Gayrard, Duranton, Ficheux and Argiles are employees of RD - Néphrologie, owner of the patent protecting the exploitation rights of the patents EP 2 362 790, JP 5 587 891 and US 8 298 427.
‡ These authors also contributed equally to this work
Recent randomised controlled trials suggest that on-line hemodiafiltration (OL-HDF) improves survival, provided that it reaches high convective volumes. However, there is scant information on the feasibility and the consequences of modifying convection volumes in clinics.
Twelve stable dialysis patients were treated with high-flux 1.8 m2 polysulphone dialyzers and 4 levels of convection flows (QUF) based on GKD-UF monitoring of the system, for 1 week each. The consequences on dialysis delivery (transmembrane pressure (TMP), number of alarms, % of achieved prescribed convection) and efficacy (mass removal of low and high molecular weight compounds) were analysed.
TMP increased exponentially with QUF (p<0.001 for N >56,000 monitoring values). Beyond 21 L/session, this resulted into frequent TMP alarms requiring nursing staff interventions (mean ± SEM: 10.3 ± 2.2 alarms per session, p<0.001 compared to lower convection volumes). Optimal convection volumes as assessed by GKD-UF-max were 20.6 ± 0.4 L/session, whilst 4 supplementary litres were obtained in the maximum situation (24.5 ± 0.6 L/session) but the proportion of sessions achieving the prescribed convection volume decreased from 94% to only 33% (p<0.001). Convection increased high molecular weight compound removal and shifted the membrane cut-off towards the higher molecular weight range.
Reaching high convection volumes as recommended by the recent RCTs (> 20L) is feasible by setting an HDF system at its optimal conditions based upon the GKD-UF monitoring. Prescribing higher convection volumes resulted in instability of the system, provoked alarms, was bothersome for the nursing staff and the patients, rarely achieved the prescribed convection volumes and increased removal of high molecular weight compounds, notably albumin.
Adding convection to standard haemodialysis was proposed in the sixties (haemofiltration) and seventies (hemodiafiltration (HDF)), to improve treatment performances [
However, the consequences of increasing convection volumes on the physics of the system and on its performances in a clinical situation have not been fully documented. These questions are particularly relevant since high convection volumes are obtained by increasing the convection flow, which depends on the transmembrane pressure (TMP) of the dialysis system. We previously studied the ratio of ultrafiltation flow over TMP, which represents the in situ global hydraulic permeability coefficient of the whole in vivo dialysis system (GKD-UF), [
Twelve stable dialysis patients were routinely treated in the dialysis clinic of Sète using HDF equipped dialysis monitors (Dialog+, B BRAUN, Melsungen, Germany) with alarms set following the recommendations of the European Renal Best Practice (ERBP) guidelines (ultrafiltration limited to 30% of the blood flow and TMP limited to 300 mmHg, as a safe maximum value) [
The abbreviations are as follows: HD, hemodialysis; OL—HDF, On-line hemodiafiltration; QUF, ultrafiltration flow.
Total dialysate production flow was set at 600 mL/min and checked for every dialysis monitor (Table 2 shows the measurements). At the beginning of the first session of the week, GKD-UF-max was determined for every patient included in the study. To establish GKD-UF-max, infusion flow rate was set at 0 mL/min and then modified stepwise by 10 mL/min from 50 to 100 or 110 mL/min. After ~1 minute of stabilization, TMP was recorded and GKD-UF calculated with QUF:
with GKD-UF, global ultrafiltration coefficient (mL.h-1.mmHg-1); QUF, ultrafiltration flow (mL.min-1); TMP, transmembrane pressure (mmHg); QINF, infusion flow (mL.min-1); QWL, ultrafiltration flow for weight loss (mL.min-1).
The vertex of the parabolic tendency line (GKD-UF over QUF) is GKD-UF-max. The corresponding total convection flow is QUF at GKD-UF-max (X value of the GKD-UF-max point) which is considered the optimal convection OL-HDF. Low convection OL-HDF was defined as 60% of optimal and the maximum-possible QUF was aimed for respecting the limits advised by the ERBP.
