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Phosphorus Removal in Low-Flux Hemodialysis, High-Flux Hemodialysis, and Hemodiafiltration

Švára, František; Lopot, František; Valkovský, Ivo; Pecha, Ondřej

doi: 10.1097/MAT.0000000000000313

Phosphorus removal by hemoelimination procedure is a important mechanism to maintain phosphorus level in acceptable level in patients on dialysis. Phosphorus is removed by both diffusion and convection, but in clinical practice, it is not possible to differentiate the contribution of this two transport modalities. We used Gutzwiller formula to quantify the amount of removed phosphorus and compared it in low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), and on-line hemodiafiltration (HDF). There were no significant differences in phosphorus predialysis concentration, duration of procedure, processed blood volume and ultrafiltration, e.g., factors, which could possibly influence phosphorus elimination. All three tested dialysis modes also did not differ in urea dialysis dose (Kt/V) as a parameter of small molecular weight removal (LFHD, 1.50 ± 0.04 vs HFHD, 1.5 ± 0.06 vs HDF, 1.5 ± 0.05). The amount of removed phosphorus in LFHD, HFHD, and HDF was 34.0 ± 1.2, 37.8 ± 1.6, and 38.3 ± 1.4 mmol, respectively. Statistically significant increase in phosphorus removal was seen only with use of high-flux membrane (HFHD and HDF) when compared with the low-flux one. No difference was, however, found between HFHD and HDF. It can thus be concluded that phosphorus removal in all three dialysis modes is a predominantly diffusive issue and contribution of convection to it is minor to negligible.

From the *Department of Medicine Strahov, General University Hospital, Prague, Czech Republic; Institute of Biophysics and Informatics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; Clinic of Internal Medicine, University Hospital Ostrava, Ostrava-Poruba, Czech Republic.

Submitted for consideration February 2015; accepted for publication in revised form November 2015

Disclosure: This publication did not receive any financial support. František Švára gave a sponsored lectures for Amgen, B Braun and Baxter, received a travel Support to meetings by Amgen. František Lopot gave sponsored lectures for B Braun. Ivo Valkovský is a member of Baxter advisory board in Czech Republic. Ondřej Pecha has no conflicts of interest to report.

Correspondence: František Švára, Department of Medicine Strahov, General University Hospital, Šermířská 5, Prague 6, 169 00, Czech Republic. E-mail:

Elevated inorganic phosphorus is a common finding in the population of end-stage renal disease (ESRD) patients. Despite advancements in renal replacement technology and pharmacotherapy, to achieve target values of predialysation, phosphatemia remains a challenge for a significant proportion of patients on renal replacement therapy as well as for their nephrologists.1 Hyperphosphatemia has a broad spectrum of negative consequences, including increased morbidity and mortality.2–4 To achieve target levels of serum phosphorus, three basic tools are used: reduced phosphorus diet, phosphorus binders, and removal of phosphorus by kidney replacement therapy. In the clinical practice, hyperphosphatemia needs to be addressed as a complex issue including proper dietary counseling to reduce oral phosphorus intake, adequate pharmacotherapy, including especially agents influencing phosphorus adsorption and other chronic kidney disease–mineral and bone disorder (CKD–MBD) parameters, and enhanced phosphorus removal by hemoelimination procedure.5,6

From those three aspects, parameters affecting phosphorus dialytic removal (flows, membrane flux, session time, and treatment mode) are the most easily quantified and controlled. However, appropriate and an easy-to-do method(s) to directly evaluate amount of phosphorus removed during a blood-cleansing procedure have been developed only about a decade ago.7,8 Moreover, the existing comparative studies of phosphorus removal by different hemoelimination methods usually compared low-flux hemodialysis (LFHD) with on-line hemodiafiltration (HDF). And because HDF when compared with LFHD features both increased diffusional transport because of more porous membrane and convection, those studies could not assess contribution of both elimination principles separately.

This study evaluated phosphorus removal in LFHD, high-flux hemodialysis (HFHD), and HDF. Comparison of LFHD and HFHD enabled to assess contribution of diffusion, whereas comparison of HFHD and HDF elucidated impact of convection.

