Attenuation of nephrotoxicity by a novel lipid nanosphere (NS-718) incorporating amphotericin B.
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NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low toxicity. We compared the toxicity of NS-718 with that of Fungizone (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood urea and creatinine concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the nephrotoxicity of amphotericin B. (+info)
Primary role of renal homografts in setting chronic blood pressure levels in rats.
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The genotype of homograft kidneys plays the primary role in determining chronic blood pressure levels in two strains of rats with opposite genetically controlled propensities for hyptertension. In hypertensive rats from the hypertension-prone (S) strain, a renal homograft from the same strain resulted in a slight rise in blood pressure to a level that was equivalent to that in appropriate uninephrectomized S controls. In contrast, a renal homograft from the hypertension-resistant (R) strain led to a sharp fall in blood pressure in hypertensive S recipients. Opposite results were found when the host came from the R strain: R homografts maintained the same low pressure as that seen in controls, whereas S homografts resulted in hypertension. We concluded that genetically controlled factors operating through the kidney can chronically modify the blood pressure up or down. The central role of the kidney in hypertension is thus further documented. (+info)
Poly IC therapy in aleutian disease of mink.
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Twenty-four virgin female aleutian mink were infected with aleutian disease agent and after 24 hours, 12 of these were treated with a course of polyinosinic acid-polycytidilic acid (Poly IC) injections. After six weeks the gammaglobulin level was significantly lower in the treated group but at 12 weeks this difference was no longer present. Four of the treated mink had normal target organ histology when killed at 20 weeks. The untreated group all showed moderate to marked changes but this difference was not statistically significant. There was a marked increase in the reactive lymphocyte blastogenesis index during the first weeks of infection and the phytohaemagglutinin response was seen to fall progressively. The antiglobulin reaction usually became positive after infection but neither antinuclear nor antierythrocyte antibodies were found. Precipitating antibodies to several polynucleotides were frequently present and were unrelated to infection or to Poly IC treatment. (+info)
Immunologic enhancement of rat renal allografts. III. Immunopathologic lesions and rejection in long-surviving passively enhanced grafts.
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Immunologic enhancement of renal allografts from (Lewis times Brown Norway) F1 to Lewis rats was achieved by administering a single dose of antidonor serum at the time of transplantation. A series of grafts functioning for 1 to 4 months after transplantation were examined by light and immunofluorescence microscopy to evaluate the long-term protective effects of the enhancing serum and to determine if previously unobserved lesions appeared in long survivors. Despite the absence of detectable circulating cytotoxic alloantibody, long-term allografts showed necrotizing glomerular and arterial lesions which resembled those seen in acutely rejecting grafts and were compatible with humoral rejection. Thus, in this model, there is a late decline in the ability of passive enhancement to inhibit humoral rejection. Long-term grafts also developed tubular lesions with deposition of immunoglobulin and complement on the tubular basement membranes (TBM). Anti-TBM antibodies were demonstrated in recipients' sera and found to be organ specific but not major histocompatibility antigen or species specific. This tubular lesion is therefore a unique form of allograft injury in which the immune response is directed against tissue antigen(s) which are distinct from the major histocompatibility antigens that induce rejection. (+info)
Metallothionein-I/II null mice are sensitive to chronic oral cadmium-induced nephrotoxicity.
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Chronic exposure to cadmium (Cd) via food and drinking water is a major human health concern. We have previously shown that metallothionein (MT), a metal-binding protein, plays an important role in protecting against Cd toxicity produced by repeated sc injections. However, it is unclear whether MT protects against Cd-induced nephrotoxicity following chronic oral exposure, a route with obvious human relevance. To clarify this issue, MT-I/II knockout (MT-null) and background-matched wild-type (WT) mice were allowed free access to drinking water containing CdCl(2) (30, 100, and 300 ppm Cd), or feed containing CdCl(2) (100 ppm Cd) for 6 months, and the resultant nephrotoxicity was examined. Chronic oral Cd exposure produced a dose-dependent accumulation of Cd in liver and kidney of WT mice, reaching levels up to 50 microg Cd/g tissue. Immunohistological localization of renal MT indicated that chronic oral Cd exposure in WT mice greatly increased MT in the proximal tubules and the medulla, with cellular localization in both the cytoplasm and nuclei. As expected, no MT was detected in kidneys of MT-null mice. After 6 months of Cd exposure, tissue Cd concentrations in MT-null mice were only about one-fifth of that in WT mice. Even though the renal Cd concentrations were much lower in the MT-null mice, they were more sensitive than WT mice to Cd-induced renal injury, as evidenced by more severe nephropathic lesions, increased urinary excretion of gamma-glutamyl-transferase and glucose, and elevated blood urea nitrogen. Six months of Cd exposure to MT-null animals resulted in greater increases in renal caspase-3 activity, an indicator of apoptosis, than to WT mice. In conclusion, this study demonstrates that lack of MT renders MT-null mice vulnerable to Cd-induced nephrotoxicity after chronic oral exposure, the primary route of human Cd exposure. (+info)
Histidine supplementation for treatment of anaemia of uraemia.
