Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients.
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BK Virus↗
Biomedical subjects
An S De Vriese
Publications and source records attributed to An S De Vriese.
Diet-induced hyperhomocysteinemia does not lead to large gene-expression differences in rat aorta.
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Animals↗
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.
Animals↗
Linezolid-induced inhibition of mitochondrial protein synthesis.
BACKGROUND: Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. METHODS: We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo. RESULTS: In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. CONCLUSION: These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.
Acetamides↗
Activation of genes inducing cell-cycle arrest and of increased DNA repair in the hearts of rats with early streptozotocin-induced diabetes mellitus.
BACKGROUND: Oxidative stress was proposed as a critical factor in diabetic complications. The etiology of cell degeneration in diabetes mellitus (DM)-induced cardiomyopathy is unclear. The transition between apoptotic degeneration and cell proliferation under stress conditions is regulated at cell-cycle checkpoints. This study was aimed at elucidating the role of a potent cellular stress-response system of the p53-dependent checkpoint genes, i.e. P21WAF1/CIP1 and 14-3-3 sigma, in the heart in diabetes. MATERIAL/METHODS: Target gene expression levels were analyzed ex vivo in cardiomyocytes of streptozotocin-induced rats by Western blots and two-dimensional immunoblots. The levels of DNA damage/repair in diabetic cardiomyocytes were evaluated by "comet assay" and compared with a control group. RESULTS: Whereas no detectable expression of 14-3-3 sigma and only traces of both p53 and p21WAF1/CIP1 were found in cardiomyocytes of the controls, high expression rates of all three genes were observed in the DM group. Individual levels of DNA breakage were significantly lower in diabetic than in non-diabetic cardiomyocytes. CONCLUSIONS: We propose a dual role for cell-cycle regulation under diabetic conditions: the expressions of both p21WAF1/CIP1 and 14-3-3 sigma genes, activated via p53 function, trigger cell-cycle arrest and DNA repair, preventing replication of mutated DNA and increasing stress resistance of heart tissue at least in early diabetes. However, the double cell-cycle arrest ultimately inhibits the replication of cells, which consequently accumulate in the G1 and G2 phases; this could lead to retarded proliferative activity and tissue degeneration in diabetic myocardium in later diabetes.
Animals↗
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.
Animals↗
A neutralizing VEGF antibody prevents glomerular hypertrophy in a model of obese type 2 diabetes, the Zucker diabetic fatty rat.
BACKGROUND: Antagonism of vascular endothelial growth factor (VEGF) has improved the outcome in experimental nephropathies of various origins, including diabetic nephropathy in a type 1 diabetic rat model and a type 2 diabetic mouse model. Neutralizing VEGF antibodies prevented glomerular hypertrophy in these models. We examined the renal effects of VEGF blockade in an obese rat model of type 2 diabetic nephropathy and investigated the mechanism underlying the inhibition of glomerular hypertrophy. METHODS: Twenty female Zucker diabetic fatty (ZDF) rats, fed a high-fat diet and aged 10 weeks, were treated with VEGF antibodies or an irrelevant isotype-matched IgG. Ten heterozygous (fa/+) littermates served as additional non-diabetic, lean controls. Urinary albumin excretion (UAE) and creatinine clearance (CrCl) were assessed at baseline, and at 3 and 5 weeks. Kidney weight and glomerular volume were determined at the end of the study. Glomerular apoptosis was examined with anti-active caspase-3 immunohistochemistry. RESULTS: All obese animals had established diabetes, hyperlipidaemia and normal blood pressure, which were not influenced by VEGF antibody treatment. ZDF control rats had increased UAE, CrCl, kidney weights and glomerular volumes compared with non-diabetic, lean control rats. VEGF antibody treatment prevented the glomerular hypertrophy, but did not affect UAE, CrCl and kidney weight. Glomerular anti-active caspase-3 immunostaining was not different between the groups. CONCLUSIONS: Inhibition of VEGF prevented early glomerular hypertrophy in ZDF rats with established diabetes. Increased apoptosis of glomerular endothelial cells does not appear to underly the inhibition of glomerular growth.
Animals↗
Pathophysiological role of vascular endothelial growth factor in the remnant kidney.