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Technique and Patients

The study included 31 stable chronic hemodialysis (HD) patients from two hospital-based HD units. The study was approved by the local ethics committee of both hospitals, and all patients gave their written informed consent. Their baseline demographic and treatment characteristics are included in Table 1. In the course of 3 weeks of this study, their treatment parameters were not changed: The patients kept using their stable oral medication including identical dose of phosphorus binders and were asked not to change their dietary habits. Also their anticoagulation and extracorporeal blood flow (QB) were strictly kept unchanged throughout the entire study. Dialysate flow rate (QD) was the same in LFHD and HFHD. For postdilutional HDF performed with AK200S Ultra machines (Gambro ab, Sweden), substitution flow (QS) was taken from the produced dialysis solution, i.e., the true QD was by QS lower.

In the first dialysis in each week cycle, i.e., after the longest intradialysis interval, treatment session in one of the three investigated modes was performed instead of the patient’s usual one (in a sequence LFHD → HFHD → HDF). All the three investigated sessions used the same QB and had the same session time in each patient, identical with patient’s regular prescription. HDF was done in the postdilution mode with substitution volume determined as at least 20% of the effective blood flow. Overview of the dialyzers and membrane characteristics is given in Table 2.

Predialysis and postdialysis blood samples were used to calculate single-pool Kt/V (spKt/V), and blood and dialysate samples were taken in the 60th minute of the session to quantify phosphorus elimination. Phosphorus removal was calculated by the formula developed by Gutzwiller8:

where M(P) is total amount of removed phosphorus in mmol, t is dialysis duration in minutes, CDs60 is phosphorus concentration in dialysate and CB60 is blood phosphorus level, both in 60th minute of the session. Guttzwiller’s formula was developed using a cohort, treated by HFHD. Its reliability for LFHD and HDF had been previously verified by us in a small-scale study against data obtained by partial dialysate collection (PDC) method9 (also see Appendix).

The conventional urea spKt/V was evaluated for each investigated session using Daugirdas10 second-generation formula:

where R = CBureapost/CBureapre, t is duration of dialysis, UF is ultrafiltration volume, and W is patient optimal body weight.

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Statistical Analysis

Data were initially tested toward normality using Kolmogorov–Smirnov test. Because normal distribution was found in all involved variables, parametric methods were used in our study. For descriptive statistics, data were expressed as mean ± SEM. Differences of means among the three methods were analyzed using one-way analysis of variance (ANOVA) with repeated measures. For all comparisons, the LFHD mode was considered as a reference method and the HFHD and HDF were compared with it separately. Subsequently, direct comparison was made between HFHD and HDF. All calculations were conducted using SPSS 17 (SPSS Inc., Chicago, IL).

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Descriptive characteristics and p values coming from the ANOVA method are summarized in Table 3. The difference between the mean M(P) obtained by the three methods was significant (p = 0.023) and nearly significant in the case of ultrafiltration rate (UFR; p = 0.055). Removed phosphorus means were almost identical between HDF (mean = 38.3 mmol) and HFHD (mean = 37.8 mmol) modes (p = 0.962), whereas M(P) reached in LFHD (mean = 34.0 mmol) was lower than HFHD (p = 0.062) and significantly lower than HDF (p = 0.033). Relation between M(P) and preprocedure phosphatemia is shown in Figure 1.

Other factors, which could theoretically influence M(P), UFR, single-pool Kt/V (spKt/V), and cumulative blood flow per procedure (VB), did not differ significantly.

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There are two principal messages clearly emerging from this study:

The first one is dissociation of dialysis efficiency in urea removal as assessed by the Kt/V and phosphorus removal assessed by its removed amount. It is merely a confirmation of a know phenomenon caused by more complex phosphorus kinetics11–13 compared with simple first-order kinetics of urea. Recently, it was nicely demonstrated by a study,14 which compared two dialysis schedules with 4 and 8 hours sessions but the same Kt/V (achieved by much lower blood flow in the latter schedule): Although the amount of removed urea was identical in both schedules, the amount of removed phosphorus was by about 40% higher in the schedule with longer session time.

