|Year : 2016 | Volume
| Issue : 3 | Page : 79-88
Effect of a single session of haemodiafiltration on nerve conduction, interleukin-6 and β2-microglobulin
Mohamed G Saadi1, Bahaa Zayed1, Mohamed Momtaz1, Amr Shaker1, Khaled Marzouk1, Ann Ali2, Rabab M Ahmed Mahmoud MSc 1
1 Department of Internal Medicine and Nephrology, Kasr Al-Aini School of Medicine, Cairo University, Cairo, Egypt
2 Department of Clinical Neurophysiology, Kasr Al-Aini School of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||20-Sep-2016|
|Date of Acceptance||20-Oct-2016|
|Date of Web Publication||2-Jan-2017|
Rabab M Ahmed Mahmoud
Assistant Lecturer of Internal Medicine and Nephrology, Kasr Al-Aini School of Medicine, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
β2-Microglobulin (β2-MG) is a uremic toxin that is retained in patients with end-stage renal disease. Interleukin-6 (IL-6) besides being an inflammatory marker has emerged as an independent predictor of mortality in end-stage renal disease patients.
The aim of the present study was to investigate the effect of online haemodiafiltration (OL-HDF) by one session per week on the serum level of both IL-6 and β2-MG and to evaluate its effect on the changes in nerve conduction in patients on chronic haemodialysis (HD).
Patients and methods
Sixty patients on regular conventional HD for more than 5 years were subjected to one session of OL-HDF by using the ‘Gambro AK 200 ULTRA’ system for 4 h and two sessions of HD for 4 h per week with a follow-up for 3 months. Furthermore, urea reduction ratio was measured during one HD and one HDF session, serum β2-MG and IL-6 reduction ratio were measured during one HD and one HDF session, and during follow-up, the serum β2-MG level and IL-6 level were measured at four time intervals. Nerve Conduction Study (NCS) was done at the start of the HDF treatment and follow up 3 months post HDF treatment.
Urea reduction ratio% was significantly higher with HDF than with HD (75.6 vs. 66.9%) and this difference was statistically significant (P<0.001). Reduction ratio of β2-MG level was 72.2% with HDF versus 26.6% with HD and this difference was statistically significant (P<0.001). The results of motor conductivity testing showed significantly higher nerve conduction velocity in post-HDF in comparison with pre-HDF in right median nerve (P<0.001) and in left peroneal nerve (P<0.001). The mean value of sensory response in amplitude as well as in nerve conduction velocity in right median nerve and left median nerve were significantly higher after HDF treatment period (P<0.05).
The OL-HDF had a good effect on clearance of β2-MG at the level of one session, at the level of follow-up for 3 months, the serum level of β2-MG did not significantly changed. Also improvement in some aspects of nerve conduction, but the level of IL-6 in OL-HDF increase.
Keywords: β2-microglobulin, haemodiafiltration, interleukin-6, nerve conduction study
|How to cite this article:|
Saadi MG, Zayed B, Momtaz M, Shaker A, Marzouk K, Ali A, Ahmed Mahmoud RM. Effect of a single session of haemodiafiltration on nerve conduction, interleukin-6 and β2-microglobulin. J Egypt Soc Nephrol Transplant 2016;16:79-88
|How to cite this URL:|
Saadi MG, Zayed B, Momtaz M, Shaker A, Marzouk K, Ali A, Ahmed Mahmoud RM. Effect of a single session of haemodiafiltration on nerve conduction, interleukin-6 and β2-microglobulin. J Egypt Soc Nephrol Transplant [serial online] 2016 [cited 2018 Jul 18];16:79-88. Available from: http://www.jesnt.eg.net/text.asp?2016/16/3/79/197382
| Introduction|| |
In the last few decades, renal replacement therapy with haemodialysis (HD) has become a standard of care for patients with end-stage renal disease (ESRD). Despite continuous improvement, annual mortality among these patients ranges between 15 and 25%. It is based on the ability of molecules to diffuse across a semi-permeable membrane, which allows adequate clearance of low molecular weight particles.
To increase the clearance of middle-to-large molecules, synthetic membranes with high water permeability (high-flux membranes) were introduced years ago .
The anticipated benefit of high-flux over low-flux HD on patient survival was not confirmed in the HD study . However, the Membrane Permeability Outcome study, as well as a post-hoc analysis of diabetic patients, showed that high-flux HD improved long-term survival in patients with hypoalbuminaemia .