BACKGROUND: Subtotal renal ablation is characterized by initial glomerular hypertrophy, followed by progressive development of glomerulosclerosis and interstitial fibrosis. Vascular endothelial growth factor (VEGF) is involved in glomerular hypertrophy and dysfunction in several pathophysiological conditions. On the other hand, progressive glomerulosclerosis and tubulo-interstitial fibrosis in the remnant kidney have been associated with loss of VEGF expression. METHODS: To explore the pathophysiological role of VEGF in the development of glomerular hypertrophy and renal damage in the remnant kidney model, we examined the effect of a neutralizing VEGF antibody on glomerular volume and kidney function in rats after subtotal nephrectomy or sham operation. Erythropoietin was administered to exclude a confounding effect of anaemia. RESULTS: Six weeks after subtotal nephrectomy, plasma urea and creatinine concentrations, urinary albumin excretion, and mean glomerular volume were elevated in the placebo-treated uraemic rats as compared with the sham-operated rats. Inhibition of VEGF partially prevented the glomerular hypertrophy and largely prevented the rise in urinary albumin excretion, but did not affect creatinine clearance in uraemic rats. CONCLUSIONS: VEGF is a mediator of glomerular hypertrophy after subtotal renal ablation. In view of glomerular hypertrophy as the initial deleterious event ultimately leading to progressive glomerulosclerosis, agents that block this glomerular growth could be useful in preventing scarring in progressive renal disease.
Animals↗
Immunopathological changes in a uraemic rat model for peritoneal dialysis.
BACKGROUND: Peritoneal dialysis (PD) is a treatment modality for patients with renal failure. Both the uraemic state of these patients and chronic exposure to PD fluid are associated with the development of functional and structural alterations of the peritoneal membrane. In a well-established chronic PD rat model, we compared rats with normal renal function with subtotal nephrectomized rats that developed uraemia. METHODS: Uraemic and control rats received daily 10 ml conventional glucose containing PD fluid, via peritoneal catheters during a 6 week period. Uraemic and control rats receiving no PD fluid served as controls. Parameters relevant for peritoneal defence and serosal healing responses were analyzed. RESULTS: Uraemic animals were characterized by 2-3-fold increased serum urea and creatinine levels, accompanied by a significantly reduced haematocrit. Uraemia (without PD fluid exposure) induced new blood vessels in different peritoneal tissues, accompanied by increased accumulation of advanced glycation end products (AGEs) and elevated levels of angiogenic factors such as vascular endothelial growth factor and monocyte chemoattractant protein-1 (MCP-1) in peritoneal lavage fluid. A much stronger peritoneal response was observed upon PD fluid exposure in non-uraemic rats. This included the induction of angiogenesis and fibrosis in various peritoneal tissues, accumulation of AGEs, immunological activation of the omentum, damage to the mesothelial cell layer, focal formation of granulation tissues and increased MCP-1 and hyaluronan levels in peritoneal lavage fluid. Finally, chronic PD fluid instillation in uraemic rats did not induce an additional peritoneal response compared to PD fluid exposure in non-uraemic rats, except for the degree of AGE accumulation. CONCLUSIONS: Both uraemia and PD fluid exposure result in pathological alterations of the peritoneum. However, uraemia did not induce major additive effects to PD fluid-induced injury. These results substantially contribute to the understanding of the pathobiology of the peritoneum under PD conditions.
Animals↗
Analytical and biochemical aspects associated with supraphysiological creatine intake.
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Animals↗
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.
Animals↗
Cytochrome P450-2C11 mRNA is not expressed in endothelial cells dissected from rat renal arterioles.
