Peritoneal effluent markers of inflammation in patients treated with icodextrin-based and glucose-based dialysis solutions

Chronic exposure to peritoneal dialysis (PD) solutions is associated with a low-grade local inflammatory state of the peritoneum. The occurrence of culture-negative peritonitis in some PD patients treated with icodextrin focused our interest on subclinical inflammation in icodextrin-treated patients without peritonitis. The aim of the present study was to compare signs of inflammation in icodextrin-treated patients with the same signs in patients using glucose/lactate-based (GL) dialysis solutions only. Overnight PD effluents from 19 patients treated with icodextrin and 19 patients treated with GL were investigated for leukocyte count (LC) and differentiation (LD), and for dialysate concentrations of cancer antigen 125 (CA125, the marker of mesothelial cell mass) and hyaluronan (marker of inflammation and tissue remodeling in the peritoneal cavity). Blood cell counts and serum dextran antibodies (DA) were also determined. Total LC in the GL group was significantly lower than that in the icodextrin group. The LD was not different between the two groups, except for the percentage of eosinophils. The blood cell count did not differ between the groups. The median value of DA was similar in both groups. The hyaluronan concentration was markedly higher in the icodextrin group. No significant difference was found for dialysate CA125. In conclusion, the higher effluent cell count, higher percentage of eosinophils, and higher effluent hyaluronan levels in icodextrin-treated patients are consistent with a greater degree of subclinical inflammation during icodextrin treatment than during GL treatmen

Clinical advantages of new peritoneal dialysis solutions

A review is given of the various mechanisms by which conventional glucose/lactate-based peritoneal dialysis solutions can induce damage to the peritoneal membrane. The potential advantages of newly developed dialysis solutions and the results of recent studies on their use in patients are discusse

Developing specific therapeutic strategies for transfusion-related acute lung injury. An overview of potentially useful animal models

Transfusion-related (TR)- acute lung injury (ALI) is the leading cause of transfusion-related morbidity and mortality. The pathogenesis of TRALI is thought to be a "two hit"-entity: the "first hit" is (any) proinflammatory pulmonary condition (e.g., pneumonia, sepsis or lung contusion) resulting in activation of lung endothelium with sequestration of polymorphonuclear neutrophils - the "second hit" is provided by transfusion of a blood product. Either antibodies against neutrophils are thought to be implicated in the activation of the sequestrated neutrophils, or bioactive lipids (which accumulate during storage of blood products) induce the "second hit", finally resulting in lung injury. Preventive measures do not prevent all TRALI cases. Also, TRALI is most probably underdiagnosed. In this review, we call for the development of therapeutic approaches for this potentially life-threatening disease. Several interventions which are beneficial in ALI and may also be beneficial in TRALI are discussed. The application of these interventions requires the development of clinically relevant TRALI animal models. We discuss the present TRALI animal models and their shortcomings and propose future animal models, in which clinically relevant "first hits" can be applied, thereby imitating the complex clinical situatio

Free water transport, small pore transport and the osmotic pressure gradient

BACKGROUND: Water transport in peritoneal dialysis (PD) patients occurs through the small pores and water channels, the latter allowing free water transport (FWT). The osmotic gradient is known to be one of the major determinants of water transport. The objective of the study was to analyse the relation between each transport route and the osmotic gradient. METHODS: The 4-h standard peritoneal permeability analyses of 80 stable PD patients were studied. Small pore transport (SPT) was calculated based on the transported amount of sodium. FWT was calculated by subtracting SPT from transcapillary ultrafiltration (TCUF). Water transport rates were determined. The osmotic gradient was calculated. The slope of the relation between FWT rate and osmotic gradient (slope(FWT)), and the elimination constant (K(e)) of the exponential relation between SPT rate and osmotic gradient (K(SPT)) were calculated for every patient. RESULTS: The FWT rate was related to the osmotic gradient (P = 0.001). A similar correlation was also found between the SPT rate and osmotic gradient when fitted exponentially (P = 0.005). The rates of FWT decreased significantly between each time point during the whole dwell. The SPT rates decreased significantly within the first half of the dwell and levelled off thereafter. No correlations were found between the slope(FWT), K(SPT) and PD duration. The slope(FWT) of the relationship between the FWT and the osmotic gradient is an indirect measurement of the amount of functioning water channels. Similarly, the K(SPT) value represents the number of functioning small pores. The absence of a relationship of these parameters with the duration of PD suggests opposing mechanisms, for instance a lower number of functioning pores in combination with an increased vascular surface area. Conclusion. The curves of the relationship between FWR, SPT and OG support the assumption that FWR is much more dependent on the OG than SPT. Non-osmotic determinants are likely to be important in small pore fluid transpor

What can we do to preserve the peritoneum?

