Abstract
Introduction
Dialysis-related amyloidosis (DRA) is a serious complication in patients undergoing long-term dialysis that leads to conditions such as carpal tunnel syndrome and destructive spondyloarthropathy. Improved removal of the precursor protein β2-microglobulin (β2-m) is considered an effective treatment strategy for DRA. Polymethylmethacrylate (PMMA) membranes have the capacity to adsorb β2-m in dialysis filters, suggesting that direct hemoperfusion with PMMA in addition to standard dialysis may enhance β2-m removal.
Methods
This prospective cohort study included 10 patients undergoing hemodialysis, who were diagnosed with DRA. The participants were treated with dialysis filter alone during visit 1, both standard dialysis filter and PMMA cartridges (FT-75, volume 75 cm3) during visits 2–4, and FT-145 PMMA cartridges (volume 145 cm3) during visits 5–7. The removal rates and clearances of β2-m were quantified. We also assessed the removal of α1-microglobulin (α1-m), matrix metalloproteinase-3 (MMP-3), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α), which may be associated with DRA symptoms.
Results
PMMA cartridge had increased β2-m removal rates compared to dialysis filter alone for treatment duration of 240 min. Similarly, the removal rates of α1-m and MMP-3 were higher with PMMA cartridges than with dialysis filter alone. β2-m, α1-m, and MMP-3 clearance improved with the addition of PMMA cartridges, depending on the cartridge size. The removal rates of IL-6 and TNF-α were higher with PMMA cartridges than with dialysis filter alone at 30 min, but not at 240 min.
Conclusion
Direct hemoperfusion with PMMA is an effective method for removing β2-m in hemodialysis patients with DRA. Beneficial effects were also observed for the removal of α1-m and MMP-3. Further research is required to evaluate the long-term efficacy of this approach in managing DRA.
Keywords: Hemoperfusion, Polymethylmethacrylate, β2-microglobulin, Dialysis-related amyloidosis
Introduction
Patients with end-stage kidney disease on dialysis have impaired quality of life, activities of daily living, and life expectancy due to kidney disease-related disorders [1–3]. Dialysis-related amyloidosis (DRA) commonly affects patients undergoing long-term dialysis [4, 5]. Amyloid fibrils derived from β2-microglobulin (β2-m) are deposited in bone and joint tissues, leading to conditions such as carpal tunnel syndrome and destructive spondyloarthropathy. Additionally, these deposits can occur in multiple organs including the gastrointestinal tract and heart, suggesting an association with the prognosis of long-term dialysis patients [6, 7].
In hemodialysis patients with severely impaired kidney function, blood levels of β2-m are up to approximately 60 times higher than in healthy individuals [8], and accumulation of β2-m is a major requirement for the development of DRA. Therefore, more efficient removal of β2-m is crucial for managing DRA. Actually, low β2-m removal rates (RRs) with hemodialysis treatment were associated with the incidence of carpal tunnel syndrome [4, 9].
Basic research suggests that the interaction of β2-m with various biomolecules is key in forming β2-m amyloid fibrils. α1-microglobulin (α1-m; molecular weight: 33,000 Da) coexists with β2-m in amyloid regions [10]. Although the specific mechanism is incompletely understood, α1-m is thought to be possibly involved in the oxidative stress in dialysis patients [11]. In addition, matrix metalloproteinase-3 (MMP-3), which leads to cartilage degradation and osteolysis, is increased by β2-m and its interaction with collagen and fibroblasts [12]. In addition, β2-m modified with advanced glycation end products promotes monocyte chemotaxis to sites of amyloid formation and the release of inflammatory cytokines from macrophages [13].
Polymethylmethacrylate (PMMA), a material used in hemodialysis and hemodiafiltration (HDF), contains nanopores, and its hydrophobic interactions can adsorb medium to large molecules [14]. PMMA filters successfully removed β2-m by adsorption during post-dilution HDF [15]. It has been documented that PMMA filters remove β2-m, a molecule linked to the formation of amyloid fibrils; thus, efficient removal of β2-m during hemodialysis may help in the treatment of DRA. The Filtor® (Toray Medical Co., Ltd., Tokyo, Japan) is a PMMA cartridge that adsorbs β2-m, and in Japan, direct hemoperfusion using this cartridge has become available for hemodialysis patients with DRA. However, its clinical performance – particularly its time-dependent clearance – has not yet been thoroughly evaluated. The addition of PMMA cartridge to regular hemodialysis in selected patients at high risk of developing DRA may increase β2-m removal, which may be associated not only with preventing the progression of DRA, but also with improved survival and economic benefits, such as use of drug and fewer DRA-related surgeries. This multicenter prospective cohort study investigated the efficacy of direct hemoperfusion with PMMA in removing β2-m and other molecules in hemodialysis patients with DRA.
