impaired monocyte-MDDC differentiation, inhibiting the acquisition of DC markers such as CD1a and DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (CD209). These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation.

Ultrafiltration and small solute transport at initiation of PD: questioning the paradigm of peritoneal function.

BACKGROUND: Human peritoneal function on commencing peritoneal dialysis (PD) is not yet adequately understood. The objective of this study was to determine peritoneal functional patterns on commencing PD. METHODS: 367 end-stage renal disease (ESRD) patients on PD for the first time were studied between their initial second to sixth weeks on PD. Urea and creatinine mass transfer area coefficients (MTAC) and standardized ultrafiltration (UF) capacity were determined. RESULTS: Mean parametric values were MTAC urea 22.9 +/- 7.04 mL/min, MTAC creatinine 10.31 +/- 4.68 mL/min, and UF 896 +/- 344 mL. Gender, patient size, and diabetes or kidney disease did not affect these parameters. The relationship between values of MTAC creatinine and UF reached statistical significance, although with a low value for Pearson's coefficient (r = -0.30, p = 0.001). Age showed a significant inverse linear correlation with UF capacity (r = -0.15, p = 0.003) and MTAC urea (r = -0.11, p < 0.05). Logistic regression analysis demonstrated that UF below 400 mL was independently related to a high MTAC creatinine and older age. Diabetes was least frequent in patients with the lowest UF. However, in the analysis of MTAC creatinine quintiles, UF values did not follow the expected inverse pattern. The lack of differences in UF between the second and third to fourth MTAC creatinine quintiles is remarkable; MTAC creatinine ranged from 6.71 to 13.54. CONCLUSIONS: The functional characteristics of human peritoneum varied markedly and there was a less intense than expected relationship between solute and water transports. This mild inverse relationship is intriguing and suggestive of the necessity of redefining some basic concepts. Age was associated with a lower peritoneal UF capacity, in part independently of small solute transport.