Effects Of Uremic Toxins Research Articles

Effects of uremic toxins and fatty acids on serum protein binding of furosemide: possible mechanism of the binding defect in uremia

To elucidate the mechanism of impaired serum binding of furosemide observed in patients with renal dysfunction, we examined in vitro the serum protein binding of furosemide in the absence and presence of uremic toxins that are endogenously retained solutes in uremic serum and act as inhibitors of drug binding. Analysis of the binding data of furosemide at its therapeutic concentration (6.6 mg/L) indicated that, among the four uremic toxins studied, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) showed the greatest inhibitory potency for the binding of furosemide to serum; moreover, the inhibition was competitive. CMPF thus most likely represents the primary determinant for the serum binding defect of furosemide in uremia. However, CMPF and oleate appear to exert a synergistic effect on the inhibition of furosemide serum binding--perhaps through a cascade effect on furosemide-binding inhibition in the oleate-CMPF-furosemide system, in which the binding of oleate to its low-affinity sites indirectly displaces furosemide from albumin and thus increases the transiently liberated CMPF molecules. Similar cascade effects on furosemide binding in the presence of CMPF were also originated by other long-chain (C18) fatty acids, linoleate and stearate, although to a lesser extent. Because CMPF is not effectively removed by ordinary hemodialysis treatment, the combined direct and cascade effects of CMPF and fatty acids appear to contribute to the increase in the free fraction of furosemide during hemodialysis.

Liver function after bilateral nephrectomy.

Consequences of bilateral nephrectomy (NX) for liver functions and for hepatic excretion of various endogenous substances were characterized in rats 24 h after NX. Plasma concentrations of urea, creatinine, fibrinogen, and glutathione increased significantly after NX, whereas the concentrations of total protein, albumin, and lipids decreased. The hepatic excretion of urea, creatinine, phospholipids, cholesterol, and aldosterone significantly increased in uremia, and excretions of protein and glutathione diminished. Active biliary transport can be diminished after NX by the effects of uremic toxins on the liver cells or by the competition phenomena between endogenous substances, which are normally excreted in urine, at the hepatocellular level. Reduced glutathione content and increased lipid peroxidation in hepatocytes have been found. Changes in lipid and protein metabolism after NX can be proved.

Mechanism of decreased calcitriol degradation in renal failure.

Metabolic clearance rate (MCR) of calcitriol is decreased in renal failure, and uremic toxins play a major role in the suppression of calcitriol degradation. In this experiment, we studied the effect of uremic toxins on renal 24- and 26-hydroxylase (HX) activities. Normal rats were infused for 20 h with 30 ml of normal or uremic plasma ultrafiltrates. At the end of infusion, renal enzymes activities were measured by the generations of 1,24,25- and 1,25,26-trihydroxyvitamin D3 10 min after the addition of 25 nM or 1 microM calcitriol. Renal 24-HX activity decreased approximately 50%, whereas 26-HX activity did not decrease in rats infused with uremic plasma ultrafiltrate. The induction of 24-HX activity by 100 ng calcitriol also decreased in rats infused with uremic ultrafiltrate. To examine whether uremic ultrafiltrate could directly inhibit the degradation enzymes, 24- and 26-HX activities were measured in kidney homogenates preincubated for 3 h with either normal or uremic ultrafiltrate. Uremic ultrafiltrate did not directly suppress 24- and 26-HX activities. Furthermore, the disappearance rate of calcitriol was similar for 90 min in kidney homogenates after they were preincubated for 3 h with uremic and normal ultrafiltrates. Because 24-HX synthesis is induced by the calcitriol-receptor complex binding to nuclear chromatin and activating genes coding for the enzyme, we studied the effect of uremic toxins on the binding affinity of calcitriol-receptor complex for DNA-cellulose. Uremic ultrafiltrate significantly reduced the binding affinity of the hormone receptor complex for DNA when the receptor was preincubated with the ultrafiltrate for 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of uremic toxins--guanidino compounds and creatinine--on proliferation of HL60 and K562 cell lines.

Growth of the promyelocytic cell line HL60 and the erythroleukemia cell line K562 is inhibited by 'uremic toxins': creatinine, guanidino propionic acid and guanidino succinic acid in a concentration range similar to that of uremic sera. Among the tested compounds, creatinine exhibits the strongest and most dose-dependent inhibitory effect on both kinds of cells. These results provide a better understanding of the mechanism involved in the anemia of uremic patients.

Biochemical and biophysical behavior of plasma albumin. III. Effects of several uremic toxins on normal plasma albumin.

The effects of some uremic toxins on the structure of normal human plasma albumin were investigated in order to cast light on the state of plasma albumin of patients with chronic renal failure. Two different ion exchange columns were prepared to isolate and purify albumin, and β-indoleacetic acid (IAA), β-indolebutyric acid (IBA), guanidinosuccinic acid (GSA) or urea as a uremic toxin was added to the normal plasma albumin. α-Helix contents as estimated from the circular dichroism spectra were found to be little affected by uremic toxins. The effect of uremic toxins on the binding of a fluorescent probe, 1-anilino-8-naphthalene sulfonate (ANS), to albumin was examined by calculating the binding parameters, the association constant and the number of binding sites. All uremic toxins decreased the association constants. GSA and urea decreased the number of binding sites, while IAA and IBA increased them. These effects increased as the concentrations of toxins added were increased, especially with IAA and IBA.

Red blood cell deformability in renal failure.

Red blood cell deformability was measured in 74 cases of renal failure and diabetic nephropathy by means of a modified nuclepore membrane filter method. Low red blood cell deformability was observed in a certain proportion of the patients. In cases of renal failure only weak correlation was found between reduced red blood cell deformability and BUN as well as between reduced red blood cell deformability and creatinine level, while simultaneous changes in these variable were observed in several patients. The reduction in red blood cell deformability in cases of diabetic nephropathy slightly exceeded that in cases of renal failure and correlated with an increment in HbA1c content. The effects of uremic toxins were unclear in in vitro tests. The red blood cell deformability was impaired in nephrectomized rabbits.