ABSTRACT
Background
Chronic limb‐threatening ischemia (CLTI) is a severe form of lower‐extremity artery disease characterized by distal lesions and microcirculatory impairment, limiting revascularization efficacy. Rheocarna is a direct hemoperfusion low‐density lipoprotein (LDL) adsorption device with potential rheological and anti‐inflammatory benefits. The