Is oxidative stress an issue in peritoneal dialysis?

During the last two decades, oxidative stress (OS) has emerged as a novel risk factor for a variety of adverse events, including atherosclerosis and mortality in chronic kidney disease (CKD) patients. Increased OS occurs even in early stages of the disease, progresses with deterioration of renal function and is further aggravated by hemodialysis (HD), due to the bioincompatibility of the method. Compared to HD, peritoneal dialysis (PD) is a more biocompatible dialysis modality, characterized by a significantly reduced, but still high, OS status. The culprit for OS in PD is mainly the composition of PD solutions (low pH, lactate buffer, increased osmolarity and high glucose concentration). After heat sterilization of PD solutions, formation of glucose degradation products (GDPs) and advanced glycation end‐products (AGEs) trigger inflammation and enhance OS. Chronic exposure of the peritoneum to this toxic, hyperglycemic environment leads to OS‐derived morphologic damage of peritoneal cells, loss of ultrafiltration capacity and decreased technique survival. Moreover, OS is linked with peritonitis, loss of residual renal function, inflammation, atherosclerosis, cardiovascular (CV) disease, and increased mortality. To ameliorate OS status in PD, a multitargeted approach is necessary that includes use of neutral pH, low GDP, low lactate and iso‐ismolar PD solutions, strict glycemic control, optimal volume management and, probably supplementation with antioxidants, N‐acetylcysteine being the most promising among them.     

Effects of atorvastatin on development of peritoneal fibrosis in rats on peritoneal dialysis

Rational: Peritoneal sclerosis is one of the important complications of long-term peritoneal dialysis (PD). In this study, efficacy of atorvastatin on peritoneal histology and functions in non-uremic rats on PD was tested. Objectives: Twenty-two non-uremic Wistar albino rats were randomized into three groups: Sham (intraperitoneal saline), peritoneal dialysis (PD, intraperitoneal 3.86% dextrose containing PD solution), and treatment (TX, intraperitoneal 3.86% dextrose containing PD solution plus atorvastatin added into drinking water). At the end of a 4-week period, 1 h peritoneal equilibration test was performed. Serum lipids and certain cytokines, mediators, markers, and antioxidant enzyme activities in serum and dialysate were studied. Peritoneal thickness was measured and peritoneal inflammation, fibrosis, and vascular proliferation were scored in histological sections. Main findings: In histological examinations, inflammation, fibrosis, and vascular proliferation were significantly more frequent in PD group than Sham group and it seemed to decrease significantly when atorvastatin was used in conjunction with PD. Additionally, peritoneum was significantly thicker in PD group when compared to that of Sham and TX groups. Serum parameters did not significantly differ between groups. On the other hand, dialysate glutathione reductase (GR) activity and TGF-β were significantly lower in TX group than that of the PD group, whereas dialysate IL-6 level was higher in TX group. Principal conclusions: In our study, atorvastatin use appeared to diminish structural changes in peritoneum. Decreased expression of TGF-β in dialysate may be one of the possible underlying mechanisms.     

Glycosaminoglycans and the peritoneaum

SUMMARY: The introduction of peritoneal dialysis (PD) over two decades ago has allowed us to manipulate the peritoneal membrane to perform as a continuous dialysing organ. to maximize the efficacy of solute transport and waste removal, conventional PD fluids require unphysiological concentrations of glucose to provide the osmotic drive, lactate to alleviate metabolic acidosis, and a low pH to prevent the caramelization of glucose during the preparation of the solutions. These factors either alone or in combination, are irritants to the peritoneal membrane. Thus, continuous exposure of the peritoneum to PD solutions, together with frequent episodes of peritonitis confers a chronic inflammatory response within the peritoneum. It is, therefore, not unexpected that with time, long-term PD patients develop structural and functional changes within the peritoneum, which in many cases develop into peritoneal fibrosis of varying degrees and compromises the peritoneal membrane as a dialysing organ. to date, numerous studies have investigated methods to improve the efficiency of PD and preserve the structure of the peritoneal membrane. Recently, a number of reports have documented the beneficial effects of intraperitoneal administration of glycosaminoglycans (GAGs) on both the structural and functional qualities of the peritoneum. In this context, GAGs have been demonstrated to inhibit collagen synthesis within the peritoneum, decrease peritoneal advanced glycosylated end-products (AGE) deposition, and modulate cytokine and growth factor synthesis. This review will examine the available data with regards to the potential role of GAGs in maintaining ultrafiltration, solute transport and the structural integrity of the peritoneum.     

