The effects of haemodialysis and metabolic acidosis on protein metabolism

Abstract: Chronic renal failure and uraemia are characterised by gradual loss of renal function with an accumulation of metabolic and toxic waste products as well as disturbances in several organs and hormone functions. Two factors affect the catabolism in renal failure - i.e., the haemodialysis procedure and metabolic acidosis. This thesis deals with how haemodialysis treatment and metabolic acidosis affect muscle protein metabolism. Both factors influence body composition and metabolism as well as long-term well-being and morbidity in patients on maintenance haemodialysis. Several methods were used to study various aspects of protein metabolism. The aims were to investigate the effects of haemodialysis, metabolic acidosis and a cortisol challenge on muscle free amino acids and muscle protein synthesis and degradation. In haemodialysis patients and healthy subjects, we studied haemodialysis with the ribosome method and the concentrations of free amino acids in plasma and in muscle. After a single haemodialysis, the total concentration and the proportion of polyribosomes decreased by 29 ± 6% and 8 ± 4% (mean ± SEM, p<0.05), respectively, in the patients and by 22 ± 5% and 7 ± 2 % (p<0.01) in the healthy subjects. With the flooding-dose technique, the fractional synthesis rate decreased in healthy subjects by 13 ± 4% (p<0.05) after dialysis. We found a loss of 5.7 g amino acid and 21.4 g glucose to the dialysate. In haemodialysis patients, correction of acidosis over a period of 6 months normalised the intracellular free branched-chain amino acids. Leucine increased by 32%, isoleucine by 28% and valine by 48% after correction of acidosis and did not differ significantly from those in healthy subjects. Muscle protein metabolism was also studied in haemodialysis patients with metabolic acidosis. Correction of acidosis reduced protein degradation, expressed as a reduction in the efflux of several amino acids and of 3-methylhistidine from the leg, and as calculated by phenylalanine kinetics. Glucocorticoids given to healthy subjects were used to create a catabolic model and validate methods for studying muscle protein synthesis and degradation. Glucocorticoids in high doses increased protein breakdown, as assessed by phenylalanine kinetics, but had no significant effect on protein synthesis. No change was observed in the transcription of mRNAs for ubiquitin and proteasome C3 subunit after prednisolone. In summary, skeletal muscle protein metabolism was studied using several techniques reflecting various aspects of synthesis and degradation in volunteers as well as in patients. Muscle protein synthesis decreased in conjunction with the haemodialysis procedure and muscle protein degradation increased during metabolic acidosis. These studies show that haemodialysis and acidosis are important catabolic factors that influence body composition and metabolism, as well as long-term well-being and morbidity in patients on maintenance haemodialysis.