The Effect of High-Flux Hemodialysis on Dialysis-Associated Amyloidosis

Abstract

Amyloidosis is an important cause of mortality and morbidity in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). In this study, depending on the idea that the clearance of middle and high molecular weight toxins could be improved, we aimed to investigate the effect of high-flux dialyzer on clearance of beta-2 microglobulin (β2-MG) and calcium (Ca) phosphorus (P) metabolism in patients under HD treatment. Forty-eight patients with ESRD under chronic HD treatment were included in the study. All patients were randomized into two groups, and HD was performed with low-flux or high-flux dialyzer for 6 months. In the high-flux group, the reduction of β2-MG and P levels during dialysis was significantly higher when compared with the low-flux group (p < 0.001). During the follow-up period, while β2-MG levels decreased significantly in the high-flux group (p < 0.05), there was an increase in the low-flux group (p < 0.05). As a result, our findings suggest that use of high-flux dialyzer can be an efficient alternative in terms of controlling the clearance of β2-MG and impaired Ca and P metabolism. These beneficial effects of high-flux dialyzers are probably mediated by the improved clearance of middle and high molecular weight toxins.

• High-flux
• Hemodialysis
• Amyloidosis
• Beta-2 microglobulin

Introduction

Hemodialysis (HD) therapy of patients with end-stage renal disease (ESRD) prolongs life expectancy by removing the metabolic end products and excess water. Despite this, the morbidity and mortality rates in this population, primarily depending on cardiovascular disease, continue to be higher than those of the general population.[1&2] Long-term complications of hemodialysis are important factors that affect the patients' quality of life.[3]

Plasma concentration of beta-2 microglobulin (β2-MG) in the case of renal insufficiency is about 20 to 30 times higher than normal. High-flux membranes are capable of clearing substances of greater molecular weight than conventional membranes.[4] The incidence of these manifestations increases with duration of HD.[5] β2-MG is associated with secondary amyloidosis, a late complication of long-term HD therapy. Its clinical expression in terms of arthralgias, destructive arthropathies, and carpal tunnel syndrome is often associated with amyloid deposits, which are mainly composed of β2-MGfibrils. In order to prevent the complications of secondary amyloidosis, β2-MG should therefore be eliminated as efficiently as possible during dialysis treatment.

While β2-MG amyloidosis occurring in patients undergoing long-term dialysis is frequently associated with joint involvement, skin lesions have rarely been encountered.[6]

High-flux membranes are expected to have better control over the clearance of middle and high molecular weight uremic toxins and to be more efficient when compared with the conventional low-flux membranes. In this study, we aimed to investigate the effect of high-flux dialyzer on dialysis-related amyloidosis and Ca and P metabolism.

Materials and Methods

Forty-eight ESRD patients, 26 male and 22 female, who were under chronic HD treatment were included in the study. The mean age was 59.1 ± 13.9 years (range 36–80 years), and median duration on HD was 46 months (range 18–96 months). All patients were having hemodialysis therapy by low-flux dialyzers. All patients were under chronic HD treatment performed by using standard heparinization applied for 4 h three times a week, with Fresenius 4008-B devices, with the rate of blood flow being 300 mL/min and the flow rate of dialysis fluid being 500 mL/min. All patients received a diet consisting of 1.2 g/kg/day protein, poor in phosphorus and potassium.

Levels of hemoglobin (Hb), hematocrit (Htc), plasma iron, transferrin, ferritin, vitamin B₁₂, folic acid, intact parathormone (iPTH), urea, albumin, total calcium, inorganic phosphorus, C-reactive protein (CRP), and β2-MG were measured in all patients before the HD session. Levels of urea, inorganic phosphorus, and β2-MG were measured again 30 min after the dialysis session. In addition, body weights before and after the HD session, mean ultrafiltration volumes, urea reduction rates (URR), and Kt/V urea rates were determined. Kt/V urea was calculated according to the Dougirdas formulation.[7]

After this initial evaluation, patients were randomized into two groups: polysulfone low-flux dialyzer (Fresenius F6 HPS) was used in the first group and polysulfone high-flux dialyzer (Fresenius F60) was used in the second group, thus HD was performed for 6 months. During this period, dialysis treatment protocols and the diets were not modified. Measurements of urea, albumin, total calcium, inorganic phosphorus, URR, and Kt/V urea were determined every month, and other measurements were repeated at the sixth month.