Effect of peritoneal dialysis on expression of vascular endothelial growth factor, basic fibroblast growth factor and endostatin of the peritoneum in peritoneal dialysis patients

Aim: The aim of this study is to investigate the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin (ES) in human peritoneum and investigate the relationship between them and peritoneum neoangiogensis in the patients with uraemia and peritoneal dialysis (PD). Methods: Peritoneal biopsies were obtained from normal subjects (n = 8), uraemic predialysis patients (n = 12) and PD patients (n = 10). The mRNA expression of VEGF, bFGF and ES in peritoneal tissues were measured through real‐time polymerase chain reaction. The protein expression of VEGF, bFGF and ES in peritoneal tissues were determined through western blot. Microvessel density (MVD) of peritoneal tissue was assessed using immunohistochemistry with CD34 monoclonal antibody. Results: The mRNA and protein of VEGF, bFGF and ES were expressed in all peritoneal samples. Compared with the normal control group, the mRNA and protein expression of VEGF and bFGF in peritoneal tissues were all significantly upregulated in the uraemic predialysis and PD group (all P < 0.05). Compared with the normal control group, the protein expression of ES were significantly upregulated in the uraemic predialysis and PD group (all (P < 0.05), but the mRNA expression of ES did not have obvious differences in the uraemic predialysis and PD group as compared to the normal control group (P > 0.05). MVD of peritoneal tissue were increased in the uraemic predialysis and PD group compared with the normal group (all P < 0.05). A significant positive correlation was found between VEGF mRNA expression and MVD, bFGF mRNA expression and MVD. Conclusion: The mRNA expression of VEGF and bFGF, the protein expression of VEGF, bFGF, and ES and microvessel density (MVD) are increased both in the uraemic predialysis and PD patients. These results show that uraemia circumstances and non‐physiological compatibility of peritoneal dialysis solution might increase VEGF, bFGF and ES expression and MVD, which might participate in the increment of the peritoneum neoangiogensis and ultrafiltration failure in PD patients.     

Peritoneal thickening is not inevitable in long-term peritoneal dialysis and is associated with peritoneal transport characteristics: a two-centre sonographic study.

BACKGROUND: The peritoneum is subject to alterations in the life-long course of peritoneal dialysis (PD). Studies of the parietal peritoneum by non-invasive ultrasonography in PD patients are limited. We hypothesize that a prolonged PD duration is associated with a thicker peritoneum on ultrasonography and alterations in Doppler indexes of mesenteric vessels. METHODS: We recruited two groups of patients, 18 who had >7 years of PD and 18 who had <12 months of PD. We excluded patients with active peritonitis, history of major abdominal surgery, cirrhosis or malignancy. We measured the sonographic thickness of the parietal peritoneum and Doppler indexes of mesenteric vessels by trans-abdominal ultrasonography at two PD units in Taiwan. RESULTS: We found no significant difference between two groups of PD patients in peritoneal thickness and in Doppler indexes. However, our univariate and multivariate analysis indicated that peritoneal thickness is associated with peritoneal transport characteristics (dialysate/plasma creatinine) but not with age, duration of dialysis, body height, body weight or Doppler index. The peritoneum is significantly thicker in rapid transporters than in slow transporters (RUQ: 0.59 +/- 0.40 mm versus 0.27 +/- 0.29 mm, P = 0.01; LUQ: 0.60 +/- 0.40 mm versus 0.27 +/- 0.32 mm, P = 0.016; LQ: 1.07 +/- 0.85 mm versus 0.48 +/- 0.53 mm, P = 0.026). In addition, rapid transporters have a marginally lower Doppler resistive index of the superior mesenteric artery (0.87 +/- 0.08 versus 0.90 +/- 0.10, P = 0.028). CONCLUSIONS: Our data showed that peritoneal thickening is not inevitable in long-term PD patients. Sonographic thickness in the parietal peritoneum is associated with transport characteristics. Rapid transporters have a significantly thicker peritoneum. The Doppler index of mesenteric vessels had no association with PD duration or transport characteristics. Trans-abdominal ultrasonography is non-invasive and useful in evaluating peritoneal characteristics of PD patients.     

