Endothelium-derived hyperpolarizing factor-mediated renal vasodilatory response is impaired during acute and chronic hyperhomocysteinemia.

BACKGROUND: Endothelial dysfunction is an early event in the development of vascular complications in hyperhomocysteinemia. Endothelial cells release a number of vasodilators, including NO and prostacyclin. Several lines of evidence have indicated the existence of a third vasodilator pathway, mediated by endothelium-derived hyperpolarizing factor (EDHF). EDHF is a major determinant of vascular tone in small resistance vessels. The influence of hyperhomocysteinemia on EDHF is unknown. The present in vivo study evaluates the integrity of the EDHF pathway in the renal microcirculation of rats with acute and chronic hyperhomocysteinemia. METHODS AND RESULTS: EDHF-mediated vasodilation was evaluated as the renal blood flow (RBF) response to intrarenal acetylcholine during systemic NO synthase and cyclooxygenase inhibition. Acute hyperhomocysteinemia induced by intravenous homocysteine did not affect EDHF-mediated vasodilation. In contrast, intravenous methionine with subsequent hyperhomocysteinemia impaired the EDHF-mediated RBF response. When the methionine infusion was preceded by adenosine periodate oxidized to prevent the cleavage of S-adenosylhomocysteine to homocysteine and adenosine, a similar impairment of EDHF was observed, but with normal homocysteine levels. Animals with chronic hyperhomocysteinemia induced by a high-methionine, low-B vitamin diet during 8 weeks had a severely depressed EDHF-mediated vasodilation compared with those on a standard diet. Endothelium-independent vasodilation to deta-NONOate and pinacidil was not affected in acute and chronic hyperhomocysteinemia, demonstrating intact vascular smooth muscle reactivity. CONCLUSIONS: EDHF-dependent responses are impaired in the kidney of hyperhomocysteinemic rats. Because EDHF is a major regulator of vascular function in small vessels, these findings have important implications for the development of microangiopathy in hyperhomocysteinemia.

Effects of new peritoneal dialysis solutions on leukocyte recruitment in the rat peritoneal membrane.

OBJECTIVES: Peritonitis remains a principal cause of dropout in peritoneal dialysis (PD). The physiological host response to a peritoneal infection involves a rise in numbers of circulating leukocytes to the peritoneal cavity. We evaluated the effects of (1) conventional peritoneal dialysis fluid (PDF), (2) bicarbonate-based PDF, low in glucose degradation products, and (3) non-glucose PDF on peritoneal leukocyte recruitment in response to an inflammatory stimulus using intravital microscopy. METHODS: The visceral peritoneum was exposed to EBSS, conventional lactate-buffered and bicarbonate/lactate-buffered glucose-based PDF and three lactate-buffered non-glucose PDF-icodextrin, amino acid-based PDF and amino acid/glycerol-based PDF. The number of rolling, adhering and extravasated leukocytes and leukocyte rolling velocity was assessed at different time intervals after stimulation with lipopolysaccharide (LPS). RESULTS: Exposure to LPS dissolved in EBSS dramatically increased the number of rolling, adhering and extravasated leukocytes and decreased leukocyte rolling velocity. Conventional PDF completely abolished LPS-induced leukocyte recruitment. Bicarbonate/lactate-buffered PDF only minimally affected the process of leukocyte recruitment, whereas icodextrin PDF resulted in partial inhibition of the immune response. The amino acid-based and the amino acid/glycerol-based PDF inhibited leukocyte recruitment to a similar extent as conventional PDF. CONCLUSIONS: Bicarbonate/lactate-buffered PDF has superior biocompatibility towards peritoneal host defense, in spite of its high glucose concentrations. Lactate-buffered non-glucose containing PDF has substantial inhibitory effects on leukocyte recruitment, indicating that the bioincompatibility of high lactate concentrations and/or low pH may not be underestimated.

Animal models in peritoneal dialysis research: a need for consensus.