Methods
Patients
This study included 10 hemodialysis patients with DRA from multiple centers. The participants used the PMMA cartridge (Filtor®, Toray Medical Co., Ltd., Tokyo, Japan) to assess the removal of β2-m and DRA-associated molecules. The inclusion criteria were (1) obtaining free and voluntary written consent; (2) age ≥18 years; (3) undergoing hemodialysis for 4 h 3 times a week; (4) diagnosis of DRA and meeting the criteria for Filtor use: (i) confirmed β2-m amyloid deposition by surgery or biopsy, (ii) history of dialysis for more than 10 years and previous carpal tunnel release surgery, and (iii) image of bone cysts confirmed by imaging [16]; (5) no residual renal function (urine output <200 mL/day); (6) predialysis systolic blood pressure (BP) ≥100 mm Hg; and (7) predialysis hemoglobin level ≥10.5 g/dL. This criterion was set so that patients on optimal dialysis, including anemia management, were selected. The exclusion criteria were (1) participation in other clinical studies or trials, (2) pregnancy or intention to become pregnant, and (3) individuals with an unstable medical condition, those considered unable to comply with the study protocol, or those with other conditions that may interfere with study participation or compromise the reliability of the data, as determined by the principal investigator. The following baseline patient data were collected: age, sex, height, weight, BMI, systolic and diastolic BP, pulse rate, dialysis duration, presence of diabetes, underlying chronic kidney disease, single-pool Kt/V, hemoglobin, albumin, C-reactive protein, calcium, phosphate, intact parathyroid hormone, and DRA-associated diseases including carpal tunnel syndrome, destructive spondyloarthropathy, and snapping finger.
Study Protocol
This was a multicenter prospective cohort study. Patients using the cartridge with hexadecyl-immobilized cellulose beads (Lixelle®, Kaneka Co., Tokyo, Japan) underwent a 2-week washout period prior to study entry. For all 10 patients, hemodialysis was performed using the previously used dialysis filter alone at visit 1 (Table 1). The FT-75 cartridge (sorbent volume 75 cm3) was used during visits 2–4, and FT-145 cartridge (sorbent volume 145 cm3) was used during visits 5–7 in combination with the dialysis filter for 4-h dialysis sessions. The PMMA cartridge was connected in series, upstream of the dialysis filter (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000546771). Blood samples were collected from the inlet and outlet of the dialysis filter at visit 1 and from the inlet and outlet of the PMMA cartridge and the outlet of the dialysis filter downstream at visits 4 and 7. Blood samples were collected at 0, 30, 60, 120, and 240 min after the start of dialysis. The blood flow (QB) was set individually for each case and remained constant throughout the study period. During all dialysis sessions, pre- and post-dialysis body weight, QB, ultrafiltration rate, transmembrane pressure (TMP), BP, pulse rate, and allergic reactions (skin rashes) were monitored.
Table 1.