Effect of Intravenous Iron Sucrose on Oxidative Stress in Peritoneal Dialysis Patients

Aim. Intravenous iron therapy is an accepted treatment for patients receiving hemodialysis and continuous ambulatory peritoneal dialysis (CAPD). Studies have found enhanced oxidative stress in hemodialysis patients receiving intravenous iron, but there are no clinical data for CAPD patients. The aim of the current study was to investigate the effect of 100 mg of intravenous iron-sucrose on the erythrocyte (RBC) antioxidant enzymes (namely, superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GSHPx]) and plasma malondialdehyde (MDA), an oxidant molecule, in CAPD patients. Methods. Twelve CAPD patients receiving maintenance intravenous iron-sucrose were recruited. After a 12-hour fast, blood samples were taken for hemoglobin, iron, ferritin, and high-sensitivity C-reactive protein (hsCRP), and for baseline activities of erythrocyte antioxidant enzymes (i.e., SOD, CAT, GSHPx) and the plasma oxidant molecule, MDA. 100 mg iron-sucrose was infused over 30 minutes. Blood samples taken during (i.e., 15 minutes after commencement of infusion) and after (i.e., at 30 minutes, 60 minutes, and 6 hours after commencement) the infusion were taken for measurement of plasma iron, ferritin, TSAT, RBC SOD, CAT, GSHPx, and plasma MDA. Results. Plasma iron and transferrin saturation elevated significantly during infusion (p < 0.05). There was no significant change in erythrocyte SOD, CAT, GSHPx, or in MDA activities. There was a reduction of GSHPx activity at the 30th minute (from 153.69 ± 66.69 to 123.68 ± 25.50 mU/mL), but it was not statistically significant. The patients were grouped according to baseline ferritin (100–400 and 400–800 ng/mL); 60th-minute MDA was significantly higher in the latter group (p < 0.05). There was no correlation between hsCRP and oxidant-antioxidant balance. No correlation was noted between RBC antioxidant enzymes or plasma oxidant molecule and ferritin levels. Conclusion. There are no acute deteriorating effects from a 100 mg of intravenous iron-sucrose in CAPD patients with optimal iron stores. This dose may be applied safely in CAPD patients.     

Peritoneal mesothelial cell biology in peritoneal dialysis

SUMMARY: Progressive peritoneal membrane hyperpermeability, ultrafiltration failure, and peritoneal fibrosis have been observed in long-term peritoneal dialysis (PD) patients, and these alterations in peritoneal structure and function may be responsible for the poor technique survival in PD. While frequent and/or severe peritonitis can result in alterations of the peritoneum, continuous exposure of the peritoneum to PD solutions may also adversely affect peritoneal structure and function. Peritoneal mesothelial cells (PMC) are directly and continuously exposed to unphysiological components of PD solution. Low pH, lactate, hyperosmolality, and glucose degradation products (GDP) reduce PMC viability and proliferation. High glucose, GDP, and advanced glycation end products (AGE) upregulate vascular endothelial growth factor (VEGF), monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and extracellular matrix protein expression by PMC, and may thus lead to peritoneal hyperpermeability, ultrafiltration failure, and peritoneal fibrosis, as observed in long-term PD. Activation of diacylglycerol (DAG)-protein kinase C (PKC) and generation of reactive oxygen species (ROS) are important upstream signalling events in high glucose-induced PMC activation. Thus, strategies to inhibit high glucose-induced PKC activation and ROS generation and the use of new PD solutions with non-glucose osmotic agents, pH neutral solutions, or solutions containing low GDP may allow better preservation of the structural and functional integrity of the peritoneal membrane during long-term PD.     

