Four-Hour Hemoperfusion with Stepwise Blood Flow Rates for Toxin Clearance and Safety in Hemodialysis Patients: A Randomized Controlled Trial

Summary

Extending hemoperfusion to 4 h enhances β2-microglobulin removal and protein preservation. Increasing blood flow up to 260 mL/min optimizes clearance of small molecules and hs-CRP via a significant dose-response relationship. This 4-h, high-flow regimen was associated with hemodynamic stability in this cohort using modern adsorbents.

Abstract

Optimal hemoperfusion (HP) parameters combined with hemodialysis (HD) for removing middle-molecule and protein-bound toxins remain undefined. This prospective randomized controlled trial investigated the effects of extending HP duration and increasing blood flow rate. Eighty-eight maintenance hemodialysis patients were randomized to 2-h or 4-h HP with 4-h HD at 220 mL/min (Phase 1). After a 2-week washout, patients received 4-h HP+HD at 180, 220, or 260 mL/min (Phase 2). Analysis of covariance (ANCOVA) adjusted for baseline imbalances, and linear trend tests evaluated dose-response effects. In Phase 1, the 4-h regimen achieved significantly superior adjusted β2-microglobulin clearance (65.11% ± 4.73% vs. 45.93% ± 4.71%; Adjusted P < 0.001) and reduced loss of hemoglobin and albumin (both P < 0.01). In Phase 2, a significant linear dose-response relationship was observed for all toxins (P for trend < 0.001). A flow rate of 260 mL/min achieved optimal reduction ratios for small molecules and hs-CRP (43.12%). Restricted cubic spline analysis suggested that apparent negative hs-CRP reduction ratios may reflect hemoconcentration-related artifacts (Model P = 0.049). All regimens maintained hemodynamic stability with mean systolic pressure drops of 4.7 ± 24.3 mmHg and 4.2 ± 22.9 mmHg in Phases 1 and 2, respectively. Adverse events were low (0–3.45%) and mild. In conclusion, a 4-h HP session combined with HD, particularly at 260 mL/min, enhances the removal of middle molecules, protein-bound toxins, and inflammatory markers without apparent hemodynamic instability in this single-session study, providing evidence for optimizing operational parameters.

Introduction

Hemodialysis (HD) serves as a cornerstone of renal replacement therapy for patients with uremia¹. However, conventional HD modalities exhibit limited efficacy in removing protein-bound and middle-to-large molecular weight uremic toxins, such as intact parathyroid hormone (iPTH) and β2-microglobulin (β2-MG)^1,2. The accumulation of these toxins is not benign; substantial evidence links them to debilitating complications in maintenance hemodialysis (MHD) patients, including refractory pruritus, malnutrition, dialysis-related amyloidosis, and carpal tunnel syndrome, which collectively severely impair survival rates and quality of life^3,4,5,6,7,8. To address this clearance gap, the combination of hemoperfusion (HP) with HD has been employed and shown to be superior to HD alone in eliminating accumulated middle and large molecule toxins, such as iPTH and inflammatory markers^6,9. This synergistic approach leverages the adsorptive capacity of HP cartridges to effectively remove a range of solutes, including middle molecules (such as iPTH and β2-MG), protein-bound toxins (such as homocysteine [Hcy]), and inflammatory cytokines more which may lead to clinical improvements such as significant alleviation of uremic pruritus^5,6.

Despite its demonstrated efficacy, the optimal operational parameters for HD+HP therapy to maximize clinical benefit remain incompletely defined and are subjects of ongoing clinical inquiry. Current clinical practice and much of the existing research, often constrained by earlier adsorbent materials, typically employ an HP treatment duration of 2–2.5 h and blood flow rates ranging from 180–250 mL/min⁹. Some foundational studies even suggested that the adsorption columns might saturate after 2–3 h, implying limited benefit from prolonging the perfusion time⁴. However, with advancements in adsorbent technology, such as the development of enhanced resins (e.g., the SR130 cartridge used in this study), the rationale for these conventional parameters warrants critical re-evaluation. Emerging evidence hints at the importance of parameter optimization. For instance, studies on the timing of HP during a combined session have found that performing HP in the latter half of a dialysis session (a de facto extension of effective adsorption time relative to blood toxin concentration) results in better clearance of iPTH and β2-MG compared to early HP⁷. This challenges the old saturation dogma and suggests that longer or differently timed HP regimens with modern adsorbers may yield superior outcomes. Conversely, while higher blood flow rates could theoretically enhance the convective mass transfer of solutes to the adsorbent surface, potentially improving clearance efficiency, they may also raise practical concerns regarding circuit coagulation and hemodynamic stability^2,8.

