A clinical study comparing the basic performance and blood compatibility characteristics of Nipro ELISIO‐H^®, Gambro Polyflux Revaclear^®, and Fresenius Optiflux^® dialyzers

The new ELISIO-H® dialyzer (henceforth referred to as ELISO-H) is a high-flux dialyzer made from the POLYNEPHRON™ fiber designed and manufactured by Nipro Corporation of Japan. The dialyzer has undergone in vitro testing, and all legally required biological safety tests have been successfully completed and certified by an external institute. A number of clinical studies have been completed for this particular dialyzer, in Japan and in Europe. Nipro ELISIO-H dialyzers have been commercially available for several years outside of United States On December 20, 2013, ELISIO-H dialyzer obtained 510k approval for use in United States. The aim of the study was to confirm the safety and clinical effectiveness of the Nipro ELISIO-H for the US market by comparing its performance characteristics and hemocompatibility with Gambro Polyflux Revaclear® (henceforth referred to as Revaclear) and Fresenius Optiflux® (henceforth referred to as Optiflux) dialyzers, currently in use in the United States. This study was performed under the oversight of the University of Missouri Columbia Institutional Review Board. As this study falls under the category of a clinical study per US requirements (with reference to the European Standard ISO 14155 and the Declaration of Helsinki), informed consent was obtained from all patients enrolled in the study. Ten clinically stable patients who satisfied inclusion criteria and were on maintenance hemodialysis were selected from the Dialysis Clinics Incorporated (DCI) in-center hemodialysis population. All patients were receiving regular maintenance HD via AV fistula for 4 hours per session, three times a week. Specific patient inclusion, exclusion, and withdrawal criteria are provided in Appendix I. All patients in the study were dialyzed on Gambro Phoenix X36 hemodialysis machine (Baxter Healthcare, Deerfield, IL, USA). The dialyzers used were the Elisio 21H, Elisio 17H (Nipro Medical Corporation, Osaka, Japan), Optiflux F200NR, Optiflux F160NR (Fresenius Medical Care, Waltham, MA, USA), and Revaclear Max and Revaclear (Baxter Healthcare) (see Table 1 for dialyzer characteristics). Orders for anticoagulation type, dosage, and administration were not changed unless specified otherwise by the investigator/physician. The total amount of anticoagulant was carefully documented for each patient. The blood flow rate (Qb) was kept in the range of 300–500 mL/min, as prescribed by the patient's nephrologist. The dialysate flow (Qd) rate was set to twice the blood flow rate. Dialyzer setup and preparation was done per dialysis clinic's normal standard operating procedure (details available on request). This involved a pre-rinsing step before the start of dialysis. The priming solution was not infused to the patient. Dialysate flow was initiated at the beginning of the rinsing procedure. All the dialyzers were pre-rinsed in the same manner. The type of heparin and dosage normally used for each individual patient, including the administration regimen (bolus injection and continuous infusion), remained unchanged unless specified otherwise by the investigator or patient's nephrologist during the evaluation. The blood flow rate (Qb) was kept between 300 and 500 mL/min. The dialysate flow rate (Qd) was kept at two times the Qb. Blood flow and dialysates flow were not changed for any patient throughout the study period. The ultrafiltration rate (Uf) was maintained per physician's orders for each patient during each treatment and appropriately documented. Three consecutive treatments were performed for each patient with each dialyzer type in a pre-specified randomly assigned sequence: Elisio, Fresenius, Gambro; Gambro, Elisio, Fresenius; and Fresenius, Gambro, Elisio. Five minutes before the collection, the flow rate was adjusted so that at time of collection, Qb = 350 mL/min, Qd = 700 mL/min, and Uf = 0 for all patients. Blood was collected from venous side first followed by arterial side. Blood was collected pre, during, and post-dialysis at appropriate intervals (see Appendix II). (See Appendix III for the equations used for the above mentioned calculations.) All blood samples were collected after confirming that the blood and dialysate flows were at the targeted rates listed above. Venous and arterial pressures at the point of collection were recorded as well. All the blood analyses were performed by a commercial laboratory (Boyce & Bynum Pathology Laboratories, P.C., Columbia, MO, USA). All data, including blood flow rates, dialysate