We demonstrated that the new Kirpa Kit™ manual dialysis configuration, which is more streamlined than prior iterations, is easy to use and may be capable of greater small solute clearance in this in vitro study. A twenty-five minute session with the Kirpa Kit™ reduced BUN and potassium by 80%, and design improvements have improved ease of use and reduced potential sources of inaccuracy, which we believe make the Kirpa Kit™ the preferred configuration for future in vivo experiments.
There are multiple potential reasons for the improved efficiency of the Kirpa Kit™ over the Prototype and Single Pass mSLAMB configurations. Although the Prototype mSLAMB was novel in its ability to harness gravity as a means of producing blood flow that replaced electricity, batteries, and pumps, this also produced “dead space” in our system, necessitating long tubing that carried blood but did not participate in clearance or ultrafiltration. By replacing gravity with manual syringe-based flow, we eliminated much of this dead space, decreasing the time required to get blood to and through the hemofilter. By using the syringe as a mini-blood reservoir, we further reduced dead space by eliminating the bag reservoirs (BR#1 and BR#2) altogether, which also allowed for smaller batch volumes without sacrificing time efficiency.
Reproducible efficacy and hemodynamic safety become of paramount importance as proof-of-concept in vivo studies begin, and as we move one step closer to first-in-human studies. Lanker et al. has recently completed the first in vivo experiments using mSLAMB in a porcine model, reproducing some of the findings of our recent work and drawing attention to previously noted safety concerns [8]. From a clearance perspective, with the Dynamic Diffusion technique (our Prototype mSLAMB above), they were able to achieve decreases in serum potassium concentration of > 0.5 mmol/L/h using very small batch volumes (1% of body weight). From a safety perspective, they did encounter inconsistencies controlling active ultrafiltration when small protocol steps were omitted/forgotten, which ultimately led to excess fluid removal [8]. Gravity driven ultrafiltration and flow can be difficult to control precisely and introduces room for error, as we have experienced and reported in our prior mSLAMB experiments [7]. The Kirpa Kit™ relies on small-batch syringe flow, which eliminates passive ultrafiltration and achieves precise active ultrafiltration, thus greatly reducing the risk of excess ultrafiltration and subsequent hemodynamic instability. The Kirpa Kit’s™ smaller extracorporeal volume (8 mL vs 48 mL for the mSLAMB circuit) also enables smaller batch volumes to be withdrawn from the patient, further reducing the risk of hemodynamic instability.
Other improvements focus on reducing the risks of bleeding and clotting, which is a design necessity for any extracorporeal system. Although this cannot be addressed in vitro, as we use plasma and platelet-free blood mixtures, the progression of configuration design has aimed to theoretically reduce these risks. The Kirpa Kit™ configuration eliminates air-blood interfaces since the blood reservoirs have been removed, decreasing a stimulus for the activation of the coagulation cascade. Furthermore, the Kirpa Kit™ reduces blood flow interruption and eliminates the pooling of static blood that previously occurred in the blood reservoirs of the mSLAMB configurations. We are reassured that there were no clotting or bleeding complications reported in the porcine models, despite only a single heparin bolus being administered as anticoagulation during the experiments [8].
This study has several limitations. We did not record the number of cycles performed in each experiment or measure the volume of dialysis fluid used. This information would have been useful in comparing the efficiency of the three techniques, potentially providing evidence to support the superiority of the Kirpa Kit™. Second, all experiments were performed by an experienced person, making clearance results not immediately translatable to less skilled users. However, the ease of use of the Kirpa Kit™ allows for a rapid learning curve. Third, we haven’t addressed the clotting risk since we used plasma-free blood mixtures; we have planned upcoming in vivo studies to address this issue. Fourth, our process of blood aspiration from the Blood Bag is not hindered by the small caliber a child’s venous catheter would interpose; in a human patient, the duration of a cycle would be longer due to the increased resistance to flow caused by the venous line, with a consequent reduction in efficiency. Lastly, in clinical practice the clearance of urea would decrease further because of the volume of urea distribution, which is largely greater than the intravascular volume alone, and the potassium reduction would decrease because our experiments have not accounted for a person’s natural potassium generation and efflux from the intracellular compartment. Although it is imprecise and unrealistic to directly translate these clearance results into clinical practice, the median urea and potassium reduction of about 82% obtained in only 25 minutes is a surprising result that lays the foundation for future in vivo studies.
We conclude that the Kirpa Kit can henceforth supplant the previous mSLAMB configurations and stand as a definite candidate to be tested in vivo, where the aforementioned issues with anticoagulation, flow limitations, volume of distribution, and inherent generation of small solute formation can be more definitively explored.