The development of an adequate animal model for peritoneal research remains an object of concern. In vivo peritoneal dialysis (PD) research is hampered by the large variety of available models that make interpretation of results and comparison of studies very difficult. Species and strain of experimental animals, method of peritoneal access, study duration, measures of solute transport and ultrafiltration, and sampling for histology differ substantially among the various research groups. A collective effort to discuss the shortcomings and merits of the different experimental models may lead to a consensus on a standardized animal model of PD.

The effects of peritoneal dialysis solutions on peritoneal host defense.

Conventional peritoneal dialysis fluid (PDF) is a bioincompatible solution owing to the acidic pH, the high glucose concentrations and the associated hyperosmolarity, the high lactate concentrations, and the presence of glucose degradation products (GDPs). This unphysiologic composition adversely affects peritoneal host defense and may thus contribute to the development of PD-related peritonitis. The viability of polymorphonuclear leukocytes, monocytes, peritoneal macrophages, and mesothelial cells is severely depressed in the presence of conventional PDF. In addition, the production of inflammatory cytokines and chemoattractants by these cells is markedly affected by conventional PDF. Further, conventional PDF hampers the recruitment of circulating leukocytes in response to an infectious stimulus. Finally, phagocytosis, respiratory burst, and bacterial killing are markedly lower when polymorphonuclear leukocytes, monocytes, and peritoneal macrophages are exposed to conventional PDF. Although there are a few discrepant results, all major PDF components have been implicated as causative factors. Generally, novel PDF with alternative osmotic agents or with alternative buffers, neutral pH, and low GDP content have much milder inhibitory effects on peritoneal host defense. Clinical studies, however, still need to demonstrate their superiority with respect to the incidence of PD-related peritonitis.

The effects of heparin administration in an animal model of chronic peritoneal dialysate exposure.

Diverse modes of heparin administration have been used in animal models of chronic peritoneal dialysate exposure to maintain catheter patency and prevent fibrinous adhesions. Heparin has biological actions independent of its well-known anticoagulant activity, including the ability to modulate extracellular matrix synthesis, cellular proliferation, angiogenesis, and inflammation. These actions may interfere with peritoneal membrane homeostasis. The present study evaluated the influence of the mode of heparin administration on technique survival and infection rate in a rat model of chronic dialysate exposure. Further, the incorporation of heparin in the peritoneal membrane was examined. A 3.86% glucose dialysate was injected twice daily into Wistar rats with a heparin-coated catheter (group A1), or with a standard catheter with heparin injections during the entire exposure time (group A2) or only during 1 week (group A3). Sham manipulations were performed in a fourth group and a fifth group was left untreated. Technique survival was 80% in group A1, 60% in group A2, and 40% in group A3. The rate of infection was highest in group A1 and lowest in group A2. Intraperitoneally administered heparin accumulated in the peritoneal membrane, whereas dextran, with a molecular weight similar to that of heparin, was not incorporated in the peritoneum. In conclusion, intraperitoneal heparin reduced the incidence of infection in an animal model of chronic dialysate exposure. The best technique survival was, however, obtained using a heparin-coated catheter. Heparin is incorporated in the peritoneal membrane, where it may exert diverse biological actions and thus bias study results. The use of a heparin-coated catheter in combination with antibiotics may be the optimal approach to obtaining peritoneal access in animal models of chronic dialysate exposure.

Antibiotic administration in an animal model of chronic peritoneal dialysate exposure.