Therefore, a significant and clinically relevant knowledge gap persists. There is a lack of robust, controlled evidence evaluating the acute clearance efficacy and safety profile of systematically extending HP duration to 4 h using modern adsorbents, and of employing systematically graded, higher blood flow rates within a single treatment session^3,6. This study was specifically designed to bridge this gap. Utilizing the SR130 hemoperfusion device, we conducted a stratified cohort study to evaluate the hypothesis that a 4-h HP regimen, compared to the conventional 2-h regimen, would provide superior clearance of key middle molecules such as β2-MG, as well as protein-bound toxins such as Hcy, while maintaining a favorable safety profile. Furthermore, we aimed to explore the dose-response effects of graded, higher blood flow rates (180, 220, and 260 mL/min) during 4-h HP+HD to determine the optimal operational range for maximizing the clearance of inflammatory markers, protein-bound solutes, and small molecule toxins without increasing adverse events, thereby offering novel evidence to refine and optimize this vital extracorporeal therapy for MHD patients.

Protocol

This was a two-phase, prospective, randomized controlled trial conducted at the Blood Purification Center of Ziyang People's Hospital between January 2025 and December 2025. The study protocol was strictly approved by the Ethics Committee of Ziyang People's Hospital (Approval No: 2025-K-2-40), and written informed consent was obtained from all participants before enrollment.

Study design and participants
A total of 88 maintenance hemodialysis (MHD) patients were recruited. For both phases, random sequence generation was performed using a computer-generated random number table. Allocation concealment was ensured through the use of sequentially numbered, opaque, sealed envelopes. A dedicated clinical research coordinator, who was not involved in direct patient care or outcome assessment, implemented the allocation and assigned participants to their respective groups. Inclusion criteria were defined as: (1) adults (≥18 years) with end-stage renal disease; (2) dialysis vintage of at least 6 months via stable vascular access (autogenous arteriovenous fistula or long-term cuffed catheter); (3) elevated baseline levels of uremic toxins, specifically intact parathyroid hormone (iPTH) > 300 pg/mL and β2-microglobulin (β2-MG) > 20 mg/L; and (4) presence of clinical complications including refractory pruritus or bone pain.

Exclusion criteria were strictly applied to ensure patient safety and data integrity. Patients were excluded if they met any of the following: severe cardiopulmonary insufficiency (New York Heart Association [NYHA] Class III or IV); acute renal failure or acute-on-chronic kidney disease; active bleeding disorders or a high risk of hemorrhage; active systemic infections; severe malnutrition (serum albumin < 30 g/L); or concurrent participation in other clinical studies.

Treatment protocol and procedures
The study comprised two distinct treatment phases separated by a 2-week washout period using standard HD. In Phase 1, the 88 participants were randomly assigned (1:1) to evaluate hemoperfusion (HP) duration (2-h vs. 4-h). The control group received 2-h HP followed by 2-h HD. The experimental group received 4-h HP concurrent with 4-h HD. Both groups maintained a total treatment time of 4 h at a fixed blood flow rate of 220 mL/min. Throughout each session, patients' vital signs, including blood pressure, heart rate, and oxygen saturation, were monitored continuously and recorded at 30-min intervals by trained nurses to ensure hemodynamic stability.

