Donald E. Oken

Renal and extrarenal considerations in high-dose mannitol therapy.

It is well recognized that the large doses of mannitol used in treating cerebral edema alter extracellular fluid (ECF) volume, osmolality, and composition to a degree which, under some circumstances, can lead to acute renal failure, cardiac decompensation, and other difficulties. It is less well appreciated that the patients body habitus, age, total body water content relative to body weight, pretreatment plasma sodium concentration and plasma osmolality, and the presence of edema or ascites also can influence the degree of ECF change and the rate of mannitol excretion to a significant degree. Here, we show how these changes occur and the way in which their magnitude can be predicted prior to therapy so as to minimize the risk of an adverse result.

Proximal tubule brush border alterations during the course of chromate nephropathy.

Abstract Tubular transport abnormalities reportedly predominate over alterations in glomerular filtration rate and epithelial morphology during the early phase of Na-chromate-induced acute renal failure. We have studied the role of the brush border membrane in the sequence of events after the subcutaneous injection of Na2CrO4 (20 mg/kg body weight) to rats. Brush border integrity was evaluated by ultrastructural criteria and the activities of several enzymes assayed in vitro on purified brush border membrane preparations. By electron microscopy, subtle alterations of microvillar morphology were present within 1 hr of chromate injection. Alkaline phosphatase activity declined significantly by 2 hr but represented the only brush border enzyme alteration at this earliest time of study. During 0–2 hr, Cin declined to 0.90 ± 0.04 ml/min from a control value of 1.30 ± 0.04 then increased during the 2–4 hr period to 1.09 ± 0.05 ml/min. The fractional excretion of lysozyme at 0–2 and 2–4 hr and of phosphate at 2–4 hr, and the urine excretion of N-acetyl-glucosaminidase at 0–2 and 2–4 hr increased significantly in chromate rats and exceeded values in saline-injected rats for the corresponding collection periods. [14C]Leucine incorporation into proteins of renal cortex and brush border was 50% or less of control at 2 hr after chromate. By 12–16 hr, brush border enzyme abnormalities were well established and became more severe with longer periods of observation coincident with advancing degrees of renal insufficiency. These results indicate that chromate-induced epithelial cell toxicity and tubular transport defects become operative within the first 2–4 hr after injection of Nachromate. Whereas injury to the brush border membrane is a feature of chromate nephropathy, the available evidence does not strongly favor the view that transport defects are attributable to microvillar pathology.

Renal function and mercury level in rats with mercuric chloride nephrotoxicity.

The levels of Hg++ in different subcellular compartments of rat kidney cortex were determined after a single subcutaneous injection of 203HgCl2, 4.7 mg/kg body weight. By 30 min after injection, cortical Hg++ level was 46.3 +/- 6.8 micrograms/g protein. A maximal cortical Hg++ value of 429 +/- 49 micrograms/g protein was reached 4 h after injection. Hg++ associated with the brush border membrane showed a progressive increase during the first 15 h after injection, but at each time interval was significantly less than cortical Hg++. The 45-hour values for cortex and brush border were equivalent. No evidence for the presence in plasma or kidney tissue of free Hg++ was obtained. Saline loading protected animals against the development of renal failure and resulted in significant lowering of cortical Hg++ levels without an effect on blood Hg++ concentration.

The effect of mercuric chloride on renal brush border membrane

Abstract Alterations in the activities of five brush border enzymes were determined in the kidneys of rats with reversible HgCl2 acute renal failure. Alanine aminopeptidase, gamma glutamyl transpeptidase, and alkaline phosphatase levels fell to 50% or less of control and remained depressed despite restoration of glomerular filtration. Maltase activity initially increased then gradually declined to control values by Day 3 after HgCl2. ATPase activity showed a progressive rise to levels 3.1 times normal by Day 10 after HgCl2. Electrophoresis of SDS solubilized brush border membranes revealed distinct differences in protein distribution of normal vs HgCl2 treated rats. The results indicate that recovery of renal function precedes normalization of brush border enzyme activity and demonstrate considerable variation in the composition of the brush border during the course of HgCl2 acute renal failure.

Renin release and the refractoriness to acute renal failure of rats recovering from prior renal failure.

Renin substrate concentrations and the release of renin in response to the rapid removal of 15 ml/kg weight blood or subcutaneous administration of 500 microgram/kg body weight isoproterenol were measured in control rats and animals recovering from prior myohemoglobinuric acute renal failure (recovery rats). Blood for these assayas was drawn from chronically implanted aortic catheters, obviating the need for animal handling and anesthesia. Baseline plasma renin titers of recovery rats were modestly elevated but renin substrate concentrations were the same as in controls. Hemorrhage produced equivalent changes in blood pressure and plasma renin titer in the two groups. Isoproternol injection in recovery rats caused a somewhat greater blood pressure fall and almost twice the rise in plasma renin concentration observed in control rats. The marked resistance of recovery animals to a second bout of acute renal failure thus cannot be attributed to impaired renin release or inadequate plasma renin substrate.

Simultaneous quantification of twenty-two amino acids in nanolitre samples of biological fluid

The technique of thin-layer chromatography and 14C-dansylation has been used for simultaneous measurements of 22 individual amino acids, taurine, serotonin, and gamma-aminobutyric acid in nanolitre samples of glomerular and renal tubule fluid. Standard curves of each amino acid mixture containing all the others showed excellent linearity at amounts ranging from 5.7.10(-13) to 1.45.10(-11) mole (regression coefficients all greater than 0.95). With careful standardization of dansylation conditions, the technique permits highly reproducible measurement of less than 1 pmole of an amino acid.