Clearance of middle-to-large molecules can be increased by combining diffusive and convective transport through haemodiafiltration (HDF). The introduction of online haemodiafiltration (OL-HDF) using ultrapure dialysate as the source of the replacement fluid has allowed the convective volume to be increased and has reduced the cost of the procedure .
Low-flux HD, which is purely a diffusive method, is of limited capacity to clear middle and large molecular weight uremic toxins. This limitation translates into many complications, including β2-microglobulin (β2-MG) amyloidosis, accelerated atherosclerosis, left ventricular hypertrophy and inflammation. HDF is a dialysis modality that combines the criteria of HD and haemofiltration, and thus acts by both diffusion and convection .
Interleukin-6 (IL-6) besides being an inflammatory marker has emerged as an independent predictor of mortality in ESRD patients .
The aim of our study was to evaluate the effect of OL-HDF by one session per week on the serum level of β2-MG and IL-6, as a marker of middle molecular weight uremic toxins and inflammatory marker, respectively, and also to evaluate its effect on the nerve conduction in patients on regular conventional HD.
| Patients and methods|| |
Our study was conducted at the Kasr Al-Aini Center for Nephrology, Dialysis and Transplantation (KAC-NDT), Faculty of Medicine, Cairo University.
A total of 60 patients with ESRD, previously on regular conventional HD of three sessions per week for more than 5 years, were subjected to one session of HDF by using the ‘Gambro AK 200 ULTRA’ system (Gambro, Lund, Sweden) for 4 h and two sessions of HD for 4 h per week with a follow-up for 3 months. The approval of the ethics committee was obtained, and all the patients signed an informed consent before participation in the study.
All candidates were subjected to and followed up for the following:
- Full history taking and complete clinical examination, which included the following:
- Laboratory tests: serum level of urea and serum β2-MG level immediately predialysis before HD and the first HDF session (before shifting to HDF) and postdialysis after HD and the first HDF session.
- Urea reduction ratio (URR) and Kt/v urea for a HD and HDF session.
- β2-MG reduction ratio for a HD and HDF session.
- Follow-up of β2-MG levels at four time intervals: at the start time of the treatment and after 1, 2 and 3 months predialysis before the session of HD and after the HDF treatment (one HDF session per week for a duration of 3 months).
- IL-6 samples were withdrawn before and after the first HD and HDF sessions and thereafter at three different time points: before first HDF session of every month for 3 consecutive months.
- Nerve conduction study regarding the latency, amplitude and conduction velocity for both motor and sensory response for the median nerves in both upper limbs as well as the peroneal nerves in both lower limbs at the start of the HDF treatment and after a period of 3 months after the HDF treatment.
Following were the inclusion criteria: age more than 18 years; ESRD with patients on regular conventional bicarbonate HD thrice weekly for more than 5 years; and a permanent blood vascular access capable of delivering blood flow rate of at least 250 ml/min.
Following were the exclusion criteria: severe chronic liver disease (cirrhosis; Child–Pugh grade C), HIV positive, failed kidney transplant, history of peripheral neuropathy and diabetes.
Low-flux HD was performed using Fresenius (Fresenius Medical Care Renal Company, Germany) 4008 s machine and Haidylena low-flux polysulfone dialyzers with a total surface area of 1.2 m2; blood flow rate was greater than or equal to 300 ml/min and dialysate flow rate was 800 ml/min. Postdilution HDF was carried out using a specifically designed system incorporating an online preparation of substitution solution (AK 200 ULTRA S; Gambro); blood was passed through a high-flux filter, where it was subjected to dialysis with ultrafiltration at a rate in excess of that required to achieve the patient’s dry weight. Fluid balance was maintained by infusing sterile nonpyrogenic substitution solution into the venous blood line. The substitution solution was derived from ultrapure dialysate by passing it through a single-use ultrafilter immediately before its infusion into the venous blood line.
The dialysate was prepared by proportioning ultrafiltered water, liquid acid concentrate and liquid bicarbonate concentrate made online from a dry powder cartridge (Bi-Cart Capsule). This dialysate was then rendered ultrapure by passage through a second ultrafilter.