Following the 2-week washout period to minimize carry-over effects and within-subject correlation, the same cohort of 88 patients was re-randomized into three parallel groups for Phase 2 to assess blood flow rates (180, 220, and 260 mL/min) during a 4-h HP+HD session. All treatments utilized hemodialysis machines and resin cartridges. Before use, the HP cartridges were primed with 2000 mL of heparinized saline (20 mg heparin/500 mL) followed by a 30-min static soak. This priming procedure is essential to ensure the biocompatibility of the resin surface and prevent the activation of the coagulation cascade upon blood contact.

Measurements and assessments
Blood samples were collected immediately before (0 h) and after (4 h) each session. The samples were drawn from the arterial line pre-treatment and from the venous line at completion (using a 15-s slow-flow method) to avoid saline dilution. The primary efficacy endpoints were the reduction ratios (RRs) of: small molecules: Creatinine (µmol/L), Urea (mmol/L), Uric Acid (µmol/L); middle-to-large molecules: β2-MG (mg/L), iPTH (pg/mL); inflammatory markers: hs-CRP (mg/L); others: Homocysteine (µmol/L), Calcium (mmol/L), Potassium (mmol/L).

The RR was calculated as: (Pre-value - Post-value)/Pre-value × 100%. To detect potential blood loss during treatment or adsorption-induced loss of essential components, we also monitored serum hemoglobin (g/L), platelets (10⁹/L), and albumin (g/L). Safety monitoring and adverse events (AEs) were assessed continuously throughout each session and recorded at 30-min intervals by nurses, including hypotension (defined as a drop in SBP >20 mmHg), muscle cramps, and allergic reactions. At the end of each session, dialyzer and cartridge coagulation were assessed using a visual scale (Grade 0: no clotting; Grade I: <5% fibers clotted; Grade II: 5%–50% fibers clotted; Grade III: >50% fibers clotted)

Statistical analysis
Statistical analyses were performed using R 4.2.2. The normality of data was assessed using the Shapiro-Wilk test. Continuous variables were expressed as mean ± SD for normally distributed data, allowing the use of independent samples t-tests (Phase 1) and one-way ANOVA (Phase 2). For non-normally distributed data, median (IQR) and Mann-Whitney U or Kruskal-Wallis tests were employed. In Phase 1, despite randomization, an incidental imbalance in baseline ultrafiltration rate was detected; therefore, an Analysis of Covariance (ANCOVA) was performed to adjust for this covariate when comparing RRs. In Phase 2, a linear trend test was applied to evaluate the dose-response relationship of blood flow rates. Bonferroni post-hoc tests were strictly applied for all pairwise comparisons in Phase 2 when significant overall differences were detected via ANOVA or Kruskal-Wallis tests to control for Type I error inflation. Additionally, a restricted cubic spline (RCS) model with four knots was utilized to explore the potential non-linear relationship between baseline hs-CRP levels and their reduction ratio. P < 0.05 was considered significant.

Results

Phase 1: Comparison of hemoperfusion duration (2-h vs. 4-h HP)
A total of 88 MHD patients were enrolled and stratified into two cohorts for the first phase of this study. The patient selection and cohort flow diagram are presented in Figure 1. The baseline demographic and clinical characteristics of the two groups were comparable (Table 1), except for a statistically significant difference in the ultrafiltration rate (10.75 ± 3.65 vs. 8.74 ± 3.06 mL/kg/h for the 2-h and 4-h HP groups, respectively; P = 0.006).

To account for this baseline imbalance, an analysis of covariance (ANCOVA) was performed. The reduction ratios (RRs, expressed as %) of key solutes are presented in Table 2 and Figure 2. Even after adjusting for the ultrafiltration rate, the 4-h HP regimen resulted in a significantly higher RR of β2-microglobulin compared to the 2-h regimen (Adjusted P < 0.001). Similar robust advantages in the 4-h group were observed for creatinine, urea, uric acid, and Hcy (all Adjusted P < 0.001). Furthermore, the 4-h HP regimen was associated with a significantly smaller reduction in hemoglobin and albumin, indicating less loss of beneficial components (Table 2).

Phase 2: Dose-response effects of different blood flow rates
Following a 2-week washout period, the cohort was reassigned into three parallel groups to assess the dose-response effect of graded blood flow rates (180, 220, and 260 mL/min) during a combined 4-h HP and HD session. The baseline characteristics of the three groups are shown in Table 3.