Characteristics of patients
| | Average | SD | Median | IQR |
|---|---|---|---|---|
| Age, years | 73.6 | 7.7 | 74.5 | 13.0 |
| Male, n | 6 (60%) | | | |
| BMI, kg/m2 | 17.7 | 2.3 | 17.3 | 3.1 |
| Systolic BP, mm Hg | 139.2 | 27.1 | 136.5 | 29.0 |
| Diastolic BP, mm Hg | 69.5 | 14.3 | 63.0 | 17.0 |
| Pulse rate, /min | 68.9 | 18.4 | 65.0 | 16.0 |
| Duration of dialysis, years | 31.8 | 9.5 | 28.8 | 11.3 |
| Hemoglobin, g/dL | 11.5 | 0.7 | 11.7 | 1.1 |
| Serum albumin, g/dL | 3.3 | 0.2 | 3.3 | 0.1 |
| Serum C-reactive protein, mg/dL | 0.2 | 0.2 | 0.2 | 0.1 |
| Serum calcium, mg/dL | 8.4 | 0.6 | 8.4 | 0.7 |
| Serum phosphate, mg/dL | 5.2 | 1.2 | 4.9 | 1.2 |
| Serum intact parathyroid hormone, pg/mL | 133.8 | 69.5 | 112.0 | 116.0 |
| Single-pool Kt/V | 1.6 | 0.4 | 1.5 | 0.4 |
| Diabetes, n | 0 (0%) | – | – | – |
| Underlying disease, n | ||||
| Diabetic nephropathy | 0 (0%) | – | – | – |
| Chronic glomerulonephritis | 9 (90%) | – | – | – |
| Nephrosclerosis | 0 (0%) | – | – | – |
| Others | 1 (10%) | – | – | – |
| DRA-associated disease, n | | – | – | – |
| Carpal tunnel syndrome | 10 (100%) | – | – | – |
| Destructive spondyloarthropathy | 2 (20%) | – | – | – |
| Snapping finger | 1 (10%) | | | |
| Dialysis membrane, n | ||||
| PS | 8 (80%) | – | – | – |
| PMMA | 1 (10%) | – | – | – |
| CTA | 1 (10%) | – | – | – |
CTA, cellulose triacetate membrane; DRA, dialysis-related amyloidosis; IQR, interquartile range; PMMA, polymethylmethacrylate; PS, polysulfone; SD, standard deviation.
Endpoints
The primary endpoint was β2-m RR at 240 min. Secondary endpoints included the β2-m and α1-m RRs and clearance at each time point. Exploratory endpoints included the RRs and clearance of MMP-3, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) at 30 and 240 min. Safety endpoints included allergic reactions, changes in BP, white blood cell (WBC) and platelet counts, and TMP during dialysis.
Sample Processing and Measurement
For evaluating complete blood count, the collected blood was immediately transferred to a dedicated container and refrigerated. For solute analysis, the collected blood was immediately centrifuged, and the serum was stored at −20°C. Samples were submitted to LSI Medience Co., Tokyo, Japan, for measuring α1-m, β2-m, MMP-3, IL-6, and blood cells. TNF-α was measured using ELISA kit (Quantikine ELISA Human TNF-α Immunoassay [DTA00D], R&D systems., Inc., Minnesota, USA) according to the specified protocol.
Endpoint Calculated Methods
The RR and clearance were calculated as follows: C0: CBi before dialysis, Ctime: CBi at each time point, CBi: solute concentration at the inlet side of the dialysis filter (visit 1) or Filtor (visits 4 and 7), Ht0: hematocrit before dialysis, Httime: hematocrit at each time point.
Clearance (CL) (mL/min) = Qp – (QP – water RR) × CBo/CBi
QP (mL/min) = QB × (100 – Httime)/100
QP: plasma flow, QB: blood flow, CBi: solute concentration at the inlet side of the dialysis filter (visit 1) or Filtor (visits 4 and 7), CBo: solute concentration at the outlet side of the dialysis filter (visit 1) or Filtor (visits 4 and 7), Httime: hematocrit at each time point.
Statistics
Summary statistics were generated for patient characteristics, RRs, and clearance of each molecule. The RRs and clearance of β2-m and α1-m were assessed for normality using the Shapiro-Wilk test and subsequently analyzed using paired t tests. Owing to the exploratory design and limited sample size, significance was set at 0.05; p values are for descriptive purposes only.
Results
Baseline Characteristics
Table 1 presents the baseline characteristics of the participants. The mean age was 73.6 ± 7.7 years, and the mean duration of dialysis was 31.8 ± 9.5 years. All patients had carpal tunnel syndrome, two had destructive spondyloarthropathy, and one had a history of snapping fingers.
β2-m RRs and Clearance
At 240 min, the β2-m RRs were 66.8 ± 9.9% with dialysis filter (HD) alone, 70.7 ± 7.8% with HD+FT-75, and 74.4 ± 6.6% with HD+FT-145, indicating higher RRs with the PMMA cartridge combinations (Fig. 1d, e). Similarly, the RRs were higher at 30, 60, and 120 min with PMMA cartridge (Fig. 1a–c, e), and total clearance was greater, especially with FT-145, at all time points (Fig. 2).
Fig. 1.
