Factors inhibiting ingestive behavior in chronic renal failure

Sammanfattning: FACTORS INHIBITING INGESTIVE BEHAVIOR IN CHRONIC RENAL FAILURE THESIS BY ABDEL-HAFIZ MAMOUN, 1997, KAROLINSKA INSTITUTE, DIVISIONSOF RENAL MEDICINE AND BAXTER NOVUM DEPARTMENT OF CLINICAL SCIENCE AND DEPARTMENTOF APPLlED NEUROENDOCRINOLOGY S-l41 86 HUDDINGE, SWEDEN Protein-energy malnutrition and wasting occur in many patients with chronic renalfailure. Reduced nutrient intake because of anorexia, nausea and vomiting, causedby uremic toxicity is an important factor. Regular dialysis therapy results in thereduction or disappearance of anorexia, suggesting that one or more dialyzable compoundscause these toxic symptoms. We used a model for studying the ingestive behavior ofconscious, free-moving rats. They were fitted with intraoral cannulas and connectedto a peristaltic pump which delivers a diet solution (Iml/min) and the time (volume)of ingestion was determined. The model was used for basic physiological studies ofthe role of glucose, amino acids and cholecystokinin octapeptide (CCK-8) in appetiteregulation as well as for specific studies on the effect of peritoneal dialysis solutionsand uremic toxins on ingestive behavior. The inhibitory effect of CCK-8 on ingestion of a protein diet was compared tothat on ingestion of a carbohydrate diet. This effect lasted for 4 hrs. Injectionof CCK-8 inhibited intake of carbohydrate but not protein. Conversely, injectionof the CCK-A receptor antagonist L-364,718 facilitated intake of carbohydrate, butnot protein. Ingestion of a protein diet caused a marked increase in the plasma levelof CCK-8 which declined to basal levels in about 4 hrs. Intake of protein also causeda large increase in plasma levels of amino acids, some of them with a time coursedescribing a mirror image of the inhibitory effect on ingestive behavior. The resultssuggest that release of CCK-8 into the general circulation is of no importance fortermination of the protein meal. Release of amino acids may be important satietysignal for protein ingestion. Intraperitoneal injection of up to 40 ml saline had no effect on carbohydrateor protien ingestion. Injection of 30 ml of peritoneal dialysis fluids containmg13.6, 22.7 and 38.6 g/l of glucose mduced a dose dependent inhibition of sucroseintake, but had no effect on protein intake, whereas injection of dialysis fluidscontaining 11, 18 and 31 g/a of amino acids reduced the intake of sucrose and proteinin a dose dependent manner. Our results indicate that inbibition of appetite causedby fluids containing glucose or amino acids is specific for each nutritional constituentand not simply an effect of hyperosmolality or large filling volume. Uremic and normal urine ultrafiltrates injected i.p. inbibited the ingestion ofboth carbohydrate and protein, but normal plasma ultrafiltrate had no effect. The1-5 kd subfraction (the middle molecule fraction, MM) isolated from uremic and normalurine ultrafiltrates elicited a dose-dependent inhibition of carbohydrate or proteinintake, whereas subfractions with lower molecular weight had no effect. These resultssuggest that toxic MM fractions which are normally excreted in the urine accumulatein uremia and may suppress appetite. Intraperitoneal and intercerebroventricularinjections 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 subfractionsact on the splanchnic region and brain to suppress ingestive behavior. To be effectiveintravenously, these MM subfractions must be given in higher doses to reach theirsite (s) of action because they are diluted in the general circulation. The MM mayact directly in the brain or via modifying neurotransmittors that regulate food intake.We demonstrated increased serotonin synthesis and doparnine turnover in uremic rats.Whether the effect of experimental uremia on cerebral monoamines is related to theeffect 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 increasedin 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. Hemodialysistreatment, 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 oxidedepletion may inhibit ingestive behavior in HD patients. Key words: rat, uremia, cholecystokinin octapeptide, nitric oxide, leptin, glucose,amino acids, anorexia, ingestive behavior, peritoneal dialysis solutions, hemodialysis ISBN 91-628-2682-4