The efficacy outcomes stratified by blood flow rates are detailed in Table 4 and Figure 3. To robustly evaluate the dose-response relationship, a linear trend test was applied. A highly significant dose-dependent trend in reduction ratios was observed across all measured biomarkers. Specifically, the RRs for small molecules (creatinine, urea, uric acid) exhibited a pronounced, robust step-wise increase with higher blood flow rates; conversely, the middle-molecule β2-microglobulin and the protein-bound toxin Hcy demonstrated more gradual, conservative increments across the graded velocity cohorts, with all analyzed solutes strictly maintaining a highly significant linear trend (all P for trend < 0.001).

For hs-CRP, while a significant linear trend was also observed (P for trend < 0.001), a subsequent non-linear restricted cubic spline (RCS) analysis (Figure 4) revealed that extreme or negative reduction ratios predominantly occurred in patients with extremely low baseline hs-CRP levels. This demonstrates that these specific anomalies were hemoconcentration artifacts driven by ultrafiltration rather than true negative clearance (Model P = 0.049).

Safety and hemodynamic profile
The safety and hemodynamic profiles during extracorporeal treatments are summarized in Table 5 and Supplementary Figure 1. The mean systolic blood pressure (SBP) drop was 4.7 ± 24.3 mmHg in Phase 1 and 4.2 ± 22.9 mmHg in Phase 2. Hemodynamic stability across the three graded blood flow rates in Phase 2 showed no statistically significant difference (ANOVA P = 0.213), indicating that pushing to higher flow rates did not compromise cardiovascular stability. No major safety signal was observed, but the study was not powered for safety endpoints. Overall, adverse events were rare, with only 4 events recorded in Phase 1 and 6 events in Phase 2. All adverse events were mild, temporary, and resolved spontaneously without interrupting the treatment.

DATA AVAILABILITY:
The raw data supporting the findings of this study, including individual-level biochemical measurements and clinical parameters, are provided as Supplementary Table 1.

Figure 1: CONSORT flow diagram of the randomized controlled trial. This diagram illustrates the enrollment, random allocation, washout, re-randomization, and analysis of participants in the two-phase study evaluating hemoperfusion duration and blood flow rates. Please click here to view a larger version of this figure.

Figure 2: Forest plot of adjusted mean differences in reduction ratios between 4-h and 2-h hemoperfusion. Points represent the adjusted mean differences (4-h minus 2-h regimen) in reduction ratios, and horizontal lines indicate the 95% confidence intervals (CIs). An Analysis of Covariance (ANCOVA) was utilized to rigorously adjust for baseline imbalances in the ultrafiltration rate. The dashed vertical line represents no difference between the two regimens. The 4-h HP regimen demonstrated significantly superior adjusted reduction ratios for β2-microglobulin, hs-CRP, creatinine, urea, uric acid, and Hcy (all Adjusted P < 0.001). Please click here to view a larger version of this figure.

Figure 3: Dose-response relationship between graded blood flow rates and toxin reduction ratios. Box plots display the median (central line), interquartile range (box), and individual outliers (red dots) for reduction ratios at blood flow rates of 180, 220, and 260 mL/min during a 4-h HP+HD session. A linear trend test was applied, with P for trend values annotated at the top of each panel, indicating a highly significant, dose-dependent linear increase in the removal of all evaluated solutes as blood flow rate increased. The negative values observed in the hs-CRP reduction ratio primarily reflect hemoconcentration artifacts due to ultrafiltration in patients with extremely low baseline levels. Please click here to view a larger version of this figure.

Figure 4: Restricted cubic spline (RCS) analysis of the non-linear relationship between baseline hs-CRP levels and reduction ratios. The solid red line represents the non-linear fit from the RCS model, and the shaded area indicates the 95% confidence interval. The model suggests that extreme negative values may be related to hemoconcentration effects when baseline hs-CRP is very low. Please click here to view a larger version of this figure.