High mobility group box 1 and tumor growth factor β: useful biomarkers in pediatric patients receiving peritoneal dialysis

Background: Peritonitis, the most important limitation of peritoneal dialysis (PD), could be detected by biomarkers in dialysate effluent, representing a noninvasive method to indirectly assess the peritoneum status. The aim of our study was to test high mobility group box 1 (HMGB1) in PD patients, evaluating its role as precocious marker of peritoneum damage during peritonitis. Transforming growth factor (TGF)-β was correlated with peritoneal transport characteristics.

Methods: Six patients, treated by ambulatory PD, were enrolled. Samples were collected at the onset of peritonitis (T1) and every day until its resolution (T-end). Serum (s) and peritoneal (p) white blood cell (WBC) count was also evaluated. Peritoneal Equilibration Test evaluated the filter activity of peritoneum.

Results: In patients with acute peritonitis, the highest serum and peritoneal HMGB1 values (64?±?3.6 and 70?±?5.3?ng/mL, respectively) were assessed, with a progressive decrease of their levels at the resolution time (T-end: sHMGB1:36?±?2.5; pHMGB1:30.5?±?7.0?ng/mL). While no differences of sWBC and pWBC were observed between baseline and T-end values, pHMGB1 levels remained higher at T-end than those observed at T0 (pHMGB1:30.5?±?7.0 versus 6.9?±?3.6; p?p?=?0.01). An inverse correlation was found between TGF-β levels and dialysate/plasmatic creatinine values (r = ?0.83; p?=?0.03).

Conclusion: HMGB1 represents a useful biomarker for peritoneum evaluation in PD patients. A prognostic role of this alarmin, as a marker of response to therapy, could be hypothesized. TGF-β could predict the peritoneal transport status and dialysis technique adequacy.     

Contribution of lactate buffer, glucose and glucose degradation products to peritoneal injury in vivo.

BACKGROUND: Long-term peritoneal dialysis (PD) is associated with the development of functional and structural alterations of the peritoneal membrane. In this study, we investigated the contribution of low pH lactate buffer, high glucose concentration and glucose degradation products to peritoneal injury in a rat peritoneal exposure model. METHODS: Rats received daily 10 ml of either heat-sterilized (3.86% glucose, pH 5.2, n = 8) or filter-sterilized PD fluid (3.86% glucose, pH 5.2, n = 8), or lactate buffer (pH 5.2, n = 8) via a mini vascular access port during a 10 week period. Untreated rats served as controls. RESULTS: The low pH lactate buffer instillation induced pronounced morphological changes including the induction of angiogenesis in various peritoneal tissues and mild damage to the mesothelial cell layer covering the peritoneum. It also evoked a cellular response characterized by an increased mesothelial cell density on the liver, the induction of milky spots and accumulation of omental mast cells in the omentum, and significant changes in the composition of peritoneal leukocytes. The addition of glucose to low pH lactate buffer (filter-sterilized PD fluid) strengthened most, but not all of the responses described above and induced a fibrogenic response. In addition to glucose and low pH lactate buffer, the presence of glucose degradation products (heat-sterilized PD fluid) significantly induced an additional omental milky spot response (P < 0.03) and caused profound mesothelial damage. The vessel density in the omentum and the mesentery was significantly correlated to both the number of tissue mast cells and the hyaluronan content in the peritoneal lavage, which might suggest a role for mast cells and hyaluronan in the induction of angiogenesis. CONCLUSIONS: Instillations of low pH lactate buffer, a high glucose concentration and glucose degradation products contribute differently and often cumulatively to peritoneal injury in vivo.     

