Review Does Hemodialysis Increase Protein Breakdown? Dissociation between Whole-Body Amino Acid Turnover and Regional Muscle Kinetics Victoria S. Lim,* T. Alp Ikizler, † Dominic S.C. Raj, ‡ and Michael J. Flanigan* *Department of Medicine, University of Iowa College of Medicine, Iowa City, Iowa; † Vanderbilt University School of Medicine, Nashville, Tennessee; and ‡ University of New Mexico Health Science Center, Albuquerque, New Mexico Hemodialysis (HD) is a protein catabolic procedure. Whole-body amino acid turnover studies identify dialysate amino acid loss and reduced protein synthesis as the catabolic events; proteolysis is not increased. Regional amino acid kinetics, however, document enhanced muscle protein breakdown as the cause of the catabolism; muscle protein synthesis also increased but to a lesser magnitude than the increment in protein breakdown. This discordance between whole-body and regional kinetics is best explained by the contrasting physiology between the muscle and the liver. During HD, muscle releases amino acids, which then are taken up by the liver for de novo protein synthesis. There seems to be a somatic to visceral recycling of amino acids. Evidence supporting this concept includes the increased fractional synthesis of albumin and fibrinogen during HD. It should be emphasized that region- or organ-specific kinetics vary, and whole-body turnover is a composite of all of the visceral and somatic compartments taken together. Reduced whole-body protein synthesis may be a compensatory adaptation to dialysate amino acid loss with a consequent reduction in plasma amino acid concentration. Notwithstanding the protein catabolic nature of HD, evidence is accumulating that intradialytic nutritional supplementation may blunt its catabolic effect. J Am Soc Nephrol 16: 862-868, 2005. doi: 10.1681/ASN.2004080624 U ntil recently, uremia was believed to be a protein catabolic state. This view is no longer tenable because numerous whole-body amino acid turnover studies have unequivocally revealed that there is no excess protein catabolism in the chronic renal failure population in the ab- sence of acidosis and/or concomitant illnesses (1). Uremic pa- tients respond to low-protein diets with appropriate down- regulation of whole-body proteolysis (2,3). Peritoneal dialysis is protein catabolic primarily because of protein and amino acid losses through the peritoneal effluent (4). The remaining unset- tled issue is whether hemodialysis (HD) induces protein catab- olism and, if it does, by what mechanism. There are theoretical reasons to believe that HD can augment protein catabolism. These include amino acid loss to the dialysate and cytokine- mediated proteolysis as a result of exposure to bio-incompati- ble membrane and endotoxin-contaminated dialysate, but to date, investigation of protein metabolism using different tech- niques has yielded conflicting results. Protein Metabolism during HD: A Review of the Literature This article reviews the available literature of protein metab- olism during HD and proposes a unifying hypothesis to explain the discordant results and diverging conclusions. The work cited in this review is categorized according to the technique used. Nitrogen Balance Combined with Urea Kinetics The seminal findings of Borah et al. (5) that nitrogen balance is always more negative or less positive, depending on the intake, on dialysis days compared with nondialysis days greatly influenced the belief that HD is a protein catabolic procedure. Lim et al. (6) also reported that nitrogen output, expressed as milligrams per minute, is greater when the inter- dialytic interval is 2 d as compared with 3 d, suggesting that each HD generates a certain degree of protein catabolism, the effect of which is minimized when the interdialytic interval is lengthened. The classical technique of nitrogen balance is in- take minus output. Output measurement is tedious for the study subjects as well as for the investigators because it re- quires urine, dialysate, and fecal collection, plus calculation of change in body urea nitrogen pool and unmeasured nitrogen loss. In the above-cited work of Borah and Lim, urea generation rate was probably overestimated by the use of unequilibrated postdialysis blood urea nitrogen. This determinate error likely accounts for the lesser nitrogen balance on dialysis days. De- spite the laborious nature of the work, nitrogen balance does not give insight into the various components that made up net nitrogen balance, and these include protein intake, breakdown, oxidation, synthesis, and others. The global nitrogen balance also does not furnish information regarding amino acid turn- over in the various region- and organ-specific protein pools. Published online ahead of print. Publication date available at www.jasn.org. Address correspondence to: Dr. Victoria S. Lim, Department of Medicine, Uni- versity of Iowa College of Medicine, Room T310, General Hospital, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. Phone: 319-356-3415; Fax: 319-384-8220; E-mail: victoria-lim@uiowa.edu Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1604-0862