Intradialytic removal of protein-bound uraemic toxins: role of solute characteristics and of dialyser membrane

In uremia there is a marked elevation of serum levels of indoxyl sulfate due to its decreased renal clearance. Indoxyl sulfate is synthesized in the liver from indole which is produced by bacteria in the intestines. To determine the role of indoxyl sulfate in the progression of chronic renal failure, we administered indole, the precursor of indoxyl sulfate, to subtotally nephrectomized uremic rats. The oral administration of indole increased the serum levels of creatinine and blood urea nitrogen and decreased creatinine, inulin, and p -aminohippuric acid clearances. The glomerular sclerosis index in the indole-treated rats was higher than in the control uremic rats. After oral administration, indole could not be detected in the urine, but large amounts of its metabolite, indoxyl sulfate. Thus, indole administration stimulated glomerular sclerosis in a uremic model through the production of indoxyl sulfate.

It is generally recognized that the uremic syndrome results in a depression of immune function, but the uremic solutes responsible remain largely unidentified. In this study, the effect of 18 known uremic retention solutes, including urea and creatinine, on hexose monophosphate shunt (HMS)-dependent glucose-1-C14 utilization (G1C-U), chemiluminescence production (CL-P) and flow cytometric parameters (FCP) of respiratory burst and phagocytosis were evaluated in granulocytes and/or monocytes. Among the compounds studied, only p-cresol depressed whole blood respiratory burst reactivity (G1C-U, CL-P) dose dependently at concentrations currently encountered in end-stage renal disease (ESRD) (P < 0.05 from 5 micrograms/ml on). The effect of p-cresol was enhanced by increasing incubation times from 10 to 120 minutes. HMS activity of isolated packed erythrocytes remained unaffected. FCP of respiratory burst activity (Bursttest, expressed as log fluorescence units, LFU) revealed a marked depression in the presence of p-cresol (from 700 +/- 167 to 291 +/- 128 LFU for granulocytes, from 278 +/- 102 to 146 +/- 52 LFU for monocytes, P < 0.01), whereas particle ingestion (Phagotest) remained unaffected. Cell-free myeloperoxidase activity was also markedly depressed in the presence of p-cresol. Polarity based HPLC-elution of a standard solution containing all the solutes studied, using a gradient from 100% formic acid to 100% methanol during 60 minutes, revealed elution of p-cresol after 46.6 minutes, pointing to its relative hydrophobicity. Conjugation of p-cresol to p-cresylsulfate anihilated the depressive effect of p-cresol on granulocyte function, and at the same time caused a shift in HPLC-elution pattern to a less lipophilic range.(ABSTRACT TRUNCATED AT 250 WORDS)