MIDDLE-SIZED MOLECULE FRACTIONS-ISOLATED FROM UREMIC ULTRAFILTRATE AND NORMAL URINE INHIBIT INGESTIVE BEHAVIOR IN THE RAT

Uremic patients with suppressed food intake may regain appetite soon a fter starting dialysis, presumably because of the removal of one or mo re toxic factors that suppress appetite. To investigate this matter, t his study used a new experimental model in free-moving, unstressed mal e Wistar rats (300 to 350 g) with feeding catheters channeled from the top of the skull to the oral cavity. When the rats recovered from sur gery, they were tested under standardized conditions by being given an intraoral infusion (1 mL/min) of a 1 M sucrose solution or a 97 g/L p rotein solution or a mixed solution of carbohydrate, protein, and fat (Fortimel(R) (Nutricia Nordica AB, Stockholm, Sweden)) while the time (volume) of ingestion was recorded, Solutions to be tested for their a bility to inhibit ingestion were injected intraperitoneally (ip) and t he intraoral infusion was started 20 min later. Plasma ultrafiltrate w as collected from end-stage renal failure patients by isolated ultrafi ltration at the beginning of their first hemodialysis and pooled. Ultr afiltrate was also obtained by filtering pooled plasma from healthy vo lunteers in vitro, using the same type of dialyzer and cellulose aceta te membranes as those used in the uremic patients. Morning urine sampl es from healthy volunteers were pooled and subjected to the same in vi tro filtration procedure as the normal plasma. Intraperitoneal injecti on of 20 mL normal ultrafiltrate had no effect on sucrose ingestion, w hereas injection of 20 mL uremic ultrafiltrate reduced the ingestion o f sucrose solution by 23% and the ingestion of Fortimel(R) by 17%. Ten mL of ultrafiltrate from normal urine reduced the sucrose intake by 4 2%. The pooled ultrafiltrates from normal and uremic plasma and normal urine were subjected to molecular filtrations using a series of membr anes with known cut-off points. The filtrations yielded four concentra ted fractions with molecular weight ranges of 0.1 to 0.5 kilodaltons ( kd), 0.5 to 1 kd, 1 to 5 kd, and 5 to 10 kd, respectively; the plasma fractions were concentrated a factor of about 25.1 and the urine fract ions by about 15:1. After an ip injection of 2 mL of each concentrated plasma fraction, only the 1 to 5 kd fraction from the uremic ultrafil trate inhibited sucrose intake, whereas the corresponding fraction fro m the normal ultrafiltrate had no effect. After injection of 1, 3, and 5 mL of the concentrated fractions of uremic ultrafiltrate, a dose-de pendent inhibition of sucrose intake was achieved with the 1 to 5 kd f raction and, to a lesser extent, with the 5 to 10 kd fraction. Intrape ritoneal injection of 0.5, 1.0, and 2 mL of the concentrated 1 to 5 kd fraction, but not of the other fractions from normal urine, also resu lted in a dose-dependent inhibition of sucrose intake. The 1 to 5 kd f ractions from the uremic ultrafiltrate and the normal urine ultrafiltr ate also inhibited protein intake in a dose-dependent manner. These re sults suggest that one or more toxic compounds in the middle-molecule weight range, which are normally excreted in the urine, accumulate in uremia and suppress food intake.