Biochemical analyses were performed with Abbott AILYON-300i device and commercial kits, and the hematological analyses were performed with Abbott Cell-dyn-1700 device and commercial kits. β-ImmunoRadio Metric Assay measured β2-MG levels with the Abbott kits, and CRP measurement was done with nephelometric immunoassay method.

Results were given as mean ± standard deviation. Paired or unpaired student's t-tests were used for the comparison of means, and chi-squared tests were used for the comparison of percentages. The statistical analyses were performed with SPSS version 10.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered as statistically significantly different.

Results

In the low-flux and high-flux groups, the initial values of the study parameters are given in Table 1. There was no statistically significant difference between these two groups in terms of the initial values of these study parameters (p > 0.05). Initial values of calcium, phosphorus, and parathormone are given in Table 2; there was no statistically significant difference between the groups.

Table 1 Initial Values of Some Study Parameters.

	Low-flux	High-flux	P
Age (years)	59.9 ± 14.9	58.3 ± 13.1	NS
Gender (male/female)	12/12	14/10	NS
Median HD period (months)	44 (18–96)	48 (20–96)	NS
Plasma albumin (g/dL)	4.5 ± 0.3	4.5 ± 0.3	NS
Urea before dialysis (mg/dL)	166 ± 13	165 ± 13	NS
Urea after dialysis (mg/dL)	58 ± 7a	56 ± 7a	NS
C-reactive protein (mg/L)	6.2 ± 4.1	6.8 ± 4.8	NS
Vitamin B12	285 ± 23	294 ± 21	NS
Folic acid	5.7 ± 1.2	5.8 ± 0.9	NS
β2-microglobulin (mg/L)	36.0 ± 7.1	37.1 ± 6.9	NS
Urea reduction rate (%)	66 ± 8	65 ± 7	NS
Kt/V urea	1.19 ± 0.21	1.17 ± 0.19	NS

^ap < 0.001 when compared with the level before dialysis; NS: not significant.

Table 2 Initial Values of Calcium, Phosphorus, and Parathormone.

	Low-flux	High-flux	P
Calcium (mg/dL)	9.2 ± 1.6	9.3 ± 1.3	NS
Phosphorus before dialysis (mg/dL)	5.5 ± 0.6	5.6 ± 0.6	NS
Phosphorus after dialysis (mg/dL)	4.1 ± 0.4a	4.2 ± 0.4a	NS
Parathormone (pmol/L)	4.65 ± 3.06	4.85 ± 2.95	NS

^ap < 0.001 when compared with the level before dialysis; NS: not significant.

In the study groups, the mean values of the study parameters at the sixth month are shown in Table 3. At the end of the follow-up period, there was no statistically significant difference between groups in terms of URR and Kt/V urea (p > 0.05). The reduction of phosphorus and β2-MG during the dialysis session was statistically higher in the high-flux dialyzer group when compared with the low-flux dialyzer group (p < 0.001 and p < 0.001, respectively). While at the sixth month the predialytic plasma β2-MG levels were significantly lower in the high-flux group when compared with the level before randomization (37.1 ± 6.9 mg/L and 31.6 ± 5.3 mg/L, p < 0.05), they increased in the low-flux group (36.0 ± 7.1 mg/L and 42.0 ± 9.1 mg/L, p < 0.05). Other parameters showed no statistically significant difference throughout the study. At the sixth month, levels of β2-MG, β2-MG clearance, calcium, phosphorus, phosphorus reduction rate, and parathormone are given in Table 4.

Table 3 Some Study Parameters After 6 Months of Follow-Up.

	Low-flux	High-flux	P
Plasma albumin (g/dL)	4.6 ± 0.3	4.5 ± 0.3	NS
Urea before dialysis (mg/dL)	166 ± 11	166 ± 13	NS
Urea after dialysis (mg/dL)	56 ± 8a	54 ± 8a	NS
C-reactive protein (mg/L)	6.7 ± 4.7	6.3 ± 4.5	NS
Vitamin B12	302 ± 30	298 ± 31	NS
Folic acid	6.0 ± 1.3	5.9 ± 1.1	NS
Urea reduction rate (%)	66 ± 7	67 ± 8	NS
Kt/V urea	1.21 ± 0.18	1.24 ± 0.20	NS

^ap < 0.001 when compared with the level before dialysis; NS: not significantly different.