The ultrafiltration rate for each patient was set at 25% of the patient’s blood flow rate. It was then increased until the rate that provided a stable transmembrane pressure (TMP) of 200 mmHg was found. This ultrafiltration rate was used in all subsequent treatments, unless monitored TMP indicated that a change was needed to keep the TMP from exceeding 200 mmHg. The AK 200 ULTRA S was set to prepare 500 ml/min of dialysate flow that could be increased up to 800 ml/min. Actual dialysate flow rates were reduced below 500 ml/min by the flow rate of substitution solution. Typical substitution solution flow rates ranged from 65 to 85 ml/min, so that the actual dialysate flow rates during HDF ranged from 415 to 435 ml/min. The infusion rate (QI) and total infusion volumes were controlled by an infusion pump via a correlation between the pump revolution and the flow rate. The total amount of postdilution infusion was around 20–22 l/session.
Anticoagulation was achieved using a loading dose of heparin and constant intravenous infusion by a heparin pump during the session.
In our study, all the 60 patients had undergone HDF sessions, which are characterized by the following: online postdilution HDF with a dialysate flow rate (QD)=700 ml/min, substitute flow rate (QI)=100 ml/min and blood flow rate (QB)=350 ml/min with a high-flux filters for 4 h per session; in addition, patients received one session per week for 3 months.
The pretreatment blood samples were drawn immediately after vascular access needle insertion. The post-treatment samples were drawn from the arterial blood line 20 s after decreasing the blood flow rate to 50 ml/min with dialysate flow in bypass.
We used high-flux filters with an effective surface area of 1.4 m2 of steam-sterilized polyamide membrane (Polyflux 140 H; Gambro).
Serum β2-microglobulin test
The β2-MG enzyme-linked immunosorbent assay (ELISA) test is based on the principle of a solid phase ELISA, corresponding a concentration of β2-MG in µg/ml (mg/l) from the standard curve.
IL-6 (pg/ml) level was determined using ELISA kits (AviBion Human IL-6; Orgenium Laboratories, Helsinki, Finland). The kit is an ELISA for the quantitative detection of human IL-6 in cell culture supernatants, plasma (heparin and citrate), serum, buffered solution and other body fluids. The assay recognizes both natural and recombinant human IL-6.
Data management and analysis were performed using the Sigma Stat program, version 3.5 (Systat Software Inc., San Jose, California, USA). The graphs were plotted using Microsoft Excel 2007. The numerical data were presented in terms of range, mean, SD or median and interquartile range. Categorical data were summarized as percentages.
Comparison between numerical variables before and after dialysis in the same session were carried out by using Student’s paired t-test for parametric data or Wilcoxon signed-rank test for nonparametric data.
Comparisons between β2-MG levels before and after dialysis at different time intervals were carried out using the one-way repeated measures analysis of variance.
Correlations between various variables were determined using Pearson’s moment correlation equation for linear relation. A P value less than 0.05 was considered significant, highly significant when it was less than 0.001 and insignificant when it was greater than 0.05.
| Results|| |
The study included 60 patients − 30 men and 30 women. Mean patient age was 44.4±13.0 years (range: 23–65 years, median: 45.5 years). Mean duration of HD of the studied patients was 9.0±5.38 years (range: 5–24 years, median: 7 years).
[Table 1] shows a comparison of the level of urea (URR) between HD and HDF through one dialysis session for each. The change of predialysis and postdialysis urea during the HD session was statistically significant (P<0.001). Similarly, the change of predialysis and postdialysis urea during the HDF session was statistically significant (P<0.001).
|Table 1 Comparison of predialysis and postdialysis urea level between haemodialysis and haemodiafiltration|
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On comparing a HD and a HDF session, the difference in the postdialysis urea level was markedly more reduced after one HDF session compared with after one HD session and it was statistically significant (P<0.001).
Predialysis β2-MG ranged from 13.5 to 39.4 mg/l and the mean value for predialysis β2-MG was higher than the high normal value. [Table 2] shows a comparison of β2-MG in plasma between HD and HDF through one dialysis session for each. We found that β2-MG did not change through one session of HD (P=0.4). On the other hand, its level showed a statistically significant difference through the HDF session (P<0.001). On comparing HD and HDF sessions, the difference in postdialysis β2-MG levels was statistically significant (P<0.001). The corrected postdialysis level was significantly lower after HDF (P<0.001)
|Table 2 Comparison of predialysis and postdialysis β2-microglobulin level between haemodialysis and haemodiafiltration|
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The mean Kt/v was 1.3 with HD versus 1.5 with HDF and this difference was statistically significant (P<0.001). Predialysis to postdialysis reduction in the serum urea concentration (URR%) was significantly higher with HDF compared with HD (75.6 vs. 66.9%, P<0.001). Predialysis to postdialysis reduction in the β2-MG level was 26.6% with HD compared with 72.2% with HDF, and this difference was statistically significant (P<0.001), as shown in [Table 3].