Comparison of β2-m RRs in each treatment condition. a At 30 min. b At 60 min. c At 120 min. d At 240 min. Data are presented as mean ± SD. The RRs were analyzed using a paired t test. e Time course of β2-m RRs at each study visit. Solid line: visit 1; dotted line: visit 4; dashed line: visit 7. SD, standard deviation.
Fig. 2.
Comparison of β2-m clearance in each treatment mode. a At 30 min. b At 60 min. c At 120 min. d At 240 min. Black bars show mean values of the total clearances, and gray bars show mean clearance values of the PMMA cartridges. The clearances were analyzed using a paired t test.
α1-m RRs and Clearance
The α1-m RRs were higher at all time points with the PMMA cartridge (Fig. 3). At 240 min, the RRs were 9.5 ± 8.4% with HD alone, 21.2 ± 9.1% with HD+FT-75, and 27.8 ± 9.0% with HD+FT-145 (Fig. 3d). Total clearance was higher with the PMMA cartridge, particularly FT-145 (Fig. 4).
Fig. 3.
Comparison of α1-m RRs in each treatment condition. a At 30 min. b At 60 min. c At 120 min. d At 240 min. Data are presented as mean ± SD. The RRs were analyzed using a paired t test. e Time course of α1-m RRs at each study visit. Solid line: visit 1; dotted line: visit 4; dashed line: visit 7. SD, standard deviation.
Fig. 4.
Comparison of α1-m clearance in each treatment mode. a At 30 min. b At 60 min. c At 120 min. d At 240 min. Black bars show mean values of the total clearance, and gray bars show mean clearance values of the PMMA cartridges. The clearances were analyzed using a paired t test.
RRs and Clearances of MMP-3 and Inflammatory Cytokines
The RRs of MMP-3 at 240 min showed a higher trend with the PMMA cartridge (online suppl. Fig. 2). Total clearance tended to be higher with the PMMA cartridge (online suppl. Fig. 2).
The RRs of IL-6 at 240 min were highest with HD alone (online suppl. Fig. 3). However, the RR of IL-6 at 30 min and clearance at 30 and 240 min were higher with the PMMA cartridge combinations (online suppl. Fig. 3). Similarly, the RR of TNF-α at 30 min was higher with the PMMA cartridge combinations, while the RRs at 240 min were highest with HD alone (online suppl. Fig. 4). Clearance tended to be highest with HD alone (online suppl. Fig. 4).
Safety Evaluation
One patient dropped out at visit 2 because of an allergic reaction (severe hypotension). Systolic BP tended to decrease before and after hemodialysis regardless of the use of PMMA cartridges, but all patients safely completed 4 h of hemodialysis (online suppl. Table 1). The post-dialysis WBC count decreased when PMMA cartridge was used; however, the predialysis WBC cell counts at visits 1, 4, and 7 were similar (online suppl. Table 1). The platelet count decreased slightly compared to the predialysis values (online suppl. Table 1). TMP changes did not exceed 20 mm Hg.
Discussion
This study demonstrated that PMMA cartridges enhanced the removal of β2-m, α1-m, and MMP-3 compared to standard hemodialysis. The adsorption performance of dialysis filters with PMMA membranes has been reported in several basic and clinical studies. Post-dilution HDF using PMMA filters effectively removed β2-m and α1-m with larger molecular weight compared to pre-dilution HDF using polysulfone filters [15]. A basic study reported that 38 of 48 cytokines in human plasma were more efficiently adsorbed by PMMA than by polysulfone [17].
Although the adsorption mechanism of β2-m and other molecules on PMMA fibers remain unclear, hydrophobic interactions are probably involved. Additionally, it is thought that the membrane has nanopores on its surface and inside, and that the entry of molecules into these pores may affect the removal of molecules from circulating blood [17].
DRA is mainly caused by accumulation of β2-m, the primary endpoint component of this study. It has been reported that clinical relevance is more closely associated with the RR and clearance of β2-m rather than changes in its serum concentration. Although β2-m blood levels are not directly associated with the incidence of carpal tunnel syndrome in hemodialysis patients, improved β2-m RRs are linked to a lower incidence of this condition [4, 9]. Furthermore, adsorption cartridges using hexadecyl-immobilized cellulose beads effectively increase the RR and clearance of β2-m [18] and improve joint symptoms and findings associated with DRA [19]. Moreover, in the HEMO study, β2-m clearance was negatively correlated with mortality in hemodialysis patients [20]. While these findings may also reflect advances in dialyzer performance, this study demonstrated that direct hemoperfusion with PMMA cartridges further enhanced β2-m RR and clearance. Taken together, the enhancement of β2-m clearance and removal with combination treatment with high-performance dialyzers and PMMA cartridges may be beneficial to suppress DRA progression.