Inhibition of Rho-kinase alleviates peritoneal fibrosis and angiogenesis in a rat model of peritoneal dialysis

Abstract

Background/Aims: The present study investigated whether Rho-kinase inhibition had a therapeutic role on the pathogenesis of peritoneal fibrosis and angiogenesis. Methods: A rat model of peritoneal dialysis was induced by a daily intraperitoneal infusion of 4.25% Dianeal. Those rats were treated with Rho-kinase inhibitor, fasudil. Immunofluorescence, Western blot and RT-PCR were used to detect the expression of TGF-β1, Collagen I, αSMA and VEGF in each group. Microvessel density (MVD) was measured by immunohistochemistry. Rho-kinase activity was determined by western immunoblotting. Results: Rho-kinase was activated in the peritoneum of the PD group, which was inhibited by fasudil. Compared with PD group, the mRNA and protein expressions of TGF-β1, αSMA and Collagen I were significantly downregulated in fasudil treatment groups in a dose-dependent manner, and the expression of VEGF and peritoneal MVD was also significantly downregulated in fasudil treatment groups in a dose-dependent manner. Conclusion: The Rho-kinase was activated in the peritoneum of the peritoneal dialysis rats, and the inhibition of Rho-kinase by fasudil can remarkably decrease peritoneal fibrosis and angiogenesis.     

Peritoneal dialysis fluid-induced changes of the peritoneal membrane are reversible after peritoneal rest in rats.

BACKGROUND: Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane. However, the (ir)reversibility of these pathological changes of the peritoneum is not understood fully. METHODS: In an experimental PD model, rats (n = 15) received daily 10 ml conventional glucose containing PD fluid, via peritoneal catheters connected to implanted subcutaneous mini vascular access ports. After 5 weeks of treatment, the first group of animals (PDF; n = 10) was sacrificed, while peritoneal catheters of the remaining group of rats (PD-rest; n = 5) were removed 1 week later. The latter group (PD-rest) was sacrificed 12 weeks after removing catheters. At both time points, untreated rats were included as controls. Cellular and morphological parameters were analysed by light and electron microscopy. RESULTS: Rats exposed to PD fluid for 5 weeks showed a severe angiogenesis in various peritoneal tissues. Peritoneal rest resulted in a significant reduction in blood vessel density in visceral (mesentery, P<0.05), but not in parietal peritoneum. Five weeks' exposure to PD fluid resulted in a profound fibrosis in the parietal peritoneum, whereas the degree of fibrosis was significantly reduced in the PD-rest group (P<0.02). Daily exposure to PD fluid induced a higher number of mast cells in the omentum compared with untreated rats, whereas peritoneal rest normalized the increased mast cell density completely (P<0.03). Likewise, continued PD fluid instillation evoked a strong omental milky spot response, which was returned to the control level after peritoneal rest (P<0.009). Furthermore, the number of mesothelial cells on the liver was significantly increased in rats treated with PD fluid, whereas animals from the PD-rest group had a lower number of mesothelial cells, although this was not statistically significant (P = 0.08). Finally, as evidenced by electron microscopy, daily exposure to PD fluid resulted in severe damage to the mesothelial cell layer covering the peritoneum, whereas this cell layer was completely recovered after peritoneal rest. CONCLUSIONS: We show that PD fluid-induced cellular and morphological alterations of the peritoneal membrane are generally reversible.     

The importance of ultrasonographic measurement of peritoneal wall thickness in pediatric chronic peritoneal dialysis patients