All the data collected during dialysis sessions (time, pressures and flow rates for dialysate or blood, infusion flow, alarms and events) were recovered from the hard disk of each dialysis monitor and were processed on a spread-sheet (Excel, Microsoft). The clinical data (weight before and after dialysis, dialysis characteristics and events) were taken from the session sheets recorded by the nurses and physicians.
For every dialysis treatment, the total balance of selected substances was established using the continuous sampling of spent dialysate (CSSD)[
Blood samples were obtained before and after dialysis of the mid-week treatment in order to assess dialysis efficacy (percentage reduction in urea and creatinine) as well as serum variation in haemoglobin, sodium, potassium, chloride, bicarbonate, calcium, phosphate, β2-m, albumin and total proteins.
For each convection condition, six dialysers were processed to assess protein adsorption to the membrane and morphology analysis by electron microscopy. The proteins adsorbed in the membrane of the dialyser were recovered following Mares
Two dialysers were mechanically cut after the EDTA–PBS rinses and ~1.5 cm length fibres were fixed with 2.5% glutaraldehyde in PHEM buffer, pH 7.2 for an hour at room temperature, followed by washing in PHEM buffer. Fixed samples were dehydrated using a graded ethanol series (30–100%), followed by 10 minutes in graded Ethanol—Hexamethyldisilazane. And then Hexamethyldisilazane alone. Subsequently, the samples were sputter coated with an approximate 10nm thick gold film and then examined under a scanning electron microscope (Hitachi S4000, at CoMET, MRI-RIO Imaging, Biocampus, INM Montpellier France) using a lens detector with an acceleration voltage of 10KV at calibrated magnifications.
Statistical analyses were performed using a SAS V9.2 (SAS Corporation, Cary, NC, USA). Differences in the continuous variables among the four different convection settings tested were assessed using an analysis of variance. Bonferroni’s test was used to check the differences between 2 of the 4 conditions. P values < 0.05 were considered significant. Values are given as mean ± standard error of the mean.
The clinical characteristics of the 12 patients (6 males and 6 females) included in the study are presented in
Patients characteristics (N = 12) | |
---|---|
6F / 6M | |
73 ± 12 | |
71 ± 2 | |
34.4 ± 1.2 | |
35.5 ± 1.4 | |
62.8 ± 1.2 |
Convection flow condition | HD | Low convection OL-HDF | Optimal convection OL-HDF | Maximum convection OL-HDF | p-values |
---|---|---|---|---|---|
Session time (min) | 232 ± 3 | 236 ± 3 | 235 ± 3 | 232 ± 3 | 0.24 |
Blood flow QB (mL.min-1) | 365 ± 6 | 368 ± 5 | 364 ± 5 | 368 ± 5 | 0.41 |
Dialysate flow (mL.min-1) | 602 ± 1 | 603 ± 1 | 602 ± 1 | 602 ± 1 | 0.69 |
UF flow for weight loss QWL(mL.min-1) | 11.9 ± 0.6 | 12.5 ± 0.5 | 12.3 ± 0.6 | 12.5 ± 0.5 | 0.73 |
Weight loss (kg) | 2.8 ± 0.2 | 3.0 ± 0.1 | 2.9 ± 0.2 | 3.0 ± 0.1 | 0.71 |
Infusion flow QINF (mL.min-1) | 0 | 41.7 ± 0.7 | 74.5 ± 1.0 | 90.9 ± 1.8 | <0.001 |
Convection flow QUF = QWL+ QINF (mL.min-1) | 11.9 ± 0.7 | 54.1 ± 0.7 | 86.8 ± 1.1 | 103.5 ± 1.9 | <0.001 |
Filtration fraction QUF/QB (%) | 3.2 ± 0.2 | 14.8 ± 0.2 | 23.9 ± 0.3 | 28.1 ± 0.4 | <0.001 |
