To our knowledge, this is the first study to directly link fiber blocking with dialyzer performance in terms of extraction and total solute removal. This cross-over study investigated fiber blocking and dialyzer extraction ratios at different dialysis time points in the Solacea™ and FX800 CorDiax dialyzers, during post-dilution hemodiafiltration with reduced anticoagulation dose. While confirming the importance of biocompatibility, it was demonstrated that kinetics of fiber blocking during dialysis is not a linear process, but is accelerated during the second half of dialysis. Furthermore, dialyzer ERs for phosphorus and myoglobin were correlated with the percentages of open fibers, and were consequently lower with the FX800 CorDiax versus Solacea™. Last, the large decrease in fiber blocking in the FX800 CorDiax during the last part of the dialysis sessions had only minor influence on total solute removal of phosphorus and the middle molecule β2M, while myoglobin solute removal was hampered.
Fiber patency in the Solacea™ dialyzer remained optimal until the end of the 240min dialysis session for 50% and even for 70% open fiber area, while, mainly due to deposition onto the membrane, fiber patency was 74% (at 60min) down to 64% (at 240min) when only counting the 90% open fibers. Apart from this thin layer, percentage open fibers in the FX800 CorDiax were already lower after a 60min dialysis, and were, for 70% open fiber area, further decreased by 66% (interval 60-240min) and 63% (interval 120-240min). These data confirm earlier work, in which it was demonstrated that better biocompatibility resulted in less activation of the coagulation cascade, even at very low levels of anticoagulation 3,5,9.
We also observed that fiber blocking is not a smooth process with linear kinetics over time, but rather follows an exponential pattern, accelerating progressively in the later stages of the dialysis session. Our current study setup unfortunately does not allow a minute-by-minute analysis of the coagulation process, as the gold standard micro-CT analysis requests that the dialysis session should be stopped. Nevertheless, our data do support a rather limited activation of coagulation in the first 120min of the dialysis session, despite very low application of anticoagulant, and a more accelerated activation thereafter. Furthermore, in the more biocompatible dialyzers, even after 240min, fiber blocking was nearly completely absent even when the cut-off is set at a minimal decrease of fiber diameter. This suggests, or is at least compatible with the hypothesis that coagulation is an on/off phenomenon and that once the cascade is activated, there is a rather rapid evolution to complete fiber blocking. However, to our knowledge, accurate tools to quantify fiber blocking online are currently not available to confirm or contradict this hypothesis.
Although a correlation was found between extraction ratio and percentage open fibers, substantial decrease in fiber patency did not result in a proportional decrease in solute extraction. Furthermore, whereas extraction rate decreased by 25% for the small solute phosphorus, and even by 41 and 48% for the middle molecules β2M and myoglobin, mathematical analysis showed relatively modest decreases in total solute removal rates of only 6, 7 and 9% for phosphorus, β2M and myoglobin, respectively, during the dialysis period 120-240min. This can be explained by the fact that the instant absolute solute removal is always a proportion of the solute concentration at the dialyzer inlet, and is thus not only determined by the extraction ratio of the dialyzer. Since inlet concentrations are declining during dialysis according to single or multicompartmental solute kinetics in the patient’s body, the absolute solute removal will also decline over time. Because fiber blocking was found to be non-linear and most accelerated during the second part of dialysis, the impact of fiber blocking near the dialysis end has a rather limited impact on overall solute removal. This effect is the smallest for those solutes with the highest reduction ratio during dialysis (i.e. with the largest decline from pre to post dialysis concentration), e.g. small water soluble solutes like urea and creatinine 10. As a result, evaluation of dialyzer coagulation based on urea removal is not representative for fiber patency. The fact that urea clearance might not be the ideal parameter to evaluate dialyzer clotting, is endorsed by previous K∙t/Vurea based studies, which did not find significances among different dialysis strategies, while visual inspection and premature termination of the session did 11,12.
Phosphorus is known to have complex kinetics in the patient, characterized by mobilization of solute transport from the deeper tissues towards the blood, once plasma levels are decreased 13,14. This results in rather constant or even increased dialyzer inlet concentrations during the second half of dialysis, giving the potential of high solute removal in case extraction would have remained constant. Theoretical calculations accordingly reveal that the hampered extraction in the FX800 Cordiax contributed to a loss in total solute removal of only 6.6%. For the more patent Solacea™ dialyzer, this loss in total solute removal is even more negligible, and limited to only 0.9%.
Middle molecules like β2M are known to have retarded transport within the patient, a property that plays a more prominent role in solute removal than dialyzer extraction ratio does 15− 17. This implies that for solutes behaving like β2M, absolute solute removal is less sensitive to ad hoc changes in extraction. Accordingly, we can explain why the loss in solute removal remained limited to a theoretically calculated 5.6% (Solacea™) and 7.6% (FX800 CorDiax), despite observed large differences in extraction ratio at the end of the dialysis session between the two filters. A further reason why both dialyzers perform in the same range is the cross-over in β2M extraction (figure 2B). The somewhat larger sieving coefficient for β2M in the FX800 CorDiax (0.85 versus 0.8 in the Solacea™) explains the higher extraction during the first half of dialysis, while the higher degree in fiber blocking during the second half decreases the dialyzer extraction.
For the middle molecule myoglobin, calculations suggest a 16.5% loss in total solute removal in the FX800 CorDiax due to the decreasing ER during dialysis. The overall lower myoglobin removal as compared to removal in Solacea™ was determined by the lower sieving coefficient (0.5 in FX800 CorDiax versus 0.8 in Solacea™) from the start of dialysis on, and the lower extraction ratio towards the end of dialysis due to fiber blocking. The patent fibers in the Solacea™ make this dialyzer superior for the removal of large middle molecules like myoglobin, with a calculated loss in TSR of only 0.9%.
Our study reveals that in routine clinical practice, many dialysis patients might still receive supra-therapeutic doses of anticoagulation for their dialysis session. Indeed, despite giving only a quarter of the regular anticoagulation dose, all sessions could be completed successfully. As bleeding complications are still prevalent in chronic dialysis patients, there is room for further optimization of the anticoagulation regime. However, such an optimization is hampered by the lack of an adequate tool to quantify coagulation online during a dialysis session. Complete blocking of the circuitry as a sign of insufficient anticoagulation is a clear and intrusive event, often leading to a permanent increase in dose of anticoagulation. However, over-anticoagulation is less easily detected and therefore, most likely, dose reductions in case of overdosed anticoagulation occur less frequently.
In order to evaluate fiber blocking kinetics, we had to perform separate dialysis sessions of different duration rather than measuring at different time points in a single session, which could be considered a limitation of the study. However, this is the only way to go when using the very sensitive micro-CT scanning technique, the gold standard to quantify dialyzer fiber blocking 2,18. In addition, patients were their own controls, and to have the best and similar cross-over starting conditions, group randomization was performed per dialyzer.
As a strength of our study, we were using the same type of dialysis strategy and the same amount of anticoagulant administered always in an identical way (i.e. single bolus at the dialysis start) for all dialysis sessions. This allowed us to make a direct comparison between the dialyzers and between the sessions of different duration.
In conclusion, this study confirmed that biocompatible dialyzers are more resistant to activation of coagulation. Fiber blocking was found to be a non-linear process which is accelerated during the second part of dialysis. While fiber blocking seemed to have only a minor impact on the removal of toxins up to at least 12kDa, the removal of larger toxins like myoglobin was found hampered by fiber blocking.