composition, heparin schedule (i.e., concentration in the pre-rinsing solution, bolus, and infusion rates), all medications given to or taken by the patient, and standard dialysis symptom/events seen routinely in dialysis patients were recorded in the case report form. Patient records included patient names, dates of birth, End Stage Renal Disease (ESRD) diagnosis, and duration of treatment on dialysis. Data were stored in a locked dataset in a secure computer in the Nephrology Research Laboratory. Data were analyzed in house using SigmaPlot for Windows 11.2 (Systat Software, Inc., San Jose, CA, USA) for statistical analysis. Parametric non-paired t-test was used to compare groups except where the data failed the normality test or the variance test, when the nonparametric Mann–Whitney Rank Sum was utilized to test for significance. The study group (Table 2) consisted of eight males and two females with an average age of 57.2 ± 10.9 years. There were six African Americans (A) and four Caucasians (C) with an average time on dialysis of 3.8 ± 3.2 years. The etiology of ESRD was Diabetes Mellitus type 2 in six, Polycystic kidney disease in three, and hypertension in one patient. Six patients had left upper arm fistulae, one patient had left forearm fistula, one patient had right upper arm fistula, and two patients had right femoral fistulae. Mean serum values of different solutes at various time points are given in Table 3 for the three dialyzers. Table 4 shows 60 minute clearances by session (Monday: seesion 1; Wednesday: session 2; and Friday: session 3) and dialyzer type with any significant differences (P < 0.05). There was no significant difference in whole blood small solute clearance or removal rates among different dialyzers. B2 microglobulin and myoglobin clearances were significantly higher in Elisio as well as Revaclear when compared to Optiflux dialyzers. No significant difference was present between Elisio and Revaclear dialyzers (Figure 1a,b). The clearance for myoglobin in Optiflux dialyzer was calculated as a negative value when compared with Elisio and Optiflux dialyzers in sessions 1 and 2 (Table 4). Removal rates of B2 microglobulin and myoglobin were significantly higher in Elisio as well as Revaclear when compared to Optiflux dialyzers (Figure 2a,b). No significant difference was found between Elisio and Revaclear dialyzers. The removal rate for myoglobin in Optiflux dialyzer was calculated as a negative value when compared with Elisio and Optiflux dialyzers in all three sessions. The percentage change in TAT levels at 240 minutes in Elisio, Revaclear, and Optiflux dialyzers was significantly higher (Figure 3) when compared to that of 60 minute values (data not shown). There was no significant difference in the percentage change at 60 or 240 minute TAT levels between any of the dialyzers studied (Table 5). C5a levels did not show any significant percentage change in any of the timed blood samples (15, 30, 60, and 240 minutes) in either Elisio or Revaclear dialyzers. In Optiflux dialyzers, C5a levels at 30, 60, and 240 minutes were significantly lower than 15 minute levels in terms of percentage change. Also, the 240 minute levels showed a significant rise when compared to 60 minute levels (data not shown). When percentage change (from baseline) in C5a levels (Table 5) was compared between various dialyzers, both Elisio and Revaclear showed significant differences at 15 minutes when compared to Optiflux (P < 0.001 and <0.001, respectively). There was also a significant change seen at 240 minutes levels between Optiflux vs. Revaclear (P < 0.005) (Table 5). The WBC count at 30, 60, and 240 minutes in Elisio dialyzers was significantly higher (percentage change) when compared to 15 minute values. No difference in WBC count was observed in Optiflux and Revaclear dialyzers between various timed blood draws (data not shown). There was no significant percentage change between different dialyzers (Table 5). The hemoglobin levels in Elisio dialyzers showed a significant rise (percentage change) at 240 minutes when compared to 15, 30, and 60 minutes. In Optiflux dialyzers, the 240 minute rise in hemoglobin was only significantly different when compared to 15 minute values. In Revaclear dialyzers, the 240 minute levels of hemoglobin were significantly higher when compared to 15 and 60 minute values (data not shown). No difference in percentage change in Hb levels was observed (Table 5). In both Elisio and Revaclear dialyzers, the mean Hematocrit levels at 240 minutes were significantly higher (percentage change) than 15 minute levels. Optiflux dialyzers showed no difference among various