|Table 3 Kt/v, urea reduction ratio and β2-microglobulin reduction ratio in haemodialysis and haemodiafiltration|
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The patients were followed up for 3 months (one session of HDF per week and two sessions of HD per week) and the changes in β2-MG levels were recorded at four time intervals (at the start, after 1, 2 and 3 months). The differences at these different time intervals were not statistically significant (P>0.05), as shown in [Table 4].
|Table 4 Comparison of β2-microglobulin at four time intervals during the study (at the start, after 1, 2 and 3 months)|
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The electrophysiological testing was carried out before and after our HDF treatment period, and at 3 months for all patients to assess the effect of HDF in improving the nerve conduction study for both right and left median nerves at the upper limbs as well as for both right and left peroneal nerves at the lower limbs.
The results of motor conductivity testing showed significantly higher nerve conduction velocity in the post-treatment phase in comparison with the pretreatment phase in the right median nerve (51.9±7.6 vs. 49.8±7.5; P<0.001) and in the left peroneal nerve (41.3±4.8 vs. 38.8±5.5; P<0.001). But the latency and amplitude of the other four tested nerves showed no significant changes before and after the HDF treatment period ([Table 5] and [Table 6]).
|Table 5 Latency and amplitude of the tested motor nerves before and after haemodiafiltration treatment (n=60)|
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|Table 6 Nerve conduction velocity of the tested motor nerves before and after haemodiafiltration treatment (n=60)|
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The mean value of sensory response in amplitude and nerve conduction velocity in the right median nerve and the left median nerve were significantly higher after the HDF treatment period (P<0.05) ([Table 7],[Table 8],[Table 9],[Table 10],[Table 11]).
|Table 7 Latency of the tested sensory nerves before and after haemodiafiltration treatment (n=60)|
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|Table 8 Amplitude of the tested sensory nerves before and after haemodiafiltration treatment (n=60)|
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|Table 9 Nerve conduction velocity of the tested sensory nerves before and after haemodiafiltration treatment (n=60)|
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|Table 10 Correlation of pretreatment and post-treatment β2-microglobulin level with baseline and final motor nerves data|
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|Table 11 Correlation of pretreatment and post-treatment β2-microglobulin level with baseline and final sensory nerves data|
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The predialysis levels of IL-6 ranged between 0.60 and 129.7 pg/ml with a median of 27.80 pg/ml. The levels of IL-6 increased significantly after HDF (P=0.004) ([Figure 1]).
|Figure 1 IL-6 levels before and after HDF. HDF, haemodiafiltration; IL-6, interleukin-6.|
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There were no statistically significant changes in the predialysis IL-6 levels over the duration of the study (P=0.182) ([Figure 2]).
|Figure 2 The predialysis levels of IL-6 over the 3-month study period. HD, haemodialysis; HDF, haemodiafiltration; IL-6, interleukin-6.|
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| Discussion|| |
The United States Renal Data System recorded that in 2005 the adjusted prevalence of ESRD in the USAs was ∼1569 patients per million; and has been increasing by ∼3% annually since 2001. Moreover, it projects that nearly 800 000 prevalent ESRD patients will be receiving renal replacement therapy in 2020 .
The European Uremic Toxin Work Group published a list of uremic toxins that are classified according to their molecular weights. In addition, a number of other compounds that might contribute to uremic toxicity remain unidentified, and the possible interaction between these compounds is undefined .
The uremic syndrome results largely from the accumulation of toxins in those with ESRD; solutes can be divided into the following general categories.
- Low molecular weight toxins (molecular weight<500 Da).
- Middle molecular weight toxins (molecular weight 500–15 000 Da): collectively referred to as middle molecules.
- Large solutes (molecular weight>15 000 Da): frequently classified as large molecular weight proteins .
The European Best Practice Guidelines for HD recommend maximizing the removal of middle molecules and further suggest using β2-MG (molecular weight 11 800 Da) as a marker for middle molecules .
β2-MG level is associated with the development of dialysis-related amyloidosis and possibly reduced survival. The larger or protein-bound toxins contribute to the high prevalence of cardiovascular disease in ESRD . The clearance of β2-MG depends on the dialyzer membrane pore size, and the prevalence of dialysis-related amyloidosis could be expected to be lower with the use of high-flux dialyzer membranes and convective therapies .