The second and probably clinically more important and novel finding of our study is the very minor role of convective transport in phosphorus dialytic removal. Comparison of the data from HFHD and HDF clearly indicate that convective component adds very little, if anything, to the diffusive removal. Unsatisfactory phosphorus balance in a patient treated by LFHD can be significantly improved by his/her transfer to HFHD. No amelioration can, however, be expected in a patient treated by HFHD with his/her transfer to HDF. This may appear in contradiction with some papers which claimed that phosphorus clearance or its removal may be improved by adding convection as an additional element to standard diffusional transport. However, those papers15–18 compared HDF with LFHD and were thus not able to separate the effect of increased diffusibility of high-flux membranes (seen already in HFHD) from the impact of significant convection (taking place in HDF only). Significant improvement in both phosphorus clearance and its removed amount with switchover from HFHD to HDF has been reported by Zehnder et al.19 But this study used lower dialysate flow for HFHD (500 ml/min) than in HDF (800 ml/min). Unfortunately, inappropriate and in view of the results of our study false statement of benefits of HDF in phosphorus removal can be found also in the European Best Practice Guidelines (EBPG) document on dialysis strategy.20 Although we can agree with its guideline G1.4 (beneficial impact of longer session time and increased HD frequency in patients with impaired phosphorus control) and G2.1 (recommendation to use high-flux membranes in hyperphosphataemia), evidence of the G2.2 guideline on superior position of HDF over HFHD in phosphorus removal seems rather weak—out of three references one21 compares HDF with acetate-free biofiltration (i.e., also principally an HDF process), one22 compares LFHD (F8 dialyzer, Fresenius Medical Care, Bad Homburg, Germany) with HDF (F B3-2 Filtryzer dialyzer, Toray Medical Company Ltd., Tokyo, Japan) and is primarily focused on evaluation of postdialysis rebound, and one23 compares HD and HDF but its abstract available on the Internet does not specify the HD mode (LFHD or HFHD). On the other side, our finding of decisive role of diffusional transport for phosphorus removal is in good correspondence with theoretical calculation of phosphorus clearances by means of the simulation software CCT (Clearance Calculation Toot, based on Michaels transport equation,24 updated to include also convective transport, Fresenius Medical Care, Figure. 2). Calculation was done for FX 10 dialyzer (for LFHD) and FX 80 (for HFHD and HDF), QB was 300 ml/min for all procedures and QS was 100 ml/min for HDF, and KoA (mass transfer area coefficient) mass transfer area coefficient for phosphorus was used to calculate phosphorus clearance.

There is a steep increase (+29 ml/min, i.e., nearly 14%) in phosphorus clearance with switchover from LFHD with low-flux polysulfone dialyzer FX10 (210 ml/min) to the corresponding high-flux type FX80 with the same surface area (239 ml/min). Further increase in clearance when using FX 80 dialyzer in HDF mode (251 ml/min) is much less pronounced (+12 ml/min, i.e., just 5%). The fact that it is still higher that the increase in removed phosphorus amount in vivo seen in our study (Figure 1) can be explained by specific behavior of Fresenius dialysis machines—the produced substitution flow is added on the top of the dialysate flow (i.e., overall production of the solution is increased in HDF when compared with HD). With Gambro machines that were mostly used in our study, substitution fluid is taken from the fixed amount of produced dialysis solution (i.e., dialysate flow rate is thus reduced in HDF when compared with HD mode).

