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It has recently been demonstrated that the rate of both hydrogen and potassium excretion can be acutely increased when a disproportion is created between the quantity of sodium and the quantity of penetrating anion available for reabsorption (1). This experimental condition was achieved by the infusion of neutral sodium phosphate into animals which had previously been maintained on a diet poor in sodium chloride. Such short-term observations raised the possibility that sustained changes in availability of penetrating anion might of themselves induce chronic alterations in body fluid composition. This hypothesis was supported by the subsequent observation that restriction of dietary chloride prevents correction of plasma bicarbonate elevations induced by chronic hypercapnia or administration of desoxycorticosterone acetate (DOCA) (2, 3). In each of the latter circumstances, however, the elevated plasma bicarbonate presumably developed as a result of direct acceleration of sodium-cation exchange and these observations, therefore, throw no light on the possible consequences of a primary loss of chloride in a normal animal. Such a loss might be expected to produce either secondary sodium (and volume) depletion, diversion of sodium reabsorption to the cation-exchange mechanism, or some combination of the two. In order to investigate this problem, chloride deficiency has been produced in dogs by the repeated infusion of nitrate, an anion known to induce chloruresis (4).

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The impairment of binding drugs and other substances to serum albumin in patients with uremia can be restored to normal or near normal levels by adsorption with charcoal or synthetic polymers at pH 3. We used a nonionic poly-styrene-divinylbenzene copolymer to treat uremic plasma at pH 3. We observed a marked improvement of binding. Subsequent elution of this resin with ethanol produced a substance that, when dried and recombined with normal plasma, caused dose-dependent impairment of phenytoin and tryptophan binding. Restoration of normal binding affinity occurred after retreatment of this abnormalized plasma with resin at pH 3. Plasma and pleural fluid exudate from patients with uremia yielded, after extraction by the above technique, and inhibitor(s) of phenytoin binding in amounts averaging five times that extracted from equal volumes of normal plasma. This inhibitor (IX) is water soluble, heat stable, and dialyzable across cellophane membranes. Unlike fatty acids, which can also interfere with binding, IX partitions primarily in the water phase in solvent partition studies but undergoes a sharp transition in th pH 4 to 5 range, suggesting the presence of carboxyl group. These findings lend further support to the hypothesis that a retained ligand(s) is responsible for impaired plasma binding associated with uremia and suggests a role for organic acids known to accumulate in renal failure.