Protein uremic toxins

Urea Pharmacokinetics. Pharmacokinetics summarizes the relationships between solute generation, solute removal, and concentration in a patient s blood stream. In the context of hemodialysis, this analysis is most readily appHed to urea, which has, as a consequence, become a surrogate for other uremic toxins in the quantitation of therapy and in attempts to describe its adequacy. In the simplest case, a patient is assumed to have no residual renal function. Urea is generated from the breakdown of dietary protein, accumulates in a single pool equivalent to the patient s fluid volume, and is removed uniformly from that pool during hemodialysis. A mass balance around the patient yields the following differential equation ... 

Sarnatskaya V, Yushko L, Nikolaev A et al (2007) New approaches to the removal of protein-bound toxins from blood plasma of uremic patients. Artif Cells Blood Substit ImmobU Biotechnol 3 287-308... 

Keywords Uremic toxins Protein bound toxins... 

The results of microcolumn experiments presented in Fig. 29.9 prove that perfusion through HSGD purifies HSA from a mixture of uremic toxins, which have high, medium and low affinity with albumin (Table 29.1) [11]. The results show that even after 4 h of perfusion the concentration of all three protein-bound uremic toxins remains low, and their clearance is respectively high [10]. 

Operationally, dialysis (cf. Section 8.2) utilizes differences in the diffusion rates of various substances across a membrane between two liquid phases. The diffusivities of substances in the membrane and liquid phases (particularly the former) decrease with increasing molecular sizes of the diffusing substances. Thus, with any hemodialyzer, the rates of removal of uremic toxins from the blood will decrease with increasing molecular size, although sharp separation at a particular molecular weight is difficult. In contrast, proteins (e.g., albumin) should be retained in the patient s blood. In the human kidney, small amounts of albumin present in the glomerular filtrate are reabsorbed in the proximal tubule. 

Infectious diseases are common and result in significant morbidity and mortality in patients with ESKD. Although multiple abnormalities in host defenses and an increased susceptibility to infection have been described, the causal link between these observations remains speculative. Absolute lymphopenia and impaired cell-mediated immunity are common in ESKD patients and may be caused by uremic toxins or protein-calorie malnutrition. Although plasma concentrations of IgG, IgM, and IgA are usually normal, antibody responses appear to be significantly depressed. Patients requiring dialysis have many problems with vascular access which puts them at higher risk for exposure to infectious sources. The risk of infections in patients with CKD, and particularly ESKD, is an important consideration when reviewing the clinical presentation of a patient, as hospitalization rates for infection and sepsis have increased dramatically in the last 10 years. ... 

Urea, the end product of nitrogen metabolism, accumulates rapidly in ARF. Most patients with ARF have a primary stressful illness that results in ureagenesis, and thus protein breakdown is markedly accelerated. Protein catabolism in ARF may be stimulated as the result of insulin resistance, metabolic acidosis, circulating proteases and inflammatory mediators, and the effects of uremic toxins. The mechanism may be direct, via modulation of protein synthesis, or indirect, by inhibiting the action of anabolic hormones. ... 

Artificial kidney designs will likely continue to experience incremental improvements in the materials and hemodynamic areas. New developments in biocompatible materials, superior transport methods for toxin removal, and improved patient management techniques will allow further maturation of hemodialysis and hemofiltration therapy. For example, considerable benefits could be realized from selective toxin removal without concomitant elimination of beneficial proteins. It has been suggested that future devices might utilize the absorption removal pathway with affinity methods as a primary technique to eliminate specific uremic toxins (Klinkmann and Vienken, 1995). 

Cresol and hippuric acid are included among uremic toxins. p-Cresol (4-methylphenol) is a volatile, low-molecular-weight phenolic compound that is largely protein-bound, mainly to albumin, with partial lipophilic properties. It is related to several biochemical, biological, and physiological functions at concentrations currently observed in uremia. 

Further complications may arise in that uremic toxicity depends on individual patient characteristics [72] and an increased capacity of the albumin molecule to bind toxins in the uremic state [73, 74], that leads to the accumulation of protein-bound uremic toxins. Consequently, either protein-permeable membranes will play a major role in the future or adsorber systems should be implemented in addition. 

Protein-Bound Uremic Toxins Among the 20 protein-bound uremic toxins identified in the EUTox review (Vanholder et al., 2003), leptin and retinol binding protein were middle molecules, and 18 others were small solutes (MW < 500 Da). Some of these protein-bound molecules exert a toxic effect at concentrations observed in dialysis patients. For example, the 3-carboxy-4-methyl propylfuranpropionic acid, which is 98% bound to albumin, inhibits erythropoiesis (Niwa et al., 1990). Similarly, P-cresol and indoxyl sulfate, both of which are nearly 100% protein bound, inhibit endothelial... 

Garcia, A. Heinanen, M. Jimenez, L.M. Barbas, C. Direct measurement of homovaniUic, vaniUylmandehc and 5-hydroxyindole acetic acids in urine by capillary electrophoresis. J. Chromatogr., A 2000, 871, 341-350. Vanholder, R. de Smet, R. Lameire, N. Protein bound uremic solutes The forgotten toxins. Kidney Inter., Suppl. 2001, 78, S266-S270. 

Vanholder R, De Smet R Lameiie N. (2001). Protein-bound uremic solutes The forgotten toxins. Kidney int 59 (Suppl. 78), S266-S270. 

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