Infusion volume VINF (L) | 0 | 9.9 ± 0.2 | 17.7 ± 0.3 | 21.5 ± 0.5 | <0.001 |
Convection volume VUF (L) | 2.8 ± 0.2 | 12.9 ± 0.2 | 20.6 ± 0.4 | 24.5 ± 0.6 | <0.001 |
Mean TMP (mmHg) | 79 ± 2 | 121 ± 2 | 185 ± 4 | 242 ± 4 | <0.001 |
Max registered TMP (mmHg) | 98 ± 2 | 152 ± 3 | 245 ± 7 | 322 ± 7 | <0.001 |
The total records of TMP during the complete dialysis session of a patient treated with the four different convection settings are given in
Panel
A total of 920 alarms were recorded on 142 sessions (
Convection flow condition | HD | Low convection OL-HDF | Optimal convection OL-HDF | Maximum convection OL-HDF | p-values |
---|---|---|---|---|---|
Sessions with TMP alarms (%) | 0% | 0% | 9% | 83% | <0.001 |
Mean non dalysis time due to alarms (min) | 0.2 ± 0.1 | 0.3 ± 0.1 | 0.7 ± 0.3 | 8.0 ± 2.9 | <0.001 |
Nurse interventions by sessions (%) | 0% | 0% | 6% | 75% | <0.001 |
Mean number of nurse interventions (nb/session) | 0 ± 0 | 0 ± 0 | 0.06 ± 0.04 | 1.0 ± 0.13 | <0.001 |
Sessions achieving the prescribed convection volume (%) | 100% | 100% | 94% | 33% | <0.001 |
Removal of urea, creatinine, acid uric and phosphate are presented in
It is observed that the variation in β-2m removal was not significantly different with HDF (slight linear increase with increasing convection volume), while the increase in removal was more evident in the higher mol wt range, being clearly exponential for albumin; albumin loss was around double when increasing from optimal convection to maximum convection HDF.
Convection flow condition | HD | Low convection OL-HDF | Optimum convection OL-HDF | Maximum convection OL-HDF | p-values | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Blood before (mmol/L) | 17,0 | ± | 1,6 | 17,5 | ± | 1,8 | 19,3 | ± | 2,1 | 17,4 | ± | 1,6 | 0,15 |
Blood after (mmol/L) | 3,9 | ± | 0,5 | 3,5 | ± | 0,5 | 3,5 | ± | 0,6 | 3,6 | ± | 0,5 | 0,22 |
Blood RR (%) | 80% | ± | 1% | 81% | ± | 1% | 81% | ± | 1% | 80% | ± | 1% | 0,52 |
Total mass |
526 | ± | 38 | 508 | ± | 37 | 545 | ± | 43 | 473 | ± | 32 | 0,21 |
Clearance (mL/min) | 228 | ± | 10 | 231 | ± | 7 | 227 | ± | 8 | 239 | ± | 8 | 0,24 |
Blood before (μmol/L) | 616 | ± | 44 | 607 | ± | 48 | 628 | ± | 46 | 616 | ± | 41 | 0,05 |
Blood after (μmol/L) | 180 | ± | 23 | 165 | ± | 21 | 163 | ± | 22 | 175 | ± | 19 | 0,10 |
Blood RR (%) | 75% | ± | 1% | 74% | ± | 2% | 74% | ± | 2% | 73% | ± | 2% | 0,93 |
Total mass |
12184 | ± | 965 | 11855 | ± | 847 | 12268 | ± | 904 | 11701 | ± | 917 | 0,51 |
Clearance (mL/min) | 138 | ± | 7 | 138 | ± | 8 | 135 | ± | 8 | 140 | ± | 8 | 0,41 |
Blood before (μmol/L) | 285 | ± | 19 | 291 | ± | 14 | 318 | ± | 19 | 283 | ± | 16 | 0,02 |
Blood after (μmol/L) | 59 | ± | 6 | 52 | ± | 4 | 56 | ± | 6 | 53 | ± | 5 | 0,36 |
Blood RR (%) | 81% | ± | 2% | 82% | ± | 1% | 83% | ± | 1% | 82% | ± | 1% | 0,53 |
Total mass |
6753 | ± | 319 | 6757 | ± | 273 | 7209 | ± | 338 | 6735 | ± | 347 | 0,33 |
Clearance (mL/min) | 193 | ± | 12 | 193 | ± | 7 | 196 | ± | 13 | 202 | ± | 10 | 0,76 |
Blood before (mmol/L) | 1,35 | ± | 0,15 | 1,32 | ± | 0,11 | 1,32 | ± | 0,11 | 1,23 | ± | 0,09 | 0,10 |
Blood after (mmol/L) | 0,51 | ± | 0,05 | 0,51 | ± | 0,04 | 0,51 | ± | 0,04 | 0,48 | ± | 0,04 | 0,49 |
Blood RR (%) | 64% | ± | 3% | 59% | ± | 3% | 59% | ± | 4% | 58% | ± | 4% | 0,25 |