OBJECTIVES: The high incidence of intraperitoneal infection remains an important problem in animal models of chronic dialysate exposure. Prophylactic antibiotic administration can be used to resolve this problem, but the isolated effects of antibiotics on peritoneal membrane function and structure are unknown. The present study examined the effects of prophylactic antibiotics on infection rate and peritoneal membrane function and structure in a rat model of chronic dialysate exposure. DESIGN: A first group of rats (A; n = 12) received 10 mL 3.86% glucose dialysate twice daily through a heparin-coated catheter. In a second group of animals (B; n = 12), oxacillin 2.5 mg/day and gentamicin 0.04 mg/day were added to the dialysate. Group C (n = 12) was injected twice daily with an identical dose of antibiotics dissolved in 1 mL of buffer solution. Group D (n = 12) was left untreated. Dialysate cultures were obtained regularly. After 8 weeks of exposure, peritoneal transport studies were performed and samples for histology were obtained. RESULTS: Technique survival was 92% in group A and 100% in the remaining groups. Five rats in group A but none of the animals in the other groups developed peritonitis. The transport rates of small solutes were elevated and net ultrafiltration was decreased in group A compared to the controls. Fibrosis, as evaluated by quantifying Picro Sirius Red staining with image analysis, was significantly elevated in group A (3.48% +/- 1.06% vs 0.72% +/- 0.51% in group D, p < 0.05) but not in group B (0.29% +/- 0.07%) or in group C (0.52% +/- 0.28%). Vascular density, measured by counting the number of blood vessels that stained positive for endothelial NO synthase, was increased in both groups that were exposed to dialysate: 153.0 +/- 12.9/microm2 in group A and 131.6 +/- 14.3/microm2 in group B, versus 76.76 +/- 12.37/microm2 in group C and 73.2 +/- 10.4/microm2 in group D (p < 0.01). CONCLUSIONS: Prophylactic administration of oxacillin and gentamicin adequately prevented intraperitoneal infection in an animal model of chronic dialysate exposure. In addition, fibrosis was absent, suggesting intraperitoneal infection rather than dialysate exposure is a causative factor.

Decreased leukocyte recruitment in the mesenteric microcirculation of rats with cirrhosis is partially restored by treatment with peginterferon: an in vivo study.

BACKGROUND/AIMS: Patients with liver cirrhosis are predisposed to develop bacterial infections. An essential process in inflammatory responses is the recruitment of circulating leukocytes through the activation of adhesion molecules. Interferon-alpha2a is a cytokine reported to influence the expression of adhesion molecules. We investigated the effect of peginterferon-alpha2a (PegIFN-alpha(2a)) in vivo on the leukocyte recruitment in the mesenteric microcirculation of cirrhotic rats after lipopolysaccharide exposure. METHODS: Leukocyte rolling, adhesion and extravasation were visualized by intravital microscopy in sham-operated and common bile duct ligated (CBDL) rats. PegIFN-alpha(2a) was administered to influence leukocyte recruitment. Endothelial P-selectin, E-selectin and ICAM-1 expression were studied by immunohistochemistry. RESULTS: CBDL placebo rats showed significantly impaired rolling, adhesion and extravasation of leukocytes compared to Sham-operated placebo rats. Endothelial P-selectin, E-selectin and ICAM-1 expressions in CBDL placebo rats were significantly reduced compared to Sham-operated placebo rats. PegIFN-alpha(2a) 18 microg normalized number of rolling leukocytes in CBDL rats, without influencing on adhering and extravasated leukocytes. PegIFN-alpha(2a) upregulates the expression of P-selectin and E-selectin in CBDL rats, but ICAM-1 expression remained significantly lower than in Sham rats. CONCLUSIONS: Leukocyte recruitment is significantly impaired in the mesenteric microcirculation of cirrhotic rats. This deficiency appears to result from a reduced endothelial P-selectin, E-selectin and ICAM-1 expression. Peginterferon-alpha(2a) treatment normalizes rolling of leukocytes in cirrhotic rats by upregulation of P-selectin and E-selectin expressions, but has no influence on adhesion and extravasation possibly due to the absence of effect on ICAM-1 expression.

What did we learn from animal models in peritoneal dialysis?