BACKGROUND: Cytochrome P450 (CYP) isoenzymes (CYP2C and CYP2J) are involved in the production of epoxyeicosatrienoic acids, which are postulated as endothelium-derived hyperpolarizing factors (EDHFs). We hypothesized that if CYP2C11 is involved in the EDHF-mediated responses, its mRNA should be expressed in endothelial cells. We, therefore, examined the mRNA expression of CYP2C11 in endothelial cells of renal arterioles. METHODS: Laser microdissection was applied to isolate endothelial cells from the renal arterioles of 4 male and 4 female Wistar rats. As a positive control of CYP2C11 expression, hepatocytes were also dissected from these rats. RNA was isolated and real-time quantitative polymerase chain reaction (Q-PCR) analysis was applied. RESULTS: Q-PCR analysis showed that CYP2C11 mRNA was not expressed in laser microdissected endothelial cells of renal arterioles of male and female rats. CYP2C11 mRNA expression was highly abundant in hepatocytes dissected from male livers, but in female livers hardly any CYP2C11 mRNA was detected. CONCLUSION: We have shown that endothelial cells can be dissected from small renal arterioles by laser microdissection to study the mRNA expression of specific genes by Q-PCR. Using this novel tool, we demonstrated that the CYP2C11 mRNA was not expressed in the endothelial cells of renal arterioles. Therefore, we speculate that CYP2C11 does not contribute to the EDHF-mediated responses in renal arterioles.
Animals↗
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.
Acetylcholine↗
Long-term renal changes in the Goto-Kakizaki rat, a model of lean type 2 diabetes.
BACKGROUND: Type 2 diabetes has become the single most frequent cause of end-stage renal disease. The Goto-Kakizaki rat is currently used as a model for lean type 2 diabetes, but its renal changes have not been fully characterized. We investigated long-term functional and structural renal changes in the Goto-Kakizaki rat to evaluate if this animal model resembles the changes observed in human diabetic kidney disease. METHODS: Urinary albumin excretion, creatinine clearance and blood pressure were measured at the age of 2, 8 and 14 months in 12 female Goto-Kakizaki rats and 10 female, non-diabetic Wistar rats. To study kidney morphology, kidney weight, glomerular volume, basement membrane thickness, mesangial fraction and total mesangial volume were determined at 14 months. RESULTS: Urinary albumin excretion rose progressively over time in both groups, but was significantly higher in Goto-Kakizaki rats than in Wistar rats. Creatinine clearance decreased over time in Goto-Kakizaki rats but not in Wistar rats. Blood pressure was in the normotensive range in all animals throughout the study. Kidney weight, glomerular volume, basement membrane thickness, mesangial fraction and total mesangial volume were significantly higher in Goto-Kakizaki rats than in Wistar rats. Body weight and blood glucose levels were higher, whereas serum insulin levels were not different or lower in Goto-Kakizaki rats compared with Wistar rats. CONCLUSION: The Goto-Kakizaki rat is a lean, hyperglycaemic, euinsulinaemic, normotensive experimental model of type 2 diabetes with robust functional and structural renal changes.
Albuminuria↗
Vascular hyporesponsiveness in the mesenteric artery of anaesthetized rats with cirrhosis and portal hypertension: an in-vivo study.
INTRODUCTION: Cirrhosis is complicated by splanchnic vasodilation. Nitric oxide (NO) and prostacyclin contribute to this. Vascular hyporesponsiveness has been reported, but the underlying pathophysiological mechanisms are unclear. OBJECTIVE: This in-vivo study examined the contribution of NO and prostacyclin to the development of vascular hyporesponsiveness in the mesenteric circulation of animals with cirrhosis and portal hypertension. METHODS: Rats underwent common bile duct ligation (CBDL) (n = 11), partial portal vein ligation (PPVL) (n = 12) and sham-operation (sham) (n = 11). Blood flow in the mesenteric artery (MBF) was measured during intramesenteric infusion of endothelium-dependent (acetylcholine) and endothelium-independent vasodilators (deta-NONOate, pinacidil) and a vasoconstrictor (L-phenylephrine). The measurements were repeated after systemic infusion of L-NAME (NO synthase inhibition) and indomethacin (cyclo-oxygenase inhibition). RESULTS: The MBF response to acetylcholine was significantly lower in CBDL and tended to be lower in PPVL than in sham. L-NAME and indomethacin significantly decreased the MBF response to acetylcholine in all groups. The hyporeactivity to acetylcholine in CBDL and PPVL was maintained after L-NAME and indomethacin. The MBF response to pinacidil, deta-NONOate and phenylephrine, before and after NO synthase and cyclo-oxygenase inhibition, was lower in CBDL and PPVL than in sham. CONCLUSION: This is the first in-vivo study demonstrating an impaired response to endothelium-dependent and endothelium-independent vasodilators as well as vasoconstrictors in the mesenteric artery of animals with cirrhosis and portal hypertension. The generalised hyporeactivity suggests an abnormality on the vascular smooth muscle cell level. The hyporesponsiveness persisted after combined NO synthase and cyclo-oxygenase inhibition.