Initially, the ability to perform HDF was severely limited by the need for large volumes of sterile substitution solution. Now systems have been developed that use sequential ultrafiltration to prepare sterile substitution solution online from water and concentrate .
On comparing one HD and HDF sessions, the difference in the postdialysis urea level was markedly more reduced after one HDF session than it was after one HD session. This difference was statistically significant (P<0.001).
On comparing β2-MG in plasma between HD and HDF in one dialysis session for each, we found that the β2-MG level did not change through the HD session (P=0.4). On the other hand, its level showed a statistically significant difference through the HDF session (P<0.001).
Predialysis to postdialysis reduction in the serum urea concentration (URR%) was significantly higher with HDF compared with HD (75.6 vs. 66.9%, P<0.001).
Moreover, predialysis to postdialysis reduction in the β2-MG level was 26.6% with HD versus 72.2% with HDF and this difference was statistically significant (P<0.001).
Our results suggested that OL-HDF has a good effect on clearance of β2-MG at the level of one session, but unfortunately the serum level of β2-MG did not change significantly at the level of follow-up of 3 months.
As regards motor response improvement after the end of the HDF treatment period, the results of motor conductivity testing showed significantly higher nerve conduction velocity in the post-treatment phase in comparison with the pretreatment phase. The latency and amplitude of the other four tested nerves on the other hand showed no significant changes before and after the HDF treatment period.
In addition, as regards sensory response improvement after the end of the HDF treatment period, the mean value of sensory response in amplitude and nerve conduction velocity in the right median nerve and the left median nerves were significantly higher after the HDF treatment period.
Thus, in our study we found that HDF could improve the nerve conduction velocity of the tested motor part of the right median nerve as well as the left peroneal nerve; furthermore, HDF could improve the amplitude and nerve conduction velocity of the tested sensory part of the right median nerve as well as the left median nerve.
A survey among more than 6000 nephrology professionals showed that 80% consider dialysis with a high-flux membrane superior to using a low-flux membrane, and among them about 50% prefer the convective therapy ,
Our results were closely in agreement with those of a study conducted on 112 patients in the Chang Gung Memorial Hospital, Taiwan, by Lin et al. .
In addition, Malberti et al.  tried to compare the effect of 1-year HD or HDF treatment on peripheral neuropathy. After a follow-up of 1 year, β2-MG was significantly reduced in HDF-treated patients (29±6.7) compared with HD-treated patients (38.8±13.9 mg/l) (P<0.01). But during the 1-year treatment, electroneurographic parameters did not change in HDF-treated patients.
In their 12-month study, Ward et al.  compared a group of HDF patients (n=24) with a group of high-flux HD patients (n=21). HDF resulted in a greater removal of β2-MG than did high-flux HD, as indicated by a significantly higher pretreatment to post-treatment change in plasma β2-MG concentration (73±1 vs. 58±1%, P<0.001).
The Dutch Convective Transport Study (CONTRAST) by Penne et al. , a prospective randomized controlled trial, showed the effect of OL-HDF on the values of β2-MG that had been estimated at baseline, 6 and 12 months for patients randomized to the HDF group and the HD group. The differences between both groups at 6 and 12 months and the decrease in the HDF group at 6 and 12 months as compared with the baseline were all statistically significant (P<0.001).
Lin et al.  in their study conducted on 58 patients who converted from high-flux HD to HDF for 8 months, pretreatment and post-treatment serum β2-MG levels markedly declined compared with high-flux HD, and there was a marked increase in the β2-MG reduction rate (76 vs. 61%).
In contrast to our results, Locatelli et al. , in their randomized multicenter trial, which included 380 patients and compared four treatment dialysis modalities with different biocompatibility and permeability of membranes (cuprophane HD, low-flux polysulfone HD, high-flux polysulfone HD and high-flux HDF), found no significant differences in treatment tolerance, nutritional status and cardiovascular stability among the four treatment groups over a follow-up of 24 months. Moreover, no difference in morbidity and mortality was found. However, the authors demonstrated a difference in predialysis β2-MG levels between convective and diffusive treatments (high-flux vs. low-flux).
Compressive neuropathies may be seen affecting the median nerve, ulnar nerve and the peroneal nerve as these nerves are more exposed at the wrist, elbow and fibular head, respectively. In a single-center study by Nardin et al., it was found that roughly 50% of patients undergoing maintenance HD have an ulnar neuropathy.