Table 4 Follow-Up Values of the β2-MG, β2-MG Clearance, Calcium, Phosphorus, Phosphorus Reduction Rate, and Parathormone.

	Low-flux	High-flux	P
β2-MG before dialysis (mg/L)	42.0 ± 9.1	31.6 ± 5.3	< 0.001
β2-MG after dialysis (mg/L)	31.9 ± 9.1a	16.9 ± 5.3a	< 0.001
β2-MG reduction rate (%)	0.24 ± 0.08	0.47 ± 0.12	< 0.001
Calcium (mg/dL)	9.3 ± 1.4	9.5 ± 1.5	NS
Phosphorus before dialysis (mg/dL)	5.2 ± 0.6	5.4 ± 0.5	NS
Phosphorus after dialysis (mg/dL)	4.0 ± 0.3a	3.3 ± 0.3a	< 0.001
Phosphorus reduction rate (%)	0.22 ± 0.04	0.39 ± 0.05	< 0.001
Parathormone (pmol/L)	4.80 ± 3.04	4.72 ± 2.83	NS

^ap < 0.001 when compared with the level before dialysis; NS: not significant.

Discussion

As there was no statistically significant difference in our groups in terms of URR and Kt/V urea, this effect does not seem to be related to the adequacy of the clearance of low molecular weight uremic toxins. High-flux membranes improving the clearance of moderate and high molecular weight toxins can contribute to the positive effects of these membranes on control of dialysis-related amyloidosis and Ca–P metabolism. In our patient group, the use of a high-flux dialyzer improved the clearance of β2-MG, and after 6 months of therapy, the predialysis plasma β2-MG level was significantly decreased in the high-flux group, while it increased in the low-flux group; this supports this idea.

In a study by Locatelli et al., 380 HD patients were followed-up for 24 months, and they showed that high-flux HD and hemofiltration treatments are significantly more efficient than low-flux treatments in terms of correcting predialytical β2-MG serum levels.[8] Similarly, we showed that high-flux membrane decreased the plasma β2-MG levels significantly. These data suggest that use of a high-flux dialyzer can have beneficial effects when used in the long term by preventing other complications depending on β2-MG accumulation.

Aggressive protein-permeable treatment often results in massive leakage of essential albumin, however, which may cause fatigue, hypotension, and a decrease in the plasma albumin concentration in some patients. A study by Kim et al. showed that by using high-flux membranes, by regulating the transmembrane pressure according to the sigmoid curve in the pressure control manner or by setting the flow rate along the concave in the flow control manner, a higher removal rate of β2-MG was given.[9] In our study, at the end of the follow-up period, there was no statistically significant difference in serum albumin levels of both groups.

Secondary hyperparathyroidism is a common complication of chronic renal disease that can lead toclinically significant bone disease. Additional consequences of secondary HPT, such as soft-tissue and vascular calcification, cardiovascular disease, and calcific uremic arteriolopathy, may contribute to the increased risk of cardiovascular morbidity and mortality among CKD patients.[10] During high-flux therapy, by improving the clearance of phosphorus and obtaining lower levels of PTH, calcification of soft tissue could be avoided. Also, lower clearance of phosphorus, low levels of Ca, D vitamin, and higher levels of PTH contribute to the morbidity and mortality by causing uremic bone disease.[11] Our study also showed that clearance of P is improved.

Koda et al. compared the incidence of carpal tunnel syndrome between high-flux and low-flux dialyzer therapy and showed that carpal tunnel incidence was significantly lower in the high-flux group.[12] Similarly Küche et al. showed that 6 years of treatment with low-flux dialyzers results in 80% of patients with carpal tunnel syndrome symptoms, while the patients treated with high-flux membranes showed no symptoms.[13] These findings are similar to those from our study, that suggest that high-flux dialyzer therapy is an efficient way to achieve β2-MG clearance.

A long-term retrospective study appropriates that efficient hemodialysis treatment reduces the incidence of dialysis-related amyloidosis and symptoms like carpal tunnel syndrome, bone cysts, and arthropathy.[14]

Conclusion

In order to improve the quality of life of hemodialysis patients and to avoid long-term complications, efficient hemodialysis therapy is essential. Our study shows that by using high-flux dialyzers, dialysis-related amyloidosis may be reduced, and the control of Ca–P metabolism is significantly efficient when compared to that from low-flux dialyzers.