Total mass |
888 | ± | 86 | 900 | ± | 105 | 942 | ± | 89 | 831 | ± | 59 | 0,15 |
Clearance (mL/min) | 144 | ± | 13 | 145 | ± | 11 | 161 | ± | 13 | 150 | ± | 13 | 0,22 |
Blood before (g/L) | 63 | ± | 2 | 60 | ± | 2 | 60 | ± | 2 | 62 | ± | 2 | 0,08 |
Blood after (g/L) | 57 | ± | 2 | 56 | ± | 2 | 54 | ± | 2 | 57 | ± | 2 | 0,46 |
Blood RR (%) | 10% | ± | 2% | 7% | ± | 2% | 9% | ± | 2% | 8% | ± | 3% | 0,80 |
Total mass |
1204 | ± | 79 | 1438 | ± | 79 | 1882 | ± | 113 | 2329 | ± | 118 | <0.001 |
Clearance (mL/min) | 0,077 | ± | 0,005 | 0,10 | ± | 0,01 | 0,13 | ± | 0,01 | 0,16 | ± | 0,01 | <0.001 |
Blood before (mg/L) | 31,43 | ± | 1,94 | 31,57 | ± | 1,99 | 29,54 | ± | 2,07 | 30,94 | ± | 1,66 | 0,48 |
Blood after cor. (mg/L) | 9,61 | ± | 1,04 | 6,90 | ± | 0,59 | 5,33 | ± | 0,76 | 5,94 | ± | 0,67 | <0.001 |
Blood RR (%) | 74% | ± | 3% | 82% | ± | 2% | 85% | ± | 2% | 84% | ± | 2% | <0.001 |
Total mass |
237 | ± | 27 | 260 | ± | 31 | 274 | ± | 35 | 290 | ± | 35 | 0,26 |
Clearance (mL/min) | 56 | ± | 5 | 75 | ± | 11 | 83 | ± | 12 | 88 | ± | 11 | 0,02 |
Blood before (g/L) | 32,13 | ± | 1,44 | 31,85 | ± | 1,27 | 32,14 | ± | 1,41 | 33,65 | ± | 0,51 | 0,31 |
Blood after cor.(g/L) | 28,43 | ± | 0,66 | 27,52 | ± | 1,68 | 27,65 | ± | 1,26 | 28,75 | ± | 1,14 | 0,88 |
Blood RR (%) | 10% | ± | 4% | 13% | ± | 4% | 14% | ± | 2% | 15% | ± | 3% | 0,87 |
Total mass |
39 | ± | 10 | 116 | ± | 16 | 386 | ± | 57 | 793 | ± | 158 | <0.001 |
Clearance (mL/min) | 0,006 | ± | 0,002 | 0,014 | ± | 0,002 | 0,045 | ± | 0,008 | 0,084 | ± | 0,007 | <0.001 |
*Total mass removed in dialysate by session
To illustrate the variation of removal with increasing convection according to protein size, β2-m and albumin were compared. With conventional dialysis, six times more β2-m than albumin was removed (ratio of removed albumin / removed β2-m = 0.167). The ratio was reversed by increasing convection and the total amount of removed albumin was 3-fold that of removed β2-m, with maximum convection OL-HDF (ratio = 2.96). The albumin / β2-m removal ratio increased by 14.3 fold when passing from dialysis to the maximum convection OL-HDF situation (
Electron microscopy of AMEMBRIS membranes after treatment clearly characterised a change in membrane pores after cake formation during the dialysis procedure (
An example of one dialyser used in hemodialysis is given in the upper panels (A, B and C; x2,000 magnification) and of one dialyser used in hemodiafiltration in the lower panels (D, E and F; x40,000 magnification). (A) The external wall displays visible pores, significantly larger than the pores of the internal wall (B and C), which are not visible at x2,000 magnification. (B) The arrow points at one erythrocyte located between 2 cumulated material and crystals from the rinsing fluid (saline and sodium dodecyl sulphate). (C) Sparse crystals are laying on the internal wall. Three different zones of the internal wall of the dialyser are displayed in the lower panels at x40,000 magnification, one with practically all the pores visible and accessible (D), one with some pores covered by a proteinaceous material (E) and one where all the pores are covered by a uniform material attached to the membrane (F).
