Effects of inhibition of the polyol pathway during chronic peritoneal exposure to a dialysis solution

BACKGROUND: Peritoneal dialysis with glucose- and lactate-containing dialysis solutions stimulates peritoneal angiogenesis and fibrosis. These serious side effects can also be induced by chronic peritoneal exposure to dialysis solutions in nonuremic rats. The high glucose concentrations of the dialysis solutions may saturate physiological glucose metabolism pathways and stimulate the polyol pathway that has been described to damage nerves and vessels in diabetes mellitus. To investigate the role of the polyol pathway in the development of fibrosis and angiogenesis during chronic peritoneal exposure, the rate-limiting aldose reductase activity in the polyol pathway was inhibited in a chronic peritoneal exposure model in the rat, in which different administration routes were compared. EXPERIMENTAL PROCEDURES: Three groups of rats received daily intraperitoneal infusion with lactate/glucose (3.86%)--containing dialysate via a peritoneal catheter with a subcutaneous puncture device, for 14 weeks: group 1 received only the dialysis solution, groups 2 and 3 received, in addition, zopolrestat, administered either orally (group 2) or intraperitoneally (group 3). After sacrifice, omental tissue was examined by histology for the presence of fibrosis (Picro Sirius Red) and the number of blood vessels (CD31). RESULTS: Histology revealed significantly less Picro Sirius Red-positive tissue in perivascular areas of both experimental groups and submesothelial areas of the oral group in comparison to the control group. There were significantly fewer CD31-positive vessels perfield in both groups treated with zopolrestat compared to the infusion-only group: group 2, 9 (7 - 12); group 3, 17 (13 - 38), compared to group 1, 37 (32 - 39), p < 0.05. CONCLUSION: The combination of peritoneal exposure to dialysis fluids and administration of zopolrestat, a newly developed inhibitor of aldose reductase activity, resulted in less fibrosis and fewer peritoneal vessels than exposure to dialysis fluids only, in a long-term exposure model in the rat. Inhibition of the polyol pathway may thus offer an important contribution to allow long-term continuation of peritoneal dialysi

Alpha-2-macroglobulin and albumin are useful serum proteins to detect subclinical peritonitis in the rat

BACKGROUND: In experimental peritoneal dialysis (PD) studies, the occurrence of peritonitis is a confounder in the interpretation of effects of chronic peritoneal exposure to dialysis solutions. Since fluid cannot be drained in most experimental PD models in the rat, it is impossible to diagnose peritonitis based on dialysate white blood cell counts. To study the value of serum markers for the presence of peritonitis, alpha-2-macroglobulin (alpha2M) and albumin were measured in rats with and without peritonitis after chronic exposure to dialysis solutions. To further investigate the time course of these markers in relation to the severity of peritonitis, nondialyzed rats were challenged with increasing numbers of bacteria and followed for 28 days. METHODS: In the first study, alpha2M and albumin were measured in rats exposed to glucose/lactate-based dialysis fluid before sacrifice. A comparison was made between animals with peritonitis, as judged from the presence of extensive infiltrates after sacrifice (gold standard) and/or clinical signs of peritonitis, or absence of peritonitis and infiltrates. In the second study, rats were intraperitoneally (IP) injected with 3 different concentrations of Staphylococcus aureus, and serum alpha2M and albumin were measured at various time points. RESULTS: In the first study, serum alpha2M was higher and serum albumin was lower in animals with peritonitis compared to animals without peritonitis (both p 40 mg/L and albumin 40 mg/L and albumin < 32 g/L are strong indicators for peritonitis. However, normal values do not exclude infectious peritonitis

Alpha-2-macroglobulin and albumin are useful serum proteins to detect subclinical peritonitis in the rat

BACKGROUND: In experimental peritoneal dialysis (PD) studies, the occurrence of peritonitis is a confounder in the interpretation of effects of chronic peritoneal exposure to dialysis solutions. Since fluid cannot be drained in most experimental PD models in the rat, it is impossible to diagnose peritonitis based on dialysate white blood cell counts. To study the value of serum markers for the presence of peritonitis, alpha-2-macroglobulin (alpha2M) and albumin were measured in rats with and without peritonitis after chronic exposure to dialysis solutions. To further investigate the time course of these markers in relation to the severity of peritonitis, nondialyzed rats were challenged with increasing numbers of bacteria and followed for 28 days. METHODS: In the first study, alpha2M and albumin were measured in rats exposed to glucose/lactate-based dialysis fluid before sacrifice. A comparison was made between animals with peritonitis, as judged from the presence of extensive infiltrates after sacrifice (gold standard) and/or clinical signs of peritonitis, or absence of peritonitis and infiltrates. In the second study, rats were intraperitoneally (IP) injected with 3 different concentrations of Staphylococcus aureus, and serum alpha2M and albumin were measured at various time points. RESULTS: In the first study, serum alpha2M was higher and serum albumin was lower in animals with peritonitis compared to animals without peritonitis (both p 40 mg/L and albumin 40 mg/L and albumin < 32 g/L are strong indicators for peritonitis. However, normal values do not exclude infectious peritoniti