The development of animal models in peritoneal dialysis has led to some breakthroughs in the application of this dialysis modality in clinical practice. These breakthroughs are (1) a better understanding of the physiology and pathophysiology of solute transport and ultrafiltration mechanisms, (2) the observation and integration of the long-term structural and functional alterations of the membrane, (3) a better understanding of the biocompatibility issues involved in PD, leading to the clinical introduction of more biocompatible dialysis solutions and finally, (4) the development of colloid osmotic solutions containing polyglucose polymers for application in the long dwells. Intravital miscroscopy provides information in live animals about diverse functional parameters, such as blood flow rate, vessel diameter, permeability to macromolecules, leukocyte-endothelium interaction, capillary recruitment, and lymph vessel kinetics. Also evaluation of different parameters in a living experimental animal, allowing integration of function and structure is possible. A variety of chronic PD models have been developed, mainly to study effects of long-term peritoneal dialysate exposure on peritoneal membrane function and structure. The implementation of different blocking agents of biochemical substances in these models has elucidated many molecular biological mechanisms involved in these processes. The important roles of aquaporins, vascular endothelial growth factor, nitric oxide, advanced glycation end product formation and their receptor (RAGE) upregulation and the integrated roles of all these factors in the fibrotic alterations of the membrane as observed in patients on long-term PD have been investigated. More recently, genetically modified mice have been used as an important tool to investigate the molecular basis of peritoneal changes during dialysis and during acute peritonitis.

Myofibroblast transdifferentiation of mesothelial cells is mediated by RAGE and contributes to peritoneal fibrosis in uraemia.

BACKGROUND: Uraemia is associated with fibrosis of the peritoneal membrane, even prior to the start of peritoneal dialysis. Increased carbonyl stress and the resultant formation of advanced glycation end-products (AGEs) are potentially involved. The interaction of AGEs with their cell surface receptor for AGE (RAGE) induces sustained cellular activation, including the production of the fibrogenic growth factor-beta (TGF-beta). TGF-beta is pivotal in the process of epithelial-to-mesenchymal transition with the acquisition of myofibroblast characteristics. We investigated whether antagonism of RAGE prevents uraemia-induced peritoneal fibrosis. In addition, we examined whether myofibroblast transdifferentiation of mesothelial cells contributes to peritoneal fibrosis in uraemia. METHODS: Uraemia was induced in rats by subtotal nephrectomy. Uraemic and age-matched sham-operated rats were treated for 6 weeks with neutralizing monoclonal anti-RAGE antibodies or placebo. Expression of AGE, RAGE, cytokeratin and alpha-smooth muscle actin was evaluated using immunohistochemistry. TGF-beta expression was examined with immunostaining and western blotting, and Snail expression with western blotting. Fibrosis was quantified with a picro-sirius red staining and measurement of the hydroxyproline content of the tissue. RESULTS: Uraemia resulted in the accumulation of AGE, up-regulation of RAGE and TGF-beta and the development of interstitial fibrosis and vascular sclerosis in the peritoneal membrane. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by colocalization of cytokeratin and alpha-smooth muscle actin in submesothelial and interstitial fibrotic tissue. The antagonism of RAGE prevented the up-regulation of TGF-beta, epithelial-to-mesenchymal transition of mesothelial cells and fibrosis in uraemia. CONCLUSION: The ligand engagement of RAGE and the subsequent up-regulation of TGF-beta induces peritoneal fibrosis in chronic uraemia. The process may be mediated by the conversion of mesothelial cells into myofibroblasts.

Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an in vivo study.