It is fair to say that the detailed statistical analysis of our data resulted in some surprising and difficult-to-explain findings. It is for instance much lower statistical significance of the difference in M(P) obtained in LFHD versus HFHD when compared with the LFHD versus HDF, despite insignificance of this difference in HDF versus HFHD. The second one is weak correlation between phosphorus removal in individual patients obtained by different dialytic modes. The key may be in dependence of this correlation on the predialysis plasma phosphorus value. There are several factors that may have affected the predialysis value. The first one is variation caused by putting one procedure with a different phosphorus removal efficiency in a sequence of standard sessions (LFHD or HDF performed in a patient who was normally dialyzed on LFHD, or vice versa one LFHD used in a patient otherwise treated by HFHD or HDF). Predialysis phosphatemia can also be significantly influenced by a short-term event such as single excess in dietary phosphorus intake and noncompliance with phosphorus binding agents. Such sudden peak in phosphatemia would logically overestimate phosphorus elimination by dialysis during the next session. Phosphorus removal is much more variable than removal of urea or creatinine, as has been recently shown25 and stressed.26 Also different saturation of inner phosphorus compartments in the different patients may have lead to different releases of phosphorus into plasma during dialysis depending on different dialytic clearances provided by the tested modes. Although existence of such compartments is generally accepted, their nature is far from being clear. Some consider bones27,28 as a possible store compartment able to release phosphorus during its massive dialytic removal from plasma, others suggest glycophosphates in body fluids13 or leave this question entirely open.11 The recently introduced “mobilization clearance” of phosphorus from inner compartments29–31 may once prove useful to asses those differences. All the previously mentioned possibilities (regardless of which came into effect in our study), however, do not change the principal finding that predialysis plasma phosphorus level seems the only confounding factor worth to be considered in any statistical evaluation of phosphorus removal.

In fact, consideration of patient-related confounding factors (namely predialysis phosphatemia and ultrafiltration) and practical inability of eliminate them in a longer time period led us to use this single procedure—in vivo—single cohort study design instead of a cross-over one done for a longer time.

It would be difficult both to fix strictly procedure parameters (as we did for those three assessed sessions) and to eliminate the previously mentioned patient-related confounding factors for several weeks required for a cross-over study.

Rather a by-product of our study is evidence that the Gutzwiller method can be easily applied to estimate phosphorus removal by dialysis, be it HD or HDF. Data on phosphorus dietary intake as the second factor determining overall phosphorus balance can be obtained either by analysis of phosphorus content in the ingested diet or roughly estimated from the protein catabolic rate.7 With the knowledge of those two factors (intake and dialytic removal), prescription of necessary phosphorus binders (accounting for their binding capacity—see for instance work of Daugirdas et al.32) could possibly be more objectively controlled. With regard to complexity of such a procedure, its use can, however, be reasonably expected only in patients with highly difficult or puzzling problems of overall phosphorus balance.

Similar results come from published papers in the area of phosphate metabolism; however, the number of published papers with this topic is markedly lower. None of these papers investigated whether the enhanced phosphorus elimination in HDF treatment is caused by increased phosphorus clearance of high permeable membrane (e.g., increased diffusion) or by high-volume ultrafiltration (partly replaced by substitution fluid, e.g., increased convection).

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Based on comparison of phosphorus removal between LFHD versus HFHD and HFHD versus HDF in our study, it can be concluded that

- It is the increased diffusibility of high-flux dialyzers which significantly augments phosphorus dialytic removal.

- Addition of convection by using the high-flux dialyzers in the HDF mode, however, does not lead to any significant further increase compared with HFHD.

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Practical applicability and accuracy of Gutzwiller’s and Gotch’s formulas for estimation of phosphorus removal M(P) both in HD and in HDF were investigated in our center in a small single center study in 2007, and the results were presented at the 34th ESAO (European Society for Artificial Organs) Congress.9 Those results were, however, subsequently not published in extenso in any article. We have, therefore, included brief information on that study to this article as an Appendix. Aim of the study9 was not comparison of elimination efficiency of different dialytic modes as in this article but verification of applicability of Gutzwiller’s and Gotch’s methods against PDC as a reference both for HD and for HDF. The detailed results for Gutzwiller’s method are shown in Figure 3.

It displays correlation between the amount of phosphorus removed during a single session in a group of 16 patients on HD (six of them on LFHD and 10 on HFHD) and 10 patients on HDF.

Next step was a comparison of combined data from LFHD, HFHD, and HDF, obtained by PDC, with results calculated by Gotch and Gutzwiller formula. Comparison of the correlations revealed slightly weaker value for the Gotch’s method when compared with that of Gutzwiller:

This together with easier and less laborious measurement procedure made us to choose the Gutzwiller’s approach for this study. The fact that it appears to underestimate M(P) against PDC did not matter in this study comparing efficacy of different blood-cleansing modes because it was applied uniformly in all of them.

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low-flux hemodialysis; high-flux hemodialysis; hemodiafiltration; Gutzwiller formula

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