Our results were closely in line with those of a study by Yan-Chun et al.  conducted on 45 patients with uremic peripheral neuropathy who were assigned randomly to the HDF group (received regular HD twice a week and HDF once a week) and the HD group (received regular HD thrice a week). The clinical symptoms and the sensory conduction velocity of the median nerve and the peroneal nerve were observed in each group before the treatment and 1 and 2 months after the treatment. They reported no improvement in the HD group, but significant improvement in the HDF group (P<0.05).
Using data from the Lombardy registry, Locatelli et al.  reviewed 6440 patients and found that the relative risk for carpal tunnel syndrome surgery was 44% lower in patients treated with HDF.
Koda et al.  observed 819 patients over a 25-year period and found that the relative risk for carpal tunnel syndrome surgery was 53% lower in patients treated with high-flux membranes compared with low-flux membranes.
Schiffl et al.  demonstrated in a logistic regression analysis that high-flux membranes and higher dialysate quality lead to improvements in the incidence of carpal tunnel syndrome, arthropathy and bone cysts.
Using data from a Japanese dialysis patient registry, Nakai et al.  in their study conducted on 1196 patients investigated which one of the treatment modalities was most effective. When the risk for a worse therapeutic effect for low-flux HD was stated as 1, the risk for patients using high-flux HD was 0.489, whereas the risk for OL-HDF was 0.013.
In addition, in a multicentre prospective study in Japan by Hasegawa et al. , conducted on 17 patients on conventional low-flux HD who were treated with OL-HDF three times a week for 1 year, it was found that the frequency of nocturnal awakening was decreased, and the severity index of joint pain and the joint mobility index significantly improved; moreover, the motor nerve conduction latency time of the median nerve was significantly reduced from 5.1±1.0 to 3.3±1.1 ms.
The secondary analysis of the HEMO study revealed that serum β2-MG levels were correlated with mortality, with each 10 mg/l increase in the predialysis level being associated with an 11% increase for all-cause mortality .
Canaud et al.  found among 2165 patients from the European Dialysis Outcomes and Practice Patterns Study a significantly lower risk for mortality in those undergoing high-volume HDF than those on conventional low-flux HD with a higher Kt/v urea levels in patients on high efficiency HDF.
Santoro et al.  demonstrated in the Italian MAMHEBI study, a multicentered randomized controlled trial that compared mortality among patients on high-flux HD and OL-HDF, a significantly higher 3-year survival with HDF (68 vs. 52%). The odds ratio of all-cause death was 0.45 for HDF compared with HD.
β2-MG is distributed within the extracellular fluid. During HDF, β2-MG must transfer into the intravascular compartment across the capillary walls. This transcapillary transfer at a rate of ∼100 ml/min slows β2-MG removal from the body. Continuing transfer after the end of a treatment session results in a significant rebound of β2-MG levels. Low-flux dialysis results in a β2-MG level of around 40 mg/l. Three times weekly, 4 h HDF can reduce β2-MG levels to around 20 mg/l. Long (nocturnal) HDF can reduce β2-MG levels to around 10 mg/l, compared with physiological levels of less than 5 mg/l .
The predialysis plasma IL-6 levels were high in 50 (90%) patients and were normal in only 10 patients, with an average of 27.8 pg/ml. This value is higher than the values seen in normal individuals and is consistent with what Vanholder et al.  reported.
The levels of IL-6 showed no significant change after low-flux HD (median 27.8 vs. 29.0 pg/ml) indicating minimal clearance of IL-6 by HD. It also implies that HD did not provoke an inflammatory response, a finding supported by Tarakçioğlu et al. .
The levels of IL-6 showed significant increase after HDF. This was unexpected as HDF increases clearance of middle molecular weight substances including IL-6 (26 kDa), and even if assuming that the clearance was minimal, the results would have been comparable to that obtained after low-flux HD. Maduell  repoted the clearance of molecules larger than IL-6 using HDF, including complement fragment Ba (33 kDa) and α1-acid glycoprotein (44.1 kDa).
The above findings point to a high production of IL-6 during the HDF session. Since plasma cytokines, including IL-6, are rapidly bound to cell surface receptors, stable plasma levels are achieved by continuous high production rate. As a consequence, the amount of IL-6 produced during HDF was greater than the expectedly higher elimination compared with low-flux HD.