BACKGROUND: In vivo evidence for angiogenesis in the splanchnic vasodilation in portal hypertension (PHT) and cirrhosis is lacking. Vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) are mediators of angiogenesis. The present study visualises in vivo structural changes (angiogenesis and vascular hyperpermeability) and examines the presence of VEGF and eNOS in the mesenteric microvasculature of animal models of PHT with and without cirrhosis. METHODS: Portal hypertension was induced by partial portal vein ligation (PPVL) and cirrhosis was induced by common bile duct ligation (CBDL) in rats. The mesenteric microcirculation was examined by intravital microscopy. Expression of VEGF, eNOS and CD31 in mesenteric tissue were studied by immunohistochemistry. RESULTS: An increased mesenteric angiogenesis was observed in PPVL and CBDL rats compared with Sham-operated and control rats, as shown by intravital microscopy and CD 31 staining. VEGF and eNOS expression was higher in CBDL and PPVL rats compared with control groups and correlated positively with vascular density. Macromolecular leakage was increased in cirrhotic rats compared with control and PPVL rats. CONCLUSION: Our study provides in vivo evidence of an increased angiogenesis in the mesenteric microvasculature of animal models of PHT and cirrhosis. Increased VEGF and eNOS expression in the mesentery of PPVL and CBDL rats may suggest their contribution. Microvascular permeability in the mesenteric vessels was only increased in cirrhotic rats.

Benefits of switching from a conventional to a low-GDP bicarbonate/lactate-buffered dialysis solution in a rat model.

BACKGROUND: Long-term exposure to standard peritoneal dialysis fluid (PDF) results in alterations in peritoneal morphology and function. Studies investigating the long-term effects on the peritoneum of a low-glucose degradation product (GDP) bicarbonate/lactate-buffered PDF demonstrated its superior biocompatibility. We examined the potential of the low-GDP bicarbonate/lactate-buffered solution to reverse or reduce standard PDF-induced peritoneal alterations. METHODS: Female Wistar rats received twice daily intraperitoneal infusions with either a lactate-buffered solution with 3.86% glucose at pH 5.5 (Dianeal, referred to as standard PDF), or a low-GDP bicarbonate/lactate-buffered solution with 3.86% glucose at physiologic pH (Physioneal, referred to as bicarbonate/lactate PDF) for different periods of time: (1) 12 weeks Dianeal (N= 9); (2) 12 weeks Physioneal (N= 9); (3) 20 weeks Dianeal (N= 11); (4) 20 weeks Physioneal (N= 10); (5) 12 weeks Dianeal followed by 8 weeks Physioneal (N= 10). RESULTS: Chronic standard PDF exposure resulted in loss of ultrafiltration capacity, increased VEGF expression and vascular density, higher advanced glycation end product (AGE) accumulation, up-regulation of TGF-beta expression, and development of fibrosis compared to low-GDP bicarbonate/lactate-buffered PDF. The PDF-induced alterations were time-dependent. Crossover from standard PDF to low-GDP bicarbonate/lactate PDF resulted in a less impaired ultrafiltration (UF), less pronounced VEGF expression and neoangiogenesis, and less severe AGE accumulation, TGF-beta expression, and fibrosis compared to continuous standard PDF exposure for 20 weeks. CONCLUSION: Low-GDP bicarbonate/lactate-buffered PDF has the potential to slow down standard PDF-induced peritoneal membrane damage.

Recent concepts in the molecular biology of the peritoneal membrane - implications for more biocompatible dialysis solutions.

This paper reviews some important recent findings on the molecular biology of the peritoneal membrane. It attempts to correlate in vitro and in vivo experimental results with the possible clinical consequences. The most common functional alteration during long-term CAPD is increased peritoneal small-solute transport rate, resulting in impaired ultrafiltration and decreased dialysis efficiency. This contribution first discusses the most relevant advances in the biochemistry and molecular biology of the peritoneal membrane following peritonitis and as consequence of the continuous exposure to unphysiological dialysis fluids. In a second part the preliminary experimental and clinical experience with more biocompatible fluids is summarized. The most relevant structural and functional alterations of the membrane following repeated peritonitis is the consequence of the response of the peritoneum to infective organisms involving the inflammatory cytokines and the interaction between membrane resident cell populations: macrophages, mesothelial cells and fibroblasts. In this setting, human biopsy studies and animal experiments have identified an increase in the peritoneal-associated vasculature, which seems to be the primary cause of increased solute transport. The structural and functional alterations in the membrane in long-term peritoneal dialysis are thought to be the consequence of the toxicity of glucose, either directly or indirectly through the generation of glucose degradation products or the formation of advanced glycation end-products. In particular, an important role for vascular endothelial growth factor and nitric oxide as downstream mediators of the alterations has been suggested. Finally, the last part of this paper reviews the actual and future research aimed at an amelioration of the biocompatibility of the dialysis fluids. Replacing glucose by other osmotic agents, changing the sterilization process, replacing the lactate buffer by bicarbonate, blocking the formation of reactive carbonyl products and of the neoangiogenesis are the most promising changes to enhance the biocompatibility. Finally, gene therapy may in the future have an important contribution. Ex vivo gene therapy involves harvesting peritoneum samples to isolate mesothelial cells that will be genetically modified before re-implantation into the peritoneal cavity.