BACKGROUND: Long-term peritoneal dialysis may lead to peritoneal membrane failure. Loss of ultrafiltration is the most important clinical abnormality. Loss of ultrafiltration is associated with an increased number of peritoneal blood vessels, with fibrotic alterations, and with loss of mesothelium. Continuous exposure to bioincompatible dialysis solutions is likely to be important in the pathogenesis of these alterations. METHODS: This article reviews the toxicity of various constituents of dialysate, current assessments of interventions, and the results of interventions aimed at preserving the peritoneum. RESULTS: Glucose, possibly in combination with lactate, and glucose degradation products (GDPs) are likely to be the most toxic constituents of dialysate. Diabetiform peritoneal neoangiogenesis is likely to be mediated by vascular endothelial growth factor (VEGF). Release of VEGF might be influenced by glucose-induced cellular pseudohypoxia, which is likely to be increased by exposure to lactate. Glucose and GDPs are both toxic to peritoneal cells. Glucose degradation products induce the formation of advanced glycosylation end-products at a much faster rate than does glucose itself, but the relative importance of GDPs and glucose in clinical PD has not been clarified. The effects of interventions should first be assessed in long-term animal models, followed by clinical studies on peritoneal transport and on effluent markers that may reflect the status of the peritoneum. Possible interventions aim at reducing peritoneal exposure to glucose, GDPs, and lactate. Techniques include peritoneal resting, replacing some glucose-based exchanges with amino acid-based and icodextrin-based dialysate, using bicarbonate as a buffer, and administering solutions that have a low GDP content. Exposure to various dialysis solutions with a reduced GDP content has resulted in an increase in the effluent concentration of the mesothelial cell marker CA125, irrespective of the buffer used. Experimental studies in a long-term peritoneal exposure model in rats showed that the combination of a reduction in the concentration of lactate and replacement of lactate with pyruvate resulted in a reduction of the number of peritoneal blood vessels. Results of drug therapy have been studied in various animal models. Their use in patients is still experimental. CONCLUSIONS: Strategies to preserve the peritoneum aim at reducing membrane exposure to bioincompatible solutions. Currently available dialysis fluids that are more biocompatible are likely to have some beneficial effects. Further research on the development of dialysis solutions that use combinations of osmotic agents and alternative buffers is necessar

Does lymphatic absorption change with the duration of peritoneal dialysis?

BACKGROUND: Ultrafiltration failure is an important complication of long-term peritoneal dialysis (PD). A high effective lymphatic absorption rate (ELAR) can contribute to impaired ultrafiltration. It is unknown whether the ELAR increases with time on PD. OBJECTIVE: The relationship between the ELAR and duration of PD was analyzed, as well as the correlation between the ELAR and other transport parameters. We also studied the relation between the ELAR and cancer antigen 125 (CA125) a marker for mesothelial cell mass. SETTING: Peritoneal dialysis unit in the Academic Medical Center, Amsterdam. DESIGN: Cross-sectional and longitudinal studies of standard peritoneal permeability analyses (SPAs; 4-hour dwells, dextran 70 as a volume marker) with glucose 3.86% in 130 PD patients. METHODS: SPAs were analyzed in 130 stable PD patients (77 males). Median duration of PD was 25 months (range 1-214) in a cross-sectional study. The last SPA from each patient was analyzed. The longitudinal analysis included 24 patients (12 males) from whom at least 3 SPAs were available with a minimum interval of 8 months. Dextran 70, 1 g/L, was administered intraperitoneally at the initiation of the test. Lymphatic absorption was calculated from the disappearance rate of dextran 70 during the 4-hour dwell. Therefore, the ELAR included both transmesothelial and subdiaphragmatic uptake of dextran 70. RESULTS: Median ELAR was 1.43 mL/minute (range 0.17- 6.59 mL/minute). No relationship was found between the ELAR and duration of PD in the cross-sectional analysis, nor was there a trend in time for 20 of the 24 patients studied longitudinally. In 4 patients, a negative trend was found. None of these had ultrafiltration failure and all 4 patients had a different cause for end-stage renal failure. The ELAR was correlated with parameters of peritoneal solute transport, but not with CA125 when investigated in a cross-sectional analysis. Only after 48 months of PD treatment was a significant relationship between the ELAR and CA125 seen (r = 0.46, p < 0.05). CONCLUSIONS: No time trend is present for the effective peritoneal lymphatic absorption rate, and it is not associated with patient or technique survival. Although increased lymphatic absorption is one of the causes of ultrafiltration failure, it is unlikely to contribute to the development of ultrafiltration failure in long-term PD patients with well-maintained transcapillary ultrafiltratio

Addition of a nitric oxide inhibitor to a more biocompatible peritoneal dialysis solution in a rat model of chronic renal failure

Biocompatible dialysis solutions have been developed to preserve peritoneal membrane morphology and function. Compared with a conventional solution, a combination of glycerol, amino acids, and dextrose in a bicarbonate/lactate buffer (GLAD) led to less peritoneal fibrosis and fewer vessels in a chronic peritoneal exposure model in the rat. However, no concomitant reduction in small-solute transport was observed. We hypothesized that this result could be attributable to peritoneal vasodilation induced by vasoactive substances such as nitric oxide. The aim of the present study was to investigate whether fast transport of small solutes and proteins induced by exposure to GLAD could be influenced by Ngamma -methyl-L-arginine acetate (L-NMMA), an inhibitor of NO. These investigations used our rat model of long-term peritoneal exposure with chronic renal failure. All rats underwent peritoneal catheter implantation and a 70% nephrectomy. Thereafter, the rats were allocated to 3 groups: 16 weeks of peritoneal exposure to GLAD and L-NMMA, to GLAD only, or to buffer (bicarbonate/lactate without any osmotic agent). Afterward, a standard peritoneal permeability analysis adjusted for the rat was performed. Subsequently, the rats were euthanized, and tissue samples were obtained for morphometric determinations. No effect of L-MNNA on the transport of small solutes and proteins was found. Also, no effect on morphology was found. Our findings make it unlikely that NO is directly involved, being more in favor of a direct effect of amino acids on peritoneal transpor