Spontaneous variability of pre-dialysis concentrations of uremic toxins over time in stable hemodialysis patients

Background and aim : Numerous outcome studies and interventional trials in hemodialysis (HD) patients are based on uremic toxin concentrations determined at one single or a limited number of time points. The reliability of these studies however entirely depends on how representative these cross-sectional concentrations are. We therefore investigated the variability of predialysis concentrations of uremic toxins over time. Methods : Prospectively collected predialysis serum samples of the midweek session of week 0, 1, 2, 3, 4, 8, 12, and 16 were analyzed for a panel of uremic toxins in stable chronic HD patients (N = 18) while maintaining dialyzer type and dialysis mode during the study period. Results : Concentrations of the analyzed uremic toxins varied substantially between individuals, but also within stable HD patients (intra-patient variability). For urea, creatinine, beta-2-micro-globulin, and some protein-bound uremic toxins, Intra-class Correlation Coefficient (ICC) was higher than 0.7. However, for phosphorus, uric acid, symmetric and asymmetric dimethylarginine, and the protein-bound toxins hippuric acid and indoxyl sulfate, ICC values were below 0.7, implying a concentration variability within the individual patient even exceeding 65% of the observed inter-patient variability. Conclusion : Intra-patient variability may affect the interpretation of the association between a single concentration of certain uremic toxins and outcomes. When performing future outcome and interventional studies with uremic toxins other than described here, one should quantify their intra-patient variability and take into account that for solutes with a large intra-patient variability associations could be missed

Antibiotics therapy.

<p>Antibiotics therapy.</p

Concentration profiles in patients on antibiotics for the protein-bound toxins PCG (p-cresylglucuronide), HA (hippuric acid), IAA (indole acetic acid), IS (indoxyl sulfate), PCS (p-cresylsulfate), and CMPF (3-carboxy-4-methyl-5-propyl-2-furanpropionic acid).

<p>The antibiotics interval is indicated in grey shadow and the time averaged concentration (TAC) per uremic toxin and per patient is added to the right side of each graph. Concentrations in mg/dL, except phosphorus (mmol/L), SDMA and ADMA (both μmol/L) and β₂M (mg/mL).</p

Intra-class correlation coefficients (ICC) corrected for different covariates, with overall toxin average concentration, and inter- and intra-patient variances.

<p>Intra-class correlation coefficients (ICC) corrected for different covariates, with overall toxin average concentration, and inter- and intra-patient variances.</p

Intra-patient variability.

<p>Box plots of predialysis serum concentrations, re-scaled in such a way that within patients (x-axis) the mean is 0 and that over the patients the SD = 1 (y-axis): for Crea (creatinine), phosphorus, total HA (hippuric acid), total IS (indoxyl sulfate), total PCS (p-cresylsulfate), and β₂M (beta-2-microglobulin).</p

Inter-patient variability.

<p>Box plots of predialysis serum concentrations on the respective original scales (y-axis) over the 18 patients (x-axis): Crea (creatinine), phosphorus, total HA (hippuric acid), total IS (indoxyl sulfate), total PCS (p-cresylsulfate), and β₂M (beta-2-microglobulin).</p

Extreme catalysts from low-temperature environments

Cold-loving or psychrophilic organisms are widely distributed in nature as a large part of the earth's surface is at temperatures around 0 degrees C. To maintain metabolic rates and to prosper in cold environments, these extremophilic organisms have developed a vast array of adaptations. One main adaptive strategy developed in order to cope with the reduction of chemical reaction rates induced by low temperatures is the synthesis of cold-adapted or psychrophilic enzymes. These enzymes are characterized by a high catalytic activity at low temperatures associated with a low thermal stability. A study of protein adaptation strategies suggests that the high activity of psychrophilic enzymes could be achieved by the destabilization of the active site, allowing the catalytic center to be more flexible at low temperatures, whereas other protein regions may be destabilized or as rigid as their mesophilic counterparts. Due to these particular properties, psychrophilic enzymes offer a high potential not only for fundamental research but also for biotechnological applications