Long-term exposure to new peritoneal dialysis solutions: Effects on the peritoneal membrane.

BACKGROUND: Chronic exposure to peritoneal dialysis fluid (PDF) affects the peritoneum, but precise causative factors are incompletely understood. We examined the effects of standard and new PDF on peritoneal function and structure. METHODS: Female Wistar rats received twice daily intraperitoneal infusions of a standard lactate-buffered 3.86% glucose PDF at pH 5.5 (Dianeal) (N= 12), a low glucose degradation product (GDP) containing bicarbonate/lactate-buffered 3.86% glucose PDF at pH 7.4 (Physioneal) (N= 12), a lactate-buffered amino acid-based PDF at pH 6.7 (Nutrineal) (N= 12) or Earle's Balanced Salt Solution at pH 7.4 (EBSS) (N= 12) during 12 weeks. RESULTS: Net ultrafiltration was lower after treatment with standard PDF, but not with low-GDP bicarbonate/lactate-buffered and amino acid-based PDF, compared to EBSS. Peritonea exposed to standard PDF were characterized by an increased expression of vascular endothelial growth factor (VEGF), microvascular proliferation as well as submesothelial fibrosis, which were not observed in other groups. Staining for methylglyoxal adducts was prominent in the standard PDF-exposed group, mild in the low GDP bicarbonate/lactate-buffered group and absent in the other groups. Standard PDF induced accumulation of advanced glycation end products (AGEs) and up-regulation of the receptor for AGE (RAGE). AGEs accumulation was absent and RAGE expression was only modestly increased in low-GDP bicarbonate/lactate-buffered and amino acid-based PDF. CONCLUSION: Long-term in vivo exposure to standard PDF adversely affects peritoneal function and structure. A low-GDP bicarbonate/lactate-buffered and amino acid-based PDF better preserved peritoneal integrity and may thus improve the longevity of the peritoneal membrane. GDPs and associated accelerated AGE formation are the main causative factors in PDF-induced peritoneal damage.

Inhibition of the interaction of AGE-RAGE prevents hyperglycemia-induced fibrosis of the peritoneal membrane.

The peritoneal membrane of long-term peritoneal dialysis patients is characterized by a loss of ultrafiltration capacity, associated morphologically with submesothelial fibrosis and neoangiogenesis. Exposure to high glucose concentrations in peritoneal dialysate and the resultant advanced glycation end-products (AGE) accumulation have been implicated in the development of these changes, but their exact pathophysiological role is unknown. We examined the effect of the interaction of AGE with one of their receptors (i.e., RAGE) on the function and structure of the peritoneum exposed to high ambient glucose concentrations. Streptozotocin-induced diabetic rats and control rats were treated during 6 wk with either neutralizing monoclonal anti-RAGE antibodies or control antibodies. The expression of RAGE was strongly enhanced in the peritoneal membrane of the diabetic animals. The diabetic peritonea were characterized by an elevated transport of small solutes, lower ultrafiltration rates, a higher vascular density, and an upregulation of endothelial nitric oxide synthase expression. These parameters were unaffected by treatment with anti-RAGE antibodies. In contrast, anti-RAGE but not control antibodies prevented upregulation of TGF-beta, development of submesothelial fibrosis, and fibronectin accumulation in the peritoneum of diabetic animals. In conclusion, binding of AGE to RAGE increases the expression of TGF-beta and contributes to the development of submesothelial fibrosis. Neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways.

