Factors inhibiting ingestive behavior in chronic renal failure

Protein-energy malnutrition and wasting occur in many patients with chronic renal failure. Reduced nutrient intake because of anorexia, nausea and vomiting, caused by uremic toxicity is an important factor. Regular dialysis therapy results in the reduction or disappearance of anorexia, suggesting that one or more dialyzable compounds cause these toxic symptoms. We used a model for studying the ingestive behavior of conscious, free-moving rats. They were fitted with intraoral cannulas and connected to a peristaltic pump which delivers a diet solution (1 ml/min) and the time (volume) of ingestion was determined. The model was used for basic physiological studies of the role of glucose, amino acids and cholecystokinin octapeptide (CCK-8) in appetite regulation as well as for specific studies on the effect of peritoneal dialysis solutions and uremic toxins on ingestive behavior.

The inhibitory effect of CCK-8 on ingestion of a protein diet was compared to that on ingestion of a carbohydrate diet. This effect lasted for 4 hrs. Injection of CCK-8 inhibited intake of carbohydrate but not protein. Conversely, injection of the CCK-A receptor antagonist L-364,718 facilitated intake of carbohydrate, but not protein. Ingestion of a protein diet caused a marked increase in the plasma level of CCK-8 which declined to basal levels in about 4 hrs. Intake of protein also caused a large increase in plasma levels of amino acids, some of them with a time course describing a mirror image of the inhibitory effect on ingestive behavior. The results suggest that release of CCK-8 into the general circulation is of no importance for termination of the protein meal. Release of amino acids may be important satiety signal for protein ingestion.

Intraperitoneal injection of up to 40 ml saline had no effect on carbohydrateor protein ingestion. Injection of 30 ml of peritoneal dialysis fluids contain mg 13.6, 22.7 and 38.6 g/l of glucose induced a dose dependent inhibition of sucrose intake, but had no effect on protein intake, whereas injection of dialysis fluids containing 11, 18 and 31 g/a of amino acids reduced the intake of sucrose and protein in a dose dependent manner. Our results indicate that inhibition of appetite caused by fluids containing glucose or amino acids is specific for each nutritional constituent and not simply an effect of hyperosmolality or large filling volume.

Uremic and normal urine ultrafiltrates injected i.p. inhibited the ingestion of both carbohydrate and protein, but normal plasma ultrafiltrate had no effect. The 1-5 kd subfraction (the middle molecule fraction, MM) isolated from uremic and normal urine ultrafiltrates elicited a dose-dependent inhibition of carbohydrate or protein intake, whereas subfractions with lower molecular weight had no effect. These results suggest that toxic MM fractions which are normally excreted in the urine accumulate in uremia and may suppress appetite. Intraperitoneal and intercerebroventricular injections of the MM subfractions had a potent inhibitory effect on ingestive behavior, but had a less marked effect when given intravenously, suggesting that these MM subfractions act on the splanchnic region and brain to suppress ingestive behavior. To be effective intravenously, these MM subfractions must be given in higher doses to reach their site (s) of action because they are diluted in the general circulation. The MM may act directly in the brain or via modifying neurotransmittors that regulate food intake. We demonstrated increased serotonin synthesis and dopamine turnover in uremic rats. Whether the effect of experimental uremia on cerebral monoamines is related to the effect of the MM observed here is, however, an open question.

Nitric oxide synthesis was markedly inhibited in predialyzed uremic patients, but increased after hemodialysis (HD) and not influenced by feeding. CCK-8 was increased in HD patients at the end of the meal and returned to the fasting level 4 hrs later. Leptin was 4-fold higher in HD patients and remained unaffected after the meal. Hemodialysis treatment, however, influenced neither the fasting concentrations of CCK-8 nor leptin. These results suggest that accumulation of CCK-8 and leptin as well as nitric oxide depletion may inhibit ingestive behavior in HD patients.