timed values (data not shown). No significant difference in percentage change was seen among various dialyzers (Table 5). There was no significant difference between various timed values of platelet counts for any of the three dialyzers studied (data not shown). The percentage change in platelet count at 30 minutes showed a significant decline in Elisio dialyzers when compared to Revaclear (P < 0.009). No other significant differences in percent change in platelet counts were observed between different dialyzers (Table 5). The small solute clearance (urea, creatinine, and phosphate) in Elisio dialyzer was comparable and not significantly different from the two reference dialyzers. In contrast, the clearances and removal rates of low molecular weight (LMW) proteins, that is, B2 microglobulin and myoglobin were significantly higher in Elisio and Revaclear dialyzers when compared to Optiflux dialyzers. There was no difference in the clearance or removal rates of LMW between Elisio and Revaclear dialyzers. The removal and clearance of larger molecules (like LMW proteins) by standard dialysis membranes is limited by their relatively higher molecular weights as well as lower sieving coefficients. The molecular weights of B2 microglobulin and myoglobin are 11 and 16.7 kDa, respectively. The sieving coefficient for B2 microglobulin is 0.7 (Revaclear) and 0.22 for myoglobin (ELISIO 15H) (Table 1). Possible contribution by membrane adsorption may also contribute to low or negative clearance of larger molecules in some membranes (i.e., Optiflux in our study). All dialysis sessions were completed successfully without any significant clotting. The TAT profile in Elisio dialyzer was similar to the other two dialyzers and not significantly different from Optiflux or Revaclear dialyzers in terms of percent change in TAT activity. The stability of C5a levels in Elisio dialyzers as well as a lack of any significant difference in percentage change in C5a activity when compared to the other two dialyzers (except with Optiflux dialyzer at 15 minutes) shows that the inflammatory activation with Elisio is similar to the other reference dialyzers. These data validate the observation that the thrombogenic and inflammatory potential of the Elisio dialyzer is overall similar to the other two reference dialyzers. The WBC count profile of the Elisio dialyzer showed significantly higher 30, 60, and 240 minute values (percentage change) when compared to 15 minute values. The lack of a significant difference in the percentage change in WBC count among different dialyzers confirms that the effect of Elisio dialyzer on WBC counts is similar to the other reference dialyzers. All three dialyzers showed a rise in hemoglobin levels with time during hemodialysis sessions (hemoconcentration effect). Similar trends were observed in hematocrit values in Elisio and Revaclear dialyzers. The lack of a significant difference in percentage change on comparing hemoglobin and hematocrit values among the three dialyzers confirms the observation that the effect of Elisio dialyzer on the hemoglobin and hematocrit is similar to the other two reference dialyzers. Similarly, platelet counts demonstrated a stable profile with Elisio dialyzers. The lack of any significant difference in percentage change in platelet counts among the three dialyzers confirms that the effect of Elisio dialyzers on platelet count is similar to the other two reference dialyzers. Taken overall, this confirms that ELISIO-H has similar hemocompatibility profile when compared to the other two reference dialyzers. This comparative analysis of Elisio-H dialyzer shows no difference in small solute clearance when compared to the Optiflux or Revaclear dialyzers. The large solute clearance by Elisio-H was similar to Revaclear and better than Optiflux dialyzers. No clinically meaningful difference was found among the three dialyzers when hemocompatibility parameters were studied. Overall, this analysis confirms the clinical effectiveness and safety profile of Elisio-H. Therefore, Eliso-H dialyzer is an acceptable alternative to other currently available dialyzers in use in the United States. Patient inclusion criteria Patient exclusion criteria Withdrawal criteria Sampling to be done for every dialysis treatment (three times per dialyzer, per patient). % Removal rate: ((([S]T0 – [S]T240) / [S]T0) * 100) % Change: (((TX1…Xi – T0) / T0) * 100) 60 minute clearance: ((([S]60'Art – [S]60'Ven) / [S]60'Art) * Qb) where [S] = solute concentration; T0 = time point 0; TX1…Xi = time points 1–4; T240 = time point 240 minutes; Qb = blood flow rate.

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