Direct hemoperfusion with PMMA cartridges improved the RR and clearance of α1-m, a component of β2-m-related amyloid lesions [10]. While α1-m has antioxidant effects [11], its function may be impaired owing to serious oxidative stress environment in dialysis patients. Oxidative stress and chronic inflammation may predispose dialysis patients to restless legs syndrome and pruritus [21]. Previous cross-sectional studies have shown that decreased removal of α1-m is associated with these symptoms [22], suggesting the importance of efficient α1-m removal.
Direct hemoperfusion using PMMA cartridges also increased the RR of MMP-3. Elevated blood concentration of MMP-3 reflects synovitis and joint destruction due to the degradation of bone matrix [23], and hemodialysis patients have higher blood levels of MMP-3 than healthy individuals [24, 25]. Furthermore, hemodialysis patients with DRA have even higher blood MMP-3 levels than those without DRA [25]. MMP-3 is a protease involved in cartilage degradation, and its removal may reduce DRA-associated joint symptoms.
PMMA cartridge showed improved RR of IL-6 at 30 min and positive clearance, indicating that the cartridge adsorbed IL-6, whereas the cartridge had increased RR of TNF-α at 30 min but negative clearance. This discrepancy may be due to the limited interpretation of clearance in large molecules, as TNF-α is present as a homotrimer in blood with a molecular weight of up to 51,000 Da.
To our knowledge, our study is the first to show the molecular removal effects of direct hemoperfusion using PMMA cartridges in hemodialysis patients with DRA. A unique strength of this study is that the removal capacity of each molecule was measured at multiple time points, allowing a detailed confirmation of the adsorption effect. However, this study has two limitations. First, this was a short-term, small-sample, open-label, single-arm study. Second, we did not assess the changes in clinical symptoms that are important for managing DRA.
In conclusion, direct hemoperfusion with PMMA cartridges was effective in removing β2-m in hemodialysis patients with DRA. Similar effects were observed for α1-m and MMP-3. Future studies are necessary to assess changes in clinical symptoms following long-term observation of a large number of participants.
Statement of Ethics
This study was approved by the Niigata University Central Review Board for Clinical Research (Approval No. 2022-0238) and registered in the Japanese Clinical Trials Registry (jRCT 1032230028). The study was sponsored by Toray Medical, Inc. The study protocol adhered to ethical standards outlined in the Declaration of Helsinki, and informed consent was obtained from all participants through signed consent forms.
Conflict of Interest Statement
This study was commissioned by Toray Medical, Inc., to Niigata University. The authors declare no competing financial interests.
Funding Sources
This study was supported by Toray Medical, Inc., Tokyo, Japan, and a Health, Labour and Welfare Sciences Research Grant (Research on Rare and Intractable Diseases, Grant No. 23FC1035).
Author Contributions
All authors contributed to study conception, design, analysis, and interpretation of data. Conception and study design: S.Yamaz., A.H., T.T., M.T., J.H., S.N., and S.Yamam.; sampling: S.Yamaz., H.S., Y.I., K.M., A.K., Y.K., K.S., and S.Yamam.; data interpretation: S.Yamaz., D.M., A.H., T.T., M.T., J.H., S.N., and S.Yamam.; manuscript drafting: S.Yamaz., A.H., T.T., T.M., and S.Yamam.; supervision or mentorship: J.H. and S.N.
Funding Statement
This study was supported by Toray Medical, Inc., Tokyo, Japan, and a Health, Labour and Welfare Sciences Research Grant (Research on Rare and Intractable Diseases, Grant No. 23FC1035).
Data Availability Statement
Data are not publicly available owing to ethical reasons. Further inquiries can be directed to the corresponding authors.
Supplementary Material.
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Associated Data
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Supplementary Materials
Data Availability Statement
Data are not publicly available owing to ethical reasons. Further inquiries can be directed to the corresponding authors.