Nephrotoxicity of Cyclosporine A in the Rat

Abstract

Cyclosporine A (15,30 or 50 mg/kg day) or olive oil (30 mg/kg day) were administered orally to 32 male Sprague-Dawley rats for 12 or 24 days, or withdrawn for 24 days following 24 days of treatment. The specific activity of a lysosomal marker enzyme N-acetyl-β-D-glucosaminidase was determined fluorometrically in single nephron segments microdissected from lyophilized kidney sections of these animals and of an additional 2 normal rats. The segments were classified according to their normal or reduced succinate dehydrogenase activity as detected in stained adjacent sections. In addition, urine specimens collected after 12, 24, 36, and 48 days of the experiment were tested for N-acetyl-β-D-glucosaminidase activity. After treatment with cyclosporine A, changes in the activities of N-acetyl-β-D-glucosaminidase were found only in the proximal tubules. In the convoluted segments with normal succinate dehydrogenase activity, the activity of N-acetyl-β-D-glucosaminidase was 138-163%, and in those with reduced succinate dehydrogenase activity, it was unchanged or 66-83% of the control values. In the straight segments with reduced succinate dehydrogenase activity, the activity of N-acetyl-β-D-glucosaminidase increased gradually along the medullary rays (122-214%) to the outer stripe of the outer medulla (178-263%) in comparison to the control values. In the urine specimens, the activity of N-acetyl-β-D-glucosaminidase was increased to 148-152%. These tubular and urinary changes were similar for each dosage and treatment period. After withdrawal of cyclosporine A they were not present. The variety of alterations occurring within the lysosomes along the proximal tubules of cyclosporine-A-treated rats implies the convoluted part as the site of increased release of N-acetyl-β-D-glucosaminidase into the urine.

Magnesium Metabolism: Basic Aspects and Implications of Ciclosporine Toxicity in Rats

“…Fractional excretion of filtered Mg (FEMg) was calculated with the following equation: FEMg = (urinary Mg/MgS) x (serum creatinine/ urinary creatinine) x 100. A sa measure o f proximal tubular damage N-acetyl-()-£>-glucosaminidase was determined fluoromctrically [23]; enzyme levels were expressed as micromoles per minute per milli mole of urinary creatinine. The urine sodium concentration was measured with a flame photometer (flame photometer AFM 5051, Eppcndorf.…”

Physical and geometric constraints shape the labyrinth-like nasal cavity

“…Numerical simulations presented in the SI confirm this picture and show that the scalar exchange efficiency is actually higher than predicted by (6), because the scalar profile is typically not fully developed and entrance effects matter. Taken together, we conclude that a gradient boundary condition, as observed in nature [34], can improve the recapturing of heat and humidity, at the expense of a lowered exchange efficiency during inhalation. Note that this lower efficiency is approximately compensated by entrance effects that improve the exchange efficiency, so we expect (7) to work for nasal cavities with gradient boundary conditions and realistic lengths.…”