A potential cause of this high IL-6 production is inadequate purification of water used for OL-HDF, which is a consequence of failure of the ultrafilters to purify water. This was verified by water samples taken from the HDF machine after the ultrafilters that revealed a bacterial count of 7 CFU/ml indicating moderate contamination of water (moderately contaminated water: bacterial count <1000 CFU/ml, LAL<0.5 EU/ml) . This is a high bacteria count for HDF dialysate, and also infusion fluid would definitely provoke an inflammatory response detected as an increase in plasma IL-6, among other cytokines. This is supported by the findings of Bossola et al.  who reported that contaminated dialysate induces IL-6 production, as well as that bacterial derived DNA fragments in dialysis fluid induce IL-6 production.
Despite of that none of the patients developed a pyrogenic reaction (chills, fever, hypotension, etc.) during any of the HDF sessions throughout the study period, indicating that the increase in IL-6 levels was ‘subclinical’. This ‘subclinical’ increase in cytokines levels in response to a high bacterial count and endotoxin content was also reported by Gordon et al. .
The water used in our centre was in compliance with the Egyptian Standards, which are almost identical to the Association for the Advancement of Medical Instrumentation (AAMI, 2004) and ISO 13959 regulations (2009), but it requires less than 50 CFU/ml of bacteria for standard dialysate (compared with 100 CFU/ml in other standards). It is worth mentioning that the water is tested monthly by the ministry of Health Central Laboratory to ensure compliance with the standards and that the bacterial count in our centre is consistently less than 10 CFU/ml.
The IL-6 levels obtained every month during the study period showed no significant changes from the basal IL-6 levels obtained at the beginning of study, although HDF per se increased IL-6. This could be explained by very short half-life of IL-6 (3–7 min) in addition to the fact that patients underwent only one HDF session per week, the small study population, and the relatively short period of the study.
There were some limitations in our research study.
- Small number of patients.
- Short period of HDF treatment follow-up.
- No data were obtained regarding the effect of HDF on other parameters such as blood pressure, haemoglobin level, phosphorus level, nutritional status and bone mineral metabolism.
No data regarding the effect of HDF on the reduction of other middle molecular weight uremic toxins of potential importance.
| Conclusion|| |
OL-HDF had a good effect on clearance of β2-MG at the level of one session and at the level of follow-up for 3 months; the serum level of β2-MG did not change significantly. Moreover, there was an improvement in some aspects of nerve conduction; on the other hand, OL-HDF increased the serum level of IL-6.
The authors thank all the patients and nurses who participated in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ahrenholz P, Winkler RE, Ramlow W, Tiess M, Müller W. On-line haemodiafiltration with pre- and post-dilution: a comparison of efficacy. Int J Artif Organs 2007; 20:81–90.
Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW et al.
Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002; 347:2010–2019.
Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V et al.
Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol 2009; 20:645–654.
Jean G, Hurot JM, Deleaval P, Mayor B, Lorriaux C. Online-haemodiafiltration vs. conventional haemodialysis: a cross-over study. BMC Nephrol 2015; 16:70.
Barreto DV, Barreto FC, Liabeuf S, Temmar M, Lemke HD, Tribouilloy C et al.
European Uremic Toxin Work Group (EUTox). Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease. Kidney Int 2010; 77:550–556.
The United States Renal Data System (USRDS). Annual data report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007.
Vanholder R, de Smet R, Glorieux G, Argiles A, Baurmeister U, Brunet P et al.
Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 2003; 63:1934–1943.
Cheung AK, Rocco MV, Yan G, Leypoldt JK, Levin NW, Greene T et al.
Serum β2-microglobulin levels predict mortality in dialysis patients: results of the HEMO Study. J Am Soc Nephrol 2006; 17:546–555.
Yavuz A, Tetta C, Ersoy FF, D’intini V, Ratanarat R, de Cal M et al.
Uremic toxins: a new focus on an old subject. Semin Dial 2005; 18:203.
Dember LM, Jaber BL. Dialysis-related amyloidosis: late finding or hidden epidemic? Semin Dial 2006; 19:105–109.
Ledebo I. Principles and practice of haemofiltration and haemodiafiltration. Artif Organs 2000; 22:20–25.
Ledebo I, Ronco C. The best dialysis therapy? Results from an international survey among nephrology professionals. NDT Plus 2008; 6:403–408.
Lin CL, Huang CC, Yu CC, Yang HY, Chuang FR, Yang CW. Reduction of advanced glycation end product levels by on-line hemodiafiltration in long-term hemodialysis patients. Am J Kidney Dis 2003; 42:524–531.
