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Pathophysiologic effects of uremic retention solutes.

The uremic syndrome can be defined as a deterioration of biochemical and physiologic functions, in parallel with the progression of renal failure, resulting in complex and variable symptomatology (1-3). The compounds that accumulate in the uremic blood and tissues during the development of end-stage renal disease (ESRD), directly or indirectly due to a deficient renal clearance, are called uremic retention solutes. These retention solutes may modify biochemical or physiologic func- tions; if they do so, they contribute to the uremic syndrome. Only a few solutes have an established role as uremic toxins. According to Bergstrom, apart from inorganic compounds, urea, oxalic acid, parathyroid hormone (PTH), and b2-micro- globulin conform to the most strict definition of uremic toxins (4). However, this does not preclude a potential toxic role for various other retention solutes (5). The following factors, which are not always considered, might affect uremic solute concentration and their impact on biologic functions. (1) In addition to classical sources of ure- mic solutes such as dietary protein breakdown, alternative sources such as environment, herbal medicines, or psychedelic drugs may play a role in uremic toxicity. (2) Many solutes with toxic capacity enter the body through the intestine. Changes in the composition of intestinal flora, or changes in intestinal production and absorption, might alter their serum concentra- tion. (3) Some uremic solutes interfere with functions that directly affect the biochemical action of other solutes: the expression of PTH receptors, the response to 1,25(OH)2 vita- min D3, as well as the protein binding and breakdown of several other solutes. (4) Most uremic patients are prescribed a host of drugs. Interference of drugs with protein binding and/or tubular secretion of uremic solutes will influence their biologic effect. (5) Lipophilic compounds may be responsible at least in part for functional alterations in uremia. ( 6) The impact of residual renal function on uremic solute retention should not be neglected. (7) The main strategy that has been used up to now to decrease uremic solute concentration is dialysis, but dialysis is nonspecific and removes essential compounds as well. (8) Uremic solutes accumulate not only in the plasma but also in the cells, where most of the biologic activity is exerted. Re- moval of intracellular compounds during dialysis through the cell membrane may be hampered, resulting in multicompart- mental kinetics and inadequate detoxification. It is of note that lower morbidity and mortality are observed in patients submit- ted to long dialysis sessions (6,7). Compounds may be cleared more efficiently with continuous or long-lasting low efficiency strategies, because removal is more gradual. Our views on the uremic syndrome and several uremic solutes have changed substantially during the last decade. Therefore, it was thought timely to summarize the present state of knowledge about the biochemical, physiologic, and/or clin- ical impact of those compounds that have been subjected to relatively thorough evaluation during these last 10 years. Spe- cific attention was also paid to generation and removal pat- terns.