Pathophysiologic Effects of Uremic Retention Solutes

Abstract

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 (1,2,3). 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 functions; if they do so, they contribute to the uremic syndrome. Only a few solutes have an established role as uremic toxins. According to Bergoström, apart from inorganic compounds, urea, oxalic acid, parathyroid hormone (PTH), and β2-microglobulin 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 uremic 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 concentration. (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 vitamin 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. Removal of intracellular compounds during dialysis through the cell membrane may be hampered, resulting in multicompartmental kinetics and inadequate detoxification. It is of note that lower morbidity and mortality are observed in patients submitted 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 clinical impact of those compounds that have been subjected to relatively thorough evaluation during these last 10 years. Specific attention was also paid to generation and removal patterns. Urea In spite of the extensive number of studies to which urea has been submitted relative to its toxicity, the number of reports in which a well-defined adverse biochemical or physiologic impact has been reported is relatively low. However, in a classical study by Johnson et al., it was demonstrated that dialysis against dialysate containing high urea concentrations worsens clinical symptoms (8). Several recent studies point to an important pathophysiologic impact of urea. Lim et al. have shown that urea inhibits NaK2Cl cotransport in human erythrocytes (9), as well as a number of cell volume-sensitive transport pathways. The NaK2Cl cotransport is a ubiquitous process that serves numerous vital functions, among which cell volume and extrarenal potassium regulation are the most important. Extracellular urea also decreases cAMP production, albeit at concentrations exceeding those observed in clinical uremia (10). The presence of urea in blood has been held responsible for a decreased affinity of oxygen for hemoglobin because of 2,3-diphosphoglycerate binding (11). Urea inhibits macrophage inducible nitric oxide synthesis at the posttranscriptional level (12). Apart from its direct toxicity, urea is a precursor of some of the guanidines, especially guanidinosuccinic acid (see below), which by itself induces direct biochemical alterations. As the most important osmotically active solute, urea may also provoke dialysis dysequilibrium, if the decrease in plasma concentration during dialysis occurs too rapidly. Urea is unequivocally recognized as a marker of solute retention and removal in dialyzed patients. It is one of the few solutes that have been correlated convincingly with clinical outcome of hemodialysis (13). However, it is not the peak concentration per s