Parameter	2-h Group (N = 42)	4-h Group (N = 46)	P-value
Age (years)	56.9 ± 10.47	57.91 ± 12.41	0.681
Dialysis vintage (years)	6.04 ± 4.21	5.49 ± 3.4	0.511
Gender (Male) n (%)	26 (61.9%)	23 (50%)	0.235
Dry weight (kg)	60.25 ± 10.39	59.25 ± 11.26	0.668
Pre-HD SBP (mmHg)	141.14 ± 23.26	133.74 ± 21.58	0.126
Pre-HD DBP (mmHg)	77.64 ± 12.59	74.7 ± 10.76	0.244
Ultrafiltration rate (mL/kg/h)	10.75 ± 3.65	8.74 ± 3.06	0.006
Total ultrafiltration volume (L)	2.51 ± 0.86	2.07 ± 0.81	0.015

Table 1: Baseline demographic and clinical characteristics of patients in Phase 1. Continuous variables are expressed as mean ± standard deviation (SD), and categorical variables are presented as counts (percentages). Differences between the 2-h and 4-h HP groups were assessed using independent t-tests or Fisher's exact tests as appropriate. A significant baseline difference was noted in the ultrafiltration rate (P = 0.006), which was subsequently adjusted for in the efficacy analysis.

Biomarker	2-hour Group (%)	4-hour Group (%)	Unadjusted P-value	Adjusted P-value
B2_MG	45.93 ± 4.71	65.11 ± 4.73	< 0.001	< 0.001
hs_CRP	38.99 ± 7.54	59.33 ± 8.87	< 0.001	< 0.001
Creatinine	59.99 ± 4.72	74.90 ± 4.56	< 0.001	< 0.001
Urea	58.97 ± 5.20	75.44 ± 5.75	< 0.001	< 0.001
Uric_Acid	59.80 ± 4.50	74.64 ± 4.05	< 0.001	< 0.001
Hcy	32.45 ± 4.12	47.85 ± 4.56	< 0.001	< 0.001

Table 2: Comparison of toxin reduction ratios between 2-h and 4-h hemoperfusion adjusted for ultrafiltration rate (Phase 1). Data are presented as mean ± SD. The unadjusted P values were calculated using independent t-tests. To account for the baseline ultrafiltration rate imbalance, an Analysis of Covariance (ANCOVA) was performed. Adjusted P values demonstrate the robust statistical superiority of the 4-h regimen independent of ultrafiltration differences.

Parameter	180 mL/min (N = 29)	220 mL/min (N = 29)	260 mL/min (N = 29)
Age	56.7 ± 10.9	57.7 ± 12.6	57.9 ± 11.2
Dialysis vintage (years)	6.3 ± 3.9	5.6 ± 3.3	5.4 ± 4.1
Dry_Weight	59.3 ± 9.4	59.7 ± 12.9	60.2 ± 10.2
Pre_SBP	132.2 ± 26.4	134.9 ± 21.7	139.6 ± 20.2
UF_Rate	9.04 ± 2.76	8.01 ± 3.14	9.37 ± 3.69

Table 3: Baseline characteristics of patients stratified by blood flow rates in Phase 2. Data are presented as mean ± SD for continuous variables. Patient demographics and baseline clinical parameters were well-balanced across the three graded blood flow rate cohorts (180, 220, and 260 mL/min).

Biomarker	P for trend	180 mL/min	220 mL/min group	260 mL/min group
B2_MG	<0.001	60.88 (59.67–62.08)	62.15 (60.37–63.93)	63.02 (61.71–64.33)
hs_CRP	<0.001	40.28 (37.96–42.61)	41.95 (39.21–44.69)	43.12 (40.14–46.10)
Creatinine	<0.001	65.62 (64.35–66.89)	69.34 (67.72–70.96)	71.85 (70.54–73.16)
Urea	<0.001	67.43 (65.84–69.03)	71.55 (69.80–73.30)	74.18 (72.92–75.44)
Uric_Acid	<0.001	62.55 (61.15–63.96)	65.88 (64.32–67.44)	68.24 (66.90–69.58)
Hcy	<0.001	35.20 (33.80–36.60)	36.68 (35.18–38.18)	37.52 (36.12–38.92)

Table 4: Dose-response effects of graded blood flow rates on toxin reduction ratios (Phase 2). Reduction ratios are presented as marginal means with 95% confidence intervals. The statistical significance of the dose-response relationship across the parallel groups was robustly evaluated using a linear trend test (P for trend).

