Uremic plasma

Plasma is the physiological milieu for blood cells. It is therefore to be expected that changes of plasma compo.sition might affect the metabolism and function of circulating cells. Previously it has been found that several substances are present in uremic plasma, which have not been found in plasma from healthy subjects. It has also been shown that some of these substances disturb the functions of phagocytic cells. 

In a group of uremic patients, plasma heat production (see Table 28) and oxygen consumption rates were found to be significantly increased compared to controls [118]. 

Heat production rate (P) of uremic plasma, compared to plasma from healthy subjects. Source reference 118. 

A significant correlation was found between rates of heat production and rates of oxygen consumption. In uremia there is apparently an activation of oxidative heat-producing processes, which nature is unknown. Heat production was significantly correlated to the plasma concentration of creatinine, whereas no such correlation was found with urea. 

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S. E. Roselaar, N. B. Nazhat, P. G. Winyard, P. Jones, J. Cunningham and D. R. Blake. Detection of Oxidants in Uremic Plasma by Electron Spin Resonance Spectroscopy, Kidne > Internationa 48( I) (1995)199-206. 

Myoinositol and other polyols, such as scylloinositol and neoinositol, are normal constituents of a class of phospholipids known as the phosphoinositides. These compounds, closely related to nervous tissue and neuronal function, are retained in uremia and have been considered a possible cause of peripheral neuropathy (D7, H8, N10). Rats receiving large amounts of myoinositol show a decrease in nerve condition velocity (C12). Adding myoinositol to root ganglion cells in vitro in concentrations known to occur in uremic plasma produces cytotoxic changes (L14). 

Recently Gallice et al. used high-performance liquid chromatography (HPLC) and nuclear magnetic resonance spectroscopy (NMR) to identify a double conjugate of glucuronidate-o-hydroxyhippuric acid in ultrafiltrates of uremic plasma (G6). This compound had been previously described by Zimmerman et al. as a fraction of the so-called uremic middle molecules (Z7, Z8). So far no data have been reported on the toxicity of this compound. 

Furst et al. reported on the separation of middle molecules that they contended were peptides (FI 2). Using high-speed gel filtration and ultraviolet absorption at 254 and 206 nm, they separated normal and uremic plasma into 10 and 11 peaks. One of these peaks, peak 7, was present in uremia but not in normal serum. Using ion-exchange chromatography, Furst and Bergstrom further separated peak 7 into seven or eight subpeaks (7a, 7b, 7c, etc.) peak 7 was prominent in uremic patients with symptoms such as malnutrition and infection (F13). Amino acid analysis indicated that peak 7c consisted of a small peptide chain with 8-10 amino acids (B17). 

G6. Gallice, P., Monti, J. P., Crevat, A., et al., A compound from uremic plasma and from normal urine isolated by liquid chromatography and identified by nuclear magnetic resonance. Clin. Chem. (Winston-Salem, N.C.) 31, 30-34 (1985). 

T3. Tavares-Almeida, 1., Gulyassy, P. F., Depner, T. H et al., Aromatic amino acid metabolites as potential protein binding inhibitors in human uremic plasma. Biochem. Pharmacol. 34, 2431-2438 (1985). 

Odani, H., Shinzato, T., Matsumoto, Y., Usami, J., and Maeda, K. 1999. Increase in three alpha, beta-dicarbonyl compound levels in human uremic plasma Specific in vivo determination of intermediates in advanced Maillard reaction. Biochem. Biophys. Res. Commun. 256 89-93. 

W2. Walser, M., The ionic composition of uremic plasma. J. Clin. Invest. S8, 1052 (1959). 

We have tentatively identified nanomolar accumulations of deoxyinosine in uremic plasma. This compound is directly toxic to lymphocyte activation. Toxicity could result from "trapping of deoxyinosine in lymphoid tissue by specific lymphoid deoxy kinases where it is phosphorylated to deoxynucleotides with resultant inhibition of DNA synthesis (9). Investigations are currently underway to examine the effect deoxynucleosides on deoxynucleotide formation in lymphocytes from uremic patients. 