Convection was sought from early sixties trying to establish a renal replacement system based upon a filtration process rather than upon a diffusion process, aiming to emulate the filtration process of the glomerulus in the “in vivo” situation [
The analysis of GKD-UF allows identifying the optimal convection in terms of differential convection obtained by a differential TMP required in a dialysis system [
To reduce the problems appearing when increasing convection in post-dilutional OL-HDF, various forms of HDF have been developed varying the point of infusion of the replacement fluid, referred to as pre-, mid- or mixed-dilution. Although these methods allow higher convection flow with less alarms, their efficiency in small mol wt compound clearances is recognized to be lower than that obtained in post-dilution and therefore they deserve further studies before being proposed indiscriminately [
Our data show that removal of small soluble compounds is not significantly enhanced by convection, while differences are visible on higher molecular weight uraemic retention solutes from the middle molecule group [
Concerning the middle molecules, increasing convection (and therefore, TMP) resulted in increasing the removal of high mol wt compounds, while the increase observed in β2-m (11.8 kDa mol wt) removal was not significant or relevant. It was clearly seen that conventional dialysis was highly selective in protein removal with a 6-fold greater removal of β2-m than albumin (67 kDa), whilst it is 1000-fold less abundant in serum (β2-m: 32±1 mg/L; albumin: 32100 ± 1400 mg/L). This selectivity diminished with increasing convection, and at the maximum convection OL-HDF, the ratio albumin / β2-m removal was reversed. Expanding the convection over the optimal setting resulted in increasing total protein removal by around 0.5 g/session (from 1.8 to 2.3 g/session) and of this 0.4 g (80%) consisted of albumin. These findings suggest that higher convection volumes and elicited TMP result in an upward shift of the molecular weight cut-off of the dialysis system, in keeping with the studies of Ahrenholz
Systems exist helping to achieve high convection volumes in post dilution OL-HDF. These systems are very efficient as they allow maximum filtration rates and consequently high convection volumes [
In conclusion, optimal convection OL-HDF as defined by GKD-UF-max allows convection volumes (>20 L per session) within the range of those found to be associated with survival benefits by some recent RCTs [
Mean and standard error of the mean for each convection condition.
(PDF)
The p values of the ANOVA test are given in the right hand side column. All the variables that were significantly different when analysing the four groups, were also different when comparing the over GKD-UF-max to the others by X2 or Bonferroni analysis.
(DOCX)
This work has been possible with the personal support of Marion Capely, Aurélie Laden, Sylvie Febbraro, Marie Thomas, and the nursing staff of NDSG. The help of Zhendong Zhang, Gilles Goubert, Cristel Baux and Christelle Cuchet is also acknowledged.
Part of the data included in this paper has been presented at the 50th annual Congress of the European Renal Association–European Dialysis and Transplantation Association.