Metric	Value
Phase 1 SBP Drop (mmHg)	4.7 ± 24.3
Phase 2 SBP Drop (mmHg)	4.2 ± 22.9
Phase 1 AEs (Events)	4
Phase 2 AEs (Events)	6

Table 5: Summary of safety profile and hemodynamic stability during extracorporeal treatments. The table outlines the absolute drop in systolic blood pressure (SBP, calculated as pre-treatment minus post-treatment values) and the total number of mild adverse events recorded in both study phases.

Supplementary Figure 1: Distribution of systolic blood pressure changes across graded blood flow rates. Violin plots combined with internal box plots illustrate the probability density and distribution of the systolic blood pressure drop (mmHg) at 180, 220, and 260 mL/min. One-way Analysis of Variance (ANOVA) indicated no statistically significant difference in hemodynamic stability across the groups (P = 0.213), confirming the cardiovascular safety of higher flow rates.Please click here to download this file.

Supplementary Table 1: Raw data including individual-level biochemical measurements and clinical parameters.Please click here to download this file.

Discussion

This study demonstrates that within a single treatment session, extending the hemoperfusion duration to 4 h and utilizing a blood flow rate as high as 260 mL/min in combination with hemodialysis significantly enhances the clearance of key uremic toxins in maintenance hemodialysis patients, while maintaining a favorable safety profile¹⁰. The findings here challenge the conventional parameters of HD+HP therapy and provide novel, evidence-based data for optimizing this extracorporeal detoxification strategy.

The superior clearance of β2-microglobulin (β2-MG) achieved with the 4-h HP regimen is an important finding. The accumulation of β2-MG is a well-established cause of dialysis-related amyloidosis (DRA), a serious long-term complication affecting bones, joints, and soft tissues^11,12. Furthermore, elevated serum β2-MG levels are an independent predictor of mortality in dialysis patients¹³. Conventional high-flux HD offers limited removal of this middle molecule¹⁴. While prior evidence supports the adjunctive use of specialized HP for β2-MG reduction¹⁵, the optimal duration for standard HP has been undefined, with most protocols adhering to 2–2.5 h based on older adsorbent technologies¹⁶. Notably, by applying ANCOVA to robustly adjust for incidental baseline imbalances in ultrafiltration rates, this study confirms that the 4-h regimen maintains a highly significant superiority in toxin reduction. This indicates that the modern SR130 resin cartridge sustains effective adsorptive capacity beyond the conventional timeframe¹⁷, supporting the principle that toxins with a larger volume of distribution or slower kinetics, like β2-MG, benefit from prolonged contact time with the adsorbent to reach equilibrium^18,19. A recent nursing and expert consensus further substantiates the role of HP in toxin clearance, providing a framework for its clinical application²⁰. Therefore, the 4-h regimen represents a meaningful step towards more effective prevention of amyloidosis complications.

Equally important is the finding that extended HP did not lead to increased loss of beneficial proteins. The significantly smaller reduction in hemoglobin and albumin in the 4-h group compared to the 2-h group suggests that the resin possesses favorable adsorption selectivity¹⁷. While effectively binding target toxins, it may spare essential proteins to a greater extent. This observation mitigates a major clinical concern regarding nutritional depletion from prolonged extracorporeal therapy and strengthens the safety proposition of the longer regimen²¹.