Acids in Uremic Plasma by Gas Chromatography-Mass Fragmentography Koenshu - lyo Masu Kenkyukai 3 125-130 (1978) GA 92 159960j... 

Heat production rate (P) of uremic plasma from patients before (Pre-HD) and after haemodialysis (Post-HD), and from patients on continuous peritoneal dialysis (CAPD) treatment. Source reference 119. 

GEA-3175 is more stable than GEA-3162 in vitro but still retains its biological activity [95]. The release of NO and NO2 by GEA 3175 was increased 140-fold in the presence of human plasma, as analyzed by ozone chemiluminescence [94]. GEA 3175 inhibited agonist-induced platelet aggregation and induced a more than 4-fold increase in platelet cGMP without affecting cAMP levels [94]. Thrombin-stimulated rises in the cytosolic free Ca2+ concentration and secretion were dose-dependently inhibited by GEA 3175. GEA 3175 showed a reduced capacity to inhibit platelet aggregation of uremic platelets compared to controls [96]. 

Myopathy and neuropathy Colchicine myoneuropathy appears to be a common cause of weakness in patients on standard therapy who have elevated plasma levels caused by altered renal function. It is often unrecognized and misdiagnosed as polymyositis or uremic neuropathy. Proximal weakness and elevated serum creatine kinase are generally present, and resolve in 3 to 4 weeks following drug withdrawal. Maiabsorption of vitamin B-f2- Colchicine induces reversible malabsorption of vitamin B-12, apparently by altering the function of ileal mucosa. 

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

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... 

Fig. 29.3 Lack of notable influence of exhaustive dialysis and conventional DHP on the melting curves of HSA extracted from blood plasma of uremic and cirrhotic patients...

Serum albumin is a natural transporter of hydrophobic metabolites it binds toxic ligands reversibly, and if the ligand can be removed from the complex then the melting curve of unloaded albumin should return to that of pure protein. However this remains a difficult task, and neither exhaustive dialysis, nor the use of conventional carbonic sorbents, influence the shape of melting curves of albumin isolated from blood plasma of uremic patients and patients with hepatic insufficiency (Fig. 29.3) [9]. 

Fig. 29.10 Melting curves of HSA from healthy donors (a) extracted from blood plasma of cirrhotic (b) and uremic patients (c) before and after (bl, cl) contact with HSGD hemosorbent...

Cyclosporine (CY) is an example of a lipophilic drug that is predominantly bound to lipoproteins in plasma, has a low extraction ratio (EH < 0.3), and a volume of distribution of about 3.9 L/kg [155], Both the CL and VD of low extraction ratio highly bound drugs such as CY are highly dependent on the unbound fraction present in plasma. It might be expected that an increase in the concentration of plasma lipoproteins would result in a decreased unbound fraction of CY and therefore decreased CL and VD. In support of this hypothesis, an inverse linear relationship has been shown between cyclosporine CL and the level of TRL-TG, TRL-CH, and LDL-TG in uremic patients [155],... 

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). 

To prevent the blood from losing its ions, these ions are included in the dialysate at the same concentration as in normal plasma to stop their diffusion through the membrane. Since uremic patients produce little or no urine, their excess water is eliminated from the blood by ultrafiltration through the membrane since blood pressure is higher than dialysate pressure. This ultrafiltration also contributes to toxin removal by carrying toxins into the dialysate. This convective transfer is more efficient than diffusion for high molecular weight toxins. 

Odetti, P., Fogarty, J., Sell, D. R., and Monnier, V. M., Chromatographic quantitation of plasma and erythrocyte pentosidine in diabetic and uremic subjects. Diabetes 41, 153—159 (1992). 

Although there is no evidence that neuropsychiatric complications of macrolides develop more readily in uremic patients, several factors may predispose toward these adverse effects, such as reduced drug clearance, altered plasma protein binding, different penetration of drug across the blood-brain barrier, and an increased propensity for drug interactions. 

Odar-Cederlof I, Borga O. Kinetics of diphenylhydan-toin in uremic patients Consequences of decreased plasma protein binding. Eur J Clin Pharmacol 1974 7 31-7. 

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