Animals↗
Systemic and splanchnic haemodynamic effects of sildenafil in an in vivo animal model of cirrhosis support for a risk in cirrhotic patients.
OBJECTIVES: Sildenafil is a selective inhibitor of the cGMP-specific phosphodiesterase type V (PDE-V) in the corpus cavernosum. PDE-V is also present in the mesenteric artery. Cirrhosis is complicated by a splanchnic vasodilation attributed to a local overproduction of nitric oxide (NO). As sildenafil potentiates the effects of NO, it may further decrease mesenteric vascular tone and increase portal venous blood flow. The aim is to evaluate the effects of sildenafil on the systemic and splanchnic haemodynamics in an experimental model of cirrhosis. METHODS: Secondary biliary cirrhosis was induced in male Wistar rats by common bile duct ligation (CBDL, n=8); control rats were sham-operated (sham, n=7). The mean arterial pressure (MAP), portal venous pressure (PVP) and arterial mesenteric blood flow (MBF) were measured after intramesenteric (0.01-10 mg/kg) and after intravenous (i.v.) (0.01-10 mg/kg) administration of sildenafil. RESULTS: Baseline PVP was significantly higher in CBDL than in sham rats, whereas baseline MAP tended to be lower and MBF tended to be higher in CBDL compared with sham rats. Both intramesenteric and i.v. injection of sildenafil significantly decreased MAP and increased MBF and PVP in a dose-dependent way. The decrease in MAP was significantly less important in CBDL than in sham rats. The increase in MBF was importantly lower in CBDL than in sham rats. PVP tended to increase more significantly in sham rats than in CBDL. CONCLUSION: Sildenafil increases MBF and PVP and induces systemic hypotension. The effects are less pronounced in cirrhosis, suggesting vascular hyporesponsiveness to sildenafil. Although the rise in PVP in cirrhotic animals is smaller than in controls, it may present a risk for haemorrhagic complications. Further studies are necessary before prescribing sildenafil to patients with cirrhosis.
Animals↗
The role of vascular endothelial growth factor (VEGF) in renal pathophysiology.
Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that promotes endothelial cell proliferation, differentiation and survival, mediates endothelium-dependent vasodilatation, induces microvascular hyperpermeability and participates in interstitial matrix remodeling. In the kidney, VEGF expression is most prominent in glomerular podocytes and in tubular epithelial cells, while VEGF receptors are mainly found on preglomerular, glomerular, and peritubular endothelial cells. The role of VEGF in normal renal physiology is essentially unknown. The absence of prominent effects of VEGF blockade in normal experimental animals suggests a limited function during homeostasis, although a role in the formation and maintenance of glomerular capillary endothelial fenestrations has been suggested. VEGF and its receptors are up-regulated in experimental animals and humans with type 1 and type 2 diabetes. Inhibition of VEGF has beneficial effects on diabetes-induced functional and structural alterations, suggesting a deleterious role for VEGF in the pathophysiology of diabetic nephropathy. VEGF is required for glomerular and tubular hypertrophy and proliferation in response to nephron reduction, and loss of VEGF is associated with the development of glomerulosclerosis and tubulointerstitial fibrosis in the remnant kidney. No firm conclusions on the role of VEGF in minimal change or membranous glomerulonephritis can be drawn. VEGF may be an essential mediator of glomerular recovery in proliferative glomerulonephritis. Glomerular and tubulointerstitial repair in thrombotic microangiopathy and cyclosporin nephrotoxicity may also be VEGF-dependent. In conclusion, VEGF is required for growth and proliferation of glomerular and peritubular endothelial cells. While deleterious in some, it may contribute to recovery in other forms of renal diseases.
Animals↗
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.
Amino Acids↗