Abstract

Loss of peritoneal function due to peritoneal fibrosing syndrome (PFS) is a major factor leading to treatment failure in chronic peritoneal dialysis (PD) patients. Although the precise biologic mechanisms responsible for these changes have not been defined, the general assumption is that alterations in peritoneal function are related to structural changes in the peritoneal membrane. Studies of the peritoneal membrane by non-invasive ultrasonography (US) in chronic PD patients are limited. The aim of the present study is to assess the relationship between functional parameters of peritoneum and peritoneal thickness measured by US in children treated by chronic PD. We recruited two groups of patients: 23 subjects (13 females, 10 males) on chronic PD (patient group) and 26 (7 females, 19 males) on predialysis out-patient follow-up (creatinine clearance: 20–60?mL/min/1.73?m²) (control group). Age, sex, weight, height, body mass index (BMI), chronic PD duration, episodes of peritonitis and the results of peritoneal equilibration test (PET) were recorded. Hemoglobin (Hb), blood pressure (BP), left ventricular mass index (LVMI) and renal osteodystrophy (ROD) parameters were also obtained. The thickness of the parietal peritoneum was measured by trans-abdominal US in all children. Statistical analyses were performed by using Student's t and Pearson's correlation tests. Mean peritoneal thickness in chronic PD patients (1028.26?±?157.26?μm) was significantly higher than control patients (786.52?±?132.33). Mean peritoneal thickness was significantly correlated with mean body height (R²?=?0.93, p?<?0.05), BMI (R²?=?0.25, p?<?0.05), chronic PD duration (R²?=?0.64, p?<?0.05), episodes of peritonitis (R²?=?0.93, p?<?0.05), D/P_creatinine (R²?=?0.76, p?<?0.05) and D4/D0_glucose (R²?=?0.81, p?<?0.05). No correlation was found between peritoneal thickness and Hb, BP, LVMI and ROD parameters. In conclusion, ultrasonographic measurement of peritoneal membrane thickness is a simple and non-invasive method in chronic PD children. This diagnostic tool likely enables to assess peritoneal structure and function in these patients.     

Multicenter laparoscopic evaluation of the peritoneum in peritoneal dialysis patients

Laparoscopic findings have been used to confirm peritoneal degenerations in peritoneal dialysis (PD) therapy. This study evaluated morphological changes in the peritoneum and their clinical relevance in patients undergoing PD. Laparoscopic findings at the rectovesical peritoneum were evaluated and scored using an imaging system at the time of PD catheter removal in this multicenter study. Angiogenesis evaluated by the vascular score (VS), color changes score (CCS), plaque score (PS), PD duration, history of peritonitis, dialysate/plasma creatinine (D/P Cr) levels, and age at PD termination were statistically analyzed. The VS of patients with PD duration more than 96 months was significantly decreased compared with that of the other patients and was negatively correlated with D/P Cr levels at PD termination. The CCS for patients with PD duration more than 96 months were significantly higher than those for the other patients and positively correlated with D/P Cr levels at PD termination. The PS of patients with recurring peritonitis were significantly higher than those of the other patients. Diminished vascularity and increased color changes in the peritoneum may be predictive of D/P Cr levels with peritoneal degradation. Laparoscopic evaluation of the abdominal cavity can provide detailed information about peritoneal injury.     

Peritoneal dialysis in children under two years of age

Background. Although results of peritoneal dialysis (PD) insmall children have improved during recent years, the youngestchildren have poorer growth, more infections and higher mortalitythan do older children. Methods. In this retrospective study, we analysed patient recordsof all children under age 2 treated with continuous peritonealdialysis (CPD) between 1995 and 2000 in Finland. Diagnoses leadingto renal failure in these 23 children were congenital nephroticsyndrome of the Finnish type (13), polycystic kidney disease(4), a urethral valve (3), renal insufficiency due to neonatalasphyxia (2) and Prune-Belly syndrome (1). Of these 23, 17 (74%)were anuric. Results. The mean age at the onset of PD was 0.4 years and themean time on dialysis 1.4 years. Hernias were diagnosed in 57%.The peritonitis rate was 1:14.5 patient-months, and 30% wereperitonitis-free. Hypertension was common, and 70% had at leastone period on antihypertensive medication. None of the patientshad pulmonary oedema or dialysis-related seizures. The meanheight standard deviation score (hSDS) at the start of PD (n= 16) was –2.0 and after 9 months –1.6. Catch-upgrowth was documented in 64% of the patients during dialysis.Hospitalization time was 124 days/patient-year. Two patients(9%) died. Conclusions. Our results are reassuring. Mortality was low,laboratory parameters were acceptable and growth was good. Peritonitisrate was comparable to that in older children. Correction ofinguinal hernia should be routinely performed; high blood pressureis still a problem.     

