Toxins uremic

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 ... 

Continuous renal replacement therapy is used for the management of fluid overload and removal of uremic toxins in patients with acute renal failure and other conditions. Drug therapy individualization for patients receiving continuous renal replacement therapy is discussed in Chap. 75. 

European Uremic Toxin Work Group (EUTox), 26 820... 

Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T (2002) Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin Its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem 83 57-66... 

Kidney failure not only decreases renal clearance of nicotine and cotinine, but also metabolic clearance of nicotine (Molander et al. 2000). Metabolic clearance of nicotine is reduced by 50% in subjects with severe renal impairment compared to healthy subjects. It is speculated that accumulation of uremic toxins may inhibit CYP2A6 activity or downregulate CYP2A6 expression in liver. Hepatic metabolism of several drugs is reduced in kidney failure, mainly via downregulation of CYP enzymes and/or inhibition of transporters (Nolin et al. 2003). 

Keywords Uremic toxins Protein bound toxins... 

Table 29.1 contains examples of weakly, moderately and strongly bound uremic toxins, permeation of which through a dialysis membrane is hindered due to the size of albumin molecules associated with them. Although these toxins are small molecules, their complexes with HSA (MW 67,000 kD) are significantly larger and cannot diffuse through the membrane. 

Table 29.1 Parameters of HSA-Ugand complex formation with some uremic toxins Uremic toxin MW/D n K /(l(yxM ) n ICj/flO xM" )...

The addition of bilirubin or uremic toxin CMPF, which are strongly bound to HSA, alters the shape of the melting curve of serum albumin producing a bimodal curve, and causes a shift of the temperature maximum of the first peak to the right (Fig. 29.2) [7,8]. 

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]. 

Fig. 29.9 Inlet and time-dependent outlet concentrations of uremic toxins CMPF ( ), indoxyl sulfate ( ) and hippuric acid (/////) during 4 h perfusion of HSA-containing mixture of these metabolites through HSGD mierocolumn...

The hemodialyzer, also known as the artificial kidney, is a device that is used outside the body to remove the so-called the uremic toxins, such as urea and creatinine, from the blood of patients with kidney disease. While it is a crude device compared to the exquisite human kidney, many patients who are unable to receive a kidney transplant can survive for long periods with the use of this device. 

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. 

As an artificial dialyzer is not used in peritoneal dialysis, use of the term artificial kidney might not be appropriate in this case. In peritoneal dialysis,the dialysate solution is infused into the peritoneal cavity of the patient and later discharged. Uremic toxins in the blood are removed as the blood flows through the capillaries in the peritoneum to the dialysate by diffusion. Water is removed by adding glucose to the dialysate, thereby making the osmolarity of dialysate higher than that of the blood. 

In animal models of acute renal failure induced in rats by bilateral nephrectomy and bilateral ureteral ligation, TAC increased, probably due to the accumulation of urate and uremic toxins with scavenging capacity, such as hyppurate (B19, S9). TAC of blood plasma was reduced in a rat endotoxic shock model (rats given i.p. 5 mg/kg lipopolysaccharide) (Cl6). 

As blood circulates along the dialyzer membrane, uremic toxins diffuse into the dialysate that is discarded, under the action of the concentration gradient (Figure 18.3). 

Deguchi T, Kusuhara H, Takadate A, et al. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int 2004 65 162-174. 

Isoniazid can cause neuropsychiatric syndromes, including euphoria, transient impairment of memory, separation of ideas and reality, loss of self-control, psychoses (421), and obsessive-compulsive neurosis (422). Isoniazid should be used with caution in patients with pre-existing psychoses, as it can cause relapse of paranoid schizophrenia (423). Patients on chronic dialysis appear to be vulnerable to neurological adverse drug reactions, because of abnormal metabolism of uremic toxins. It is therefore recommended that a... 

R.M. Deppisch, W. Beck, H. Goehl and E. Ritz, Complement Components as Uremic Toxins and Their Potential Role as Mediators of Microinflammation, Kidney International 59(Suppl. 78) (2001) 271-277. 

W. H. Horl, Genesis of the Uremic Syndrome Role of Uremic Toxins(Editorial), Wien Klinik Wochenschrift 110 (1998) 511-520. 

Patients with accumulation of uremic toxins have increased sensitivity to certain drugs. There may be an enhanced response to CNS depressants (such as barbiturates and benzodiazepines), hemorrhagic effects from aspirin or warfarin, and other bleeding effects from antibiotics that inhibit platelet aggregation, such as carbenicillin, ticarcillin, and piperacillin. 

RP-HPLC procedures for the determination of creatinine and purine metabolites, such as allantoin, uric acid, xanthine, and hypoxanthine in ruminant urine, were described. Chromatography was achieved with a Cig column under isocratic conditions, and detection at 218 nm without allantoin derivatization. The chromatographic conditions were a compromise between the sensitivity and specificity of the measurement of each analyte, analysis time, and resolution of all analyte peaks from interfering compounds.Uremic toxins creatine, creatinine, uric acid, and xanthine were simultaneously determined in human biofluids, simply after dilution, with UV detection at 200 nm. This method was compared, for creatinine and uric acid, with conventional routine methods and did not give significantly different results. 

Kochansky, C.J. Strein, T.G. Determination of uremic toxins in biofluids Creatinine, creatine, uric acid and xanthines. J. Chromatogr., B 2000, 747, 211-221. 

Uremic toxins are chemicals and waste products normally excreted by the kidneys they are responsible for many of the signs of kidney disease. Blood urea nitrogen (BUN) is one of those substances, but it is not the only one. Early definitions (in 1978) proposed the following as minimal for the identification of uremic toxins ... 

Nowadays, this definition can be considered as classical. Because all of these criteria are rarely met simultaneously, the concept of uremic toxins has changed. In the new concept, substances that damage normal physiological functions, or interfere with physiological defense mechanisms in renal failure, have also been recognized as uremic toxins. Some may play a role in the progression of renal disease, inducing uremic symptoms, and may contribute to dialysis-related complications. 

Table 1 summarizes substances considered as possible uremic toxins. Fig. 1 illustrates the chemical structures of some of the most important uremic toxins that are determined by high-performance liquid chromatography (HPLC). In this paper, some of the most important uremic toxins are discussed (concerning their chromatographic determination). 

The reliable determination of uremic toxins, creatine, and creatinine in biofluids is a matter of great importance in clinical chemistry. 

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