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The effects of supplemental histidine on the anaemia of 16 chronically uraemic patients and 26 patients undergoing maintenance dialysis were assessed. Patients were given either L-histidine 4 g/day or placebo for a mean of 17-5 weeks in a randomized double-blind controlled study. Haemoglobin and packed cell volume increased slightly and to a similar degree in the patients on dialysis receiving placebo and histidine, but this change was statistically significant only in those on placebo. Plasma histidine rose significantly in the histidine-treated patients undergoing dialysis and decreased in the uraemic patients receiving placebo. These results suggest that supplementary L-histidine in patients with uraemia or patients undergoing maintenance dialysis does not improve anaemia. (+info)
Urea kinetic analysis of automated peritoneal dialysis allows calculation of a CAPD-equivalent Kt/V(urea).
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BACKGROUND: Based on evidence of increased mortality with decreasing urea clearance, the Dialysis Outcomes Quality Initiative (DOQI) recommended a weekly Kt/Vurea of 2.0 or higher for patients receiving continuous ambulatory peritoneal dialysis (CAPD). DOQI recommendations for automated peritoneal dialysis (APD) are based on efforts to determine the clearance providing urea mass removal equivalent to CAPD. We have adapted a variable volume direct quantitation urea kinetic model (UKM) in an effort to assess DOQI APD guidelines. METHODS: The daily urea mass removed with a weekly Kt/Vurea of 2.0 was calculated using standardized CAPD patient profiles. Using this value and defining the pre-APD plasma urea nitrogen (PUN) as C0 and equal to the CAPD steady-state PUN, the UKM reiteratively calculated the urea clearance from an APD treatment that provided a urea mass removal equivalent to CAPD. A total weekly Kt/Vurea was calculated for various levels of continuous urea clearance (defined as Kprt/Vurea) and plotted against Kprt/Vurea (weekly). The impact of dialytic time (t), drain volume of the daytime dwell (delta), and ultrafiltration volume (phi) were assessed, and all profiles were performed with C0 equal to the corresponding blood urea nitrogen of 60, 70, and 80 mg/dL. RESULTS: The relationship between requisite weekly Kt/Vurea and Kprt/Vurea (weekly) was linear. Weekly Kt/Vurea declined with increasing Kprt/Vurea, t, delta, and phi. The effect of phi on the weekly Kt/Vurea was independent of Kprt/Vurea, and the magnitude of the effect of t and delta on the weekly Kt/Vurea decreased with increasing continuous clearance. Weekly Kt/Vurea values were independent of V and C0. The latter observation allowed extrapolation of CAPD clearance and urea generation relationships to APD: CAPD-equivalent weekly Kt/Vurea = [700 x (UD + Ur)]/(C0 x V), where UD and Ur are the daily urea mass (mg) in dialysate and urine, respectively. CONCLUSIONS: The APD urea clearance, which provides urea mass removal equivalent to CAPD, varies as a function of a combination of patient and treatment variables. However, a CAPD-equivalent weekly Kt/Vurea can be calculated by collecting appropriate dialysis and urine samples and estimating patient V. The results can be evaluated in the context of evidence-based CAPD guidelines, increasing the precision of adjustment and monitoring of the APD prescription. (+info)
Fat oxidation, lipolysis, and free fatty acid cycling in obesity-prone and obesity-resistant rats.
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Defects in fat metabolism may contribute to the development of obesity, but what these defects are and where they occur in the feeding/fasting cycle are unknown. In the present study, basal fat metabolism was characterized using a high-fat diet (HFD)-induced model of obesity development. Male rats consumed a HFD (45% fat, 35% carbohydrate) ad libitum for either 1 or 5 wk (HFD1 or HFD5). After 1 wk on the HFD, rats were separated on the basis of body weight gain into obesity-prone (OP, > or =48 g) or obesity-resistant (OR, +info)