Malberti F, Surian M, Farina M, Vitelli E, Mandolfo S, Guri L et al.
Effect of hemodialysis and hemodiafiltration on uremic neuropathy. Blood Purif 2009; 9:285–295.
Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W. A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol 2000; 11:2344–2350.
Penne EL, Blankestijn PJ, Bots ML, van den Dorpel MA, Grooteman MP, Nubé MJ et al.
Effect of increased convective clearance by on-line haemodiafiltration on all cause and cardiovascular mortality in chronic haemodialysis patients: the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomized controlled trial. Curr Control Trials Cardiovasc Med 2005; 6:8.
Lin CL, Yang CW, Chiang CC, Chang CT, Huang CC. Long-term on-line haemodiafiltration reduces pre-dialysis β2-microglobulin levels in chronic haemodialysis patients. Blood Purif 2001; 19:301–307.
Locatelli F, Mastrangelo F, Redaelli B, Ronco C, Marcelli D, la Greca G, Orlandini G. Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters. The Italian Cooperative Dialysis Group. Kidney Int 2006; 50:1293–1302.
Nardin R, Chapman KM, Raynor EM. Prevalence of ulnar neuropathy in patients receiving haemodialysis. Arch Neurol 2005; 62:271–275.
Chi Yan-Chun, Song Li-Gun, Yang Xiao-Mei. The Forth Affiliated Hospital of Harbin Medical University, Harbin, China. J Baotou Med College 2002; 15:62–65.
Locatelli F, Hannedouche T, Jacobson S, la Greca G, Loureiro A, Martin-Malo A et al.
The effect of membrane permeability on ESRD: design of a prospective randomised multicentre trial. J Nephrol 2000; 12:85–88.
Koda Y, Nishi S, Miyazaki S, Haginoshita S, Sakurabayashi T, Suzuki M et al.
Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of haemodialysis patients. Kidney Int 2007; 52:1096–1101.
Schiffl H, Fischer R, Lang SM, Mangel E. Clinical manifestations of AB-amyloidosis: effects of biocompatibility and flux. Nephrol Dial Transplant 2000; 15:840–845.
Nakai S, Iseki K, Tabei K, Kubo K, Masakane I, Fushimi K et al.
Outcomes of haemodiafiltration based on Japanese Dialysis Patient Registry. Am J Kidney Dis 2001; 38(Suppl 1):S212–S216.
Hasegawa H, Kaketaka A, Negi S, Uchita K, Kita Y, Ageta S et al.
The clinical effect of B2M removal by HDF on DRA: a multicentre prospective study. Nephrol Dial Transplant 2004; 15:58–64.
Canaud B, Bragg-Gresham JL, Marshall MR, Desmeules S, Gillespie BW, Depner T, Klassen P, Port FK. Mortality risk for patients receiving haemodiafiltration versus haemodialysis: European results from the DOPPS. Kidney Int 2006; 69:2087.
Santoro A, Mancini E. Effects of online haemofiltration versus bicarbonate dialysis on mortality and morbidity in haemodialysis patients: a prospective, randomized, multicenter trial (MAMHEBI Study). J Am Soc Nephrol 2006; 17:24.
Ward RA, Greene T, Hartmann B, Samtleben W. Resistance to inter-compartmental mass transfer limits β2-microglobulin removal by post-dilution haemodiafiltration. Kidney Int 2006; 69:1431–1437.
Tarakçioğlu M, Erbağci AB, Usalan C, Deveci R, Kocabaş R. Acute effect of hemodialysis on serum levels of the proinflammatory cytokines. Mediators Inflamm 2003; 12:15–19.
Maduell F. Hemodiafiltration. Hemodial Int 2005; 9:47–55.
Lonnemann G. When good water goes bad: how it happens, clinical consequences and possible solutions. Blood Purif 2004; 22:124–129.
Bossola M, Sanguinetti M, Scribano D, Zuppi C, Giungi S, Luciani G et al.
Circulating bacterial-derived DNA fragments and markers of inflammation in chronic hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:379–385.
Gordon SM, Oettinger CW, Bland LA, Oliver JC, Arduino MJ, Aquero SM et al.
Pyrogenic reactions in patients receiving conventional, high-efficiency, or high-flux hemodialysis treatments with bicarbonate dialysate containing high concentrations of bacteria and endotoxin. J Am Soc Nephrol 1992; 2:1436–1444.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]