Regarding blood flow optimization, our trend analysis reveals a clear dose-response relationship: incrementally higher flow rates (220 and 260 mL/min) linearly enhance the clearance of small molecules and β2-MG, and the protein-bound toxin Hcy compared to 180 mL/min (all P for trend < 0.001)^18,22. This is consistent with the fundamental principles of dialysis, where increased flow improves the solute concentration gradient and mass transfer. The most striking observation was the clearance of hs-CRP at 260 mL/min. While a robust linear clearance trend was evident, the RCS analysis (Model P = 0.049) crucially identified that instances of apparent "negative clearance" at lower flow rates were primarily hemoconcentration artifacts in patients with near-zero baseline hs-CRP levels²³. This may inform future studies of inflammatory marker modulation.

The safety data are reassuring. The incidence of dialyzer coagulation and adverse events was low across all groups, including the high-flow 260 mL/min group²⁴. To ensure clinical success, proactive troubleshooting is essential: if transmembrane pressure (TMP) rises rapidly, clinicians should immediately evaluate anticoagulation efficacy and consider saline flushing. In cases of intra-dialytic hypotension, blood flow should be promptly reduced, and the patient's fluid status reassessed^25,26. Furthermore, blood flow rate adjustments must be personalized. While 260 mL/min is effective, a more conservative initial flow (e.g., 200–220 mL/min) with gradual titration is recommended for elderly patients or those with fragile vascular access and unstable cardiovascular status.

In clinical practice, hyperhomocysteinemia (HHcy) in uremic patients is associated with an increased risk of myocardial infarction and osteoporosis²⁷. Conventional low-flux and high-flux hemodialysis are inefficient in removing adequate amounts of Hcy^28,29. Although super-flux dialyzers can remove protein-bound Hcy by also removing serum albumin, this approach often leads to significant protein loss^30,31. Previous studies confirmed that HD combined with HP aids in Hcy clearance^32,33, which is fully consistent with our results demonstrating that extended hemoperfusion duration significantly optimizes Hcy reduction ratios.

For CKD patients, a low-grade inflammatory state is common even in the absence of overt infection³⁴. This inflammatory state is closely associated with vascular calcification, pruritus, and cardiovascular events^35,36. Although HP therapy clears inflammatory factors, the transient fluctuations in CRP levels in this study warrant further investigation. As this study assessed only a single HP treatment session, it may not fully reflect the actual inflammatory and metabolomic status of patients in our center³⁷.

Several limitations of this study must be acknowledged. First, this was a single-session study evaluating acute clearance. Importantly, the high solute reduction ratios achieved at the 260 mL/min blood flow rate reflect acute clearance efficiency under highly controlled clinical trial conditions; in routine clinical practice, these percentages may fluctuate depending on individual vascular access conditions, blood pump stability, and longitudinal patient tolerance over real-world maintenance hemodialysis. While our data provide robust evidence for optimizing per-session efficiency, more emphasis must be placed on long-term follow-up studies. Future investigations should focus on the clinical impact of the 4-h, high-flow regimen on patient survival and quality of life to provide further validation of long-term efficacy^18,20. Second, the single-center nature and sample size may limit the generalizability of the findings¹⁶. Third, we did not perform a formal cost-effectiveness analysis²¹.

In conclusion, this prospective randomized controlled trial suggests that modern hemoperfusion allows for the safe and effective extension of treatment time to 4 h and the use of higher blood flow rates up to 260 mL/min^17,24. This optimized protocol delivers significantly improved clearance of protein-bound and middle-molecular-weight toxins without compromising safety^16,20. These findings offer concrete operational guidance for clinicians aiming to maximize detoxification benefits.

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Hemodialysis Machine	Fresenius Medical Care	4008S	Hemodialysis delivery system used for all treatment sessions.
Resin Adsorption Cartridge	Chongqing Healthcom Blood Purification Equipment Research&Development Co.,Ltd.	SR130	Resin adsorption cartridge (130 mL) containing hyper-cross-linked styrene-divinylbenzene resin.
Hemodialyzer	Chengdu OCI MEDICAL Devices Co., Ltd.	OCI-HD150	High Flux Polyethersulfone Hollow Fiber Hemodialyzer with a membrane area of 1.5m² and ultrafiltration coefficient of 48mL/h/mmHg.
Low-molecular-weight Heparin	Pfizer	Fragmin	Anticoagulant used for systemic anticoagulation during the procedure.