The potential of matrix metalloproteinase-2 as a marker of peritoneal injury, increased solute transport, or progression to encapsulating peritoneal sclerosis during peritoneal dialysis--a multicentre study in Japan.

BACKGROUND: Long-term peritoneal dialysis (PD) leads to peritoneal injury. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. The mortality rate of EPS is extremely high. To perform PD safely, monitoring of peritoneal injury that leads to EPS is a necessity. METHODS: A total of 444 PD patients with end-stage renal disease at 60 centres in Japan were analysed (sex, 54% males; median age, 56 years; median PD duration, 55 months). Matrix metalloproteinase (MMP)-2 and MMP-9 in the peritoneal effluents were analysed with gelatin zymography or enzyme-linked immunosorbent assay. Cells expressing MMP-2 in the peritoneal tissue were investigated immunohistologically with anti-MMP-2 antibodies. Peritoneal solute transport was assessed with the peritoneal equilibration test (PET). RESULTS: The MMP-2 levels in peritoneal effluents obtained with the PET were significantly correlated with the D/P Cr ratio (R = 0.69, P < 0.001) and the D/D0 glucose ratio (R = -0.59, P < 0.001). The MMP-2 levels in patients with mild peritoneal injury, moderate peritoneal injury, severe peritoneal injury (EPS) and infectious peritonitis were significantly higher than those in control patients (P < 0.001, P < 0.001, P < 0.01 and P < 0.05, respectively). MMP-2 was produced by myofibroblast-like mesenchymal cells and macrophages in the peritoneum. The peritoneal effluents from patients with infectious peritonitis showed strong MMP-9 signals. CONCLUSIONS: From these results, MMP-2 levels in peritoneal effluents reflect peritoneal solute transport and changes in MMP-2 levels are associated with peritoneal injury that leads to EPS. MMP-2 may be a useful marker of peritoneal injury, increased solute transport or progression to EPS.     

Citrate supplementation of PD fluid: effects on net ultrafiltration and clearance of small solutes in single dwells

Background. Inflammatory reactions affect the general performanceas well as the technique survival of peritoneal dialysis (PD).Anti-inflammatory additives like heparin and sodium citratehave shown favourable results in these respects. The presentstudy is the first to evaluate citrate-supplemented PD fluids(PDFs) in humans. Methods. Crossover design was used to evaluate sodium citrateand heparin-supplemented Gambrosol Trio® (2.5% glucose)in 28 stable outpatients from the PD unit. Comparisons weremade between single dwells of each fluid. Citrate supplementationat 5 mM/L was compared with standard PDF, and citrate supplementationat 10 mM/L was compared with low-molecular-weight heparin (4500units of tinzaparin) supplementation and standard PDF. The initialosmolarity of the fluids was equalized by adding sodium chloride. Results. Citrate supplementation at 5 mM/L significantly increasednet ultrafiltration, measured as drained volume gain, by 126mL. Creatinine and phosphate clearance, but not glucose clearance,was significantly improved by supplementation with citrate orheparin. Heparin supplementation created an insignificant trendtowards an increased ultrafiltration (P = 0.08). No negativeside effects were reported for any of the treatments; however,citrate supplementation led to a small calcium loss by the drainedPD fluid (0.4 mmol) and a transient fall in the plasma concentration(0.04 mM/L) of free calcium ions at 5 mM/L citrate. Effectson plasma bicarbonate concentration were insignificant. Conclusions. Citrate supplementation of PD fluid improved ultrafiltrationand clearance of small solutes with only minor effects on calciumturnover. The mechanism is unknown and, according to the results,not related to complement inhibition.     