Effects of conventional and new peritoneal dialysis fluids on leukocyte recruitment in the rat peritoneal membrane.

Peritonitis remains an important cause of morbidity and technique failure in peritoneal dialysis (PD). Conventional peritoneal dialysate fluids (PDF) inhibit peritoneal leukocyte function in vitro and may thus adversely affect the immune response to peritonitis. New PDF have been designed with neutral pH, low glucose degradation product (GDP) contents, and bicarbonate as buffer. The present intravital microscopy study examined the effects of conventional and new PDF on leukocyte behavior in the peritoneal microcirculation of Wistar rats. The visceral peritoneum was superfused by a control solution (EBSS), a conventional (CAPD), or a new bicarbonate-buffered PDF with neutral pH and low GDP content (CAPD BicaVera). In addition, spent conventional and new PDF were tested. The number of rolling, adhering, and extravasated leukocytes and leukocyte rolling velocity were assessed at different time intervals after exposure to lipopolysaccharide (LPS) or cell-free supernatants of coagulase-negative staphylococci (CNS-CFS). Exposure to LPS or CNS-CFS dissolved in EBSS dramatically increased the number of rolling, adhering and extravasated leukocytes and decreased leukocyte rolling velocity. Superfusion by CAPD abolished the LPS- or CNS-CFS-induced leukocyte recruitment, whereas CAPD BicaVera had significantly fewer depressant effect. Spent PDF affected the leukocyte response in a similar way as fresh PDF. High lactate concentrations, GDP, and hypertonicity appeared to be mainly responsible for the inhibition of leukocyte recruitment. In conclusion, conventional PDF abolish in vivo leukocyte recruitment in response to potent inflammatory stimuli. Bicarbonate-buffered pH-neutral PDF with low GDP contents have fewer depressant effects and may therefore contribute to a better preservation of peritoneal host defense.

Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role of acidity, buffer choice, glucose concentration, and glucose degradation products.

Conventional peritoneal dialysis fluids (PDF) are unphysiologic because of their hypertonicity, high glucose and lactate concentrations, acidic pH, and presence of glucose degradation products (GDP). Long-term exposure to conventional PDF may cause functional and structural alterations of the peritoneal membrane. New PDF have a neutral pH, a low GDP content, and contain bicarbonate or lactate as the buffer. Intravital microscopy was used to analyze the vasoactive effects of conventional and new PDF on the rat peritoneal membrane. A conventional, acidic pH, lactate-buffered 4.25% glucose PDF induced maximal vasodilation of mesenteric arteries, resulting in a doubling of the arteriolar flow and a 20% increase of the perfused capillary length per area. The hemodynamic effects of conventional PDF were similar after pH-adjustment with NaOH, indicating that acidity per se is not essential for the changes. Superfusion by a pH-neutral, lactate-buffered PDF with low GDP content caused only a transient arterial vasodilation despite continuous exposure, with a commensurate effect on arteriolar flow and capillary recruitment. Application of a pH-neutral, bicarbonate-buffered PDF with low GDP content did not affect the hemodynamic parameters. Resterilization of the bicarbonate solution increased GDP levels and completely restored the vasodilatory capacity. The corresponding 1.5% glucose PDF induced similar but less pronounced changes. Conventional PDF have important vasoactive effects on the peritoneal circulation, mainly because of the presence of GDP and transiently because of high lactate concentrations. Capillary recruitment may increase effective peritoneal vascular surface area. In addition, chronic vasodilation may induce structural adaptations in the blood vessel wall, contributing to vascular sclerosis. PDF with reduced GDP content induce no major hemodynamic effects and may thus have the potential to better preserve peritoneal vascular integrity.