Role of mitochondrial respiratory chain complex III in high glucose peritoneal dialysate-induced hyperpermeability of HPMCs

Background: High-glucose-based peritoneal dialysis solution (PDS) is considered to be one of the primary causes for the increase of ionic permeability in peritoneum as detected by transmesothelial electrical resistance (TER) measurements and claudin-1 expression. However, the mechanism is not clear. The aim of this study is to test the hypothesis that high-glucose PDS induces hyperpermeability in human peritoneal mesothelial cell (HPMC) monolayer by mitochondrial respiratory chain complex III pathway. Methods: HPMCs were cultured in a 1 : 1 mix of Dulbecco's modified Eagle's medium (DMEM) and PDS containing 1.5% and 4.25% glucose for 24 h. A 1 : 1 mixture of 160 mg/L glutathione and 4.25% glucose PDS was also added as an antioxidant group. TER measurement and immunostaining and western blot analysis of claudin-1 expression were examined for detection of permeability damage in HPMCs. MitoSOX? Red staining and respiratory chain complexes' activities were determined for detection of mitochondrial reactive oxygen species (ROS) production and mitochondrial complexes' activities. Results: TER decreased in a time- and concentration-dependent manner after culture with high-glucose PDS for 24 h. Claudin-1 was also downregulated. Complex III activity was inhibited accompanied by increasing mitochondrial ROS generation. These changes were partially prevented by glutathione. Conclusion: These findings demonstrate that mitochondrial respiratory complex III pathway has crucial importance in maintaining permeability of HPMCs, which might reveal a valuable target for novel therapies to fight hyperpermeability of peritoneum during the prolonged PD treatment.     

Comparison of peritoneal dialysis and haemodialysis after renal transplant failure

Background. A growing number of patients are returning to dialysisafter renal transplant failure. The aim of this study is todetermine whether peritoneal dialysis (PD) is a safe and goodtreatment option for these patients. Methods. All patients returning to PD or haemodialysis (HD)after renal transplant failure before 1 October 2002 at theUniversity Hospital Gasthuisberg, Leuven, Belgium, were evaluated.Data were collected until death, retransplantation (reTx), transferto HD or PD or until 1 January 2003. Results. Twenty-one patients starting PD (PDpostTx-group) and39 patients starting HD (HDpostTx-group) after renal transplantfailure were included in the study. There were no significantdifferences in age, sex, serum albumin- and CRP-levels at baseline.The total time on renal replacement therapy at transplant failureand time to transplant failure did not differ between the twogroups either. Furthermore, the baseline comorbidity was similarin both groups. During follow-up, the outcome did not differsignificantly between the two groups. However, there was a tendencytowards higher patient survival and reTx tended to be more frequentin the PDpostTx-group. Moreover, patients in the HDpostTx-grouptended to accrue more new comorbidity. The incidence of peritonitisand the evolution of dialysis adequacy (renal and peritonealKt/V and creatinine clearances) with time in the PDpostTx-groupwas similar to that seen in our centre's PD patients who hadnever undergone transplantation before. Conclusions. This study suggests that the outcome in patientsstarting PD after renal transplant failure is at least as goodas the outcome in those starting HD. Although these observationalfindings warrant further confirmation, PD therefore can be regardedas a safe and good treatment option for patients returning todialysis after renal transplant failure.     

Peritoneal fibrosis and its prevention

SUMMARY: Peritoneal fibrosing syndrome (PFS) is composed of a wide spectrum of peritoneal alterations observed in patients under peritoneal dialysis (PD). Long-term peritoneal exposure to unphysiological PD solutions and recurrent bacterial peritonitis had been claimed as the most common causes predisposing to the development of PFS in a PD population. With the advances in molecular research, physicians and pathologists recognized that peritoneal injury and the accompanied accumulation of extracellular matrix (ECM) within the peritoneum are key events leading to PFS. Bioincompatible solution and it's related products, inflammatory mediators, growth factors as well as cytokines in the peritoneal cavity are contributing factors. Therapeutic strategies antagonizing these mediators and/or their downstream intracellular signalling pathways with either drug molecules or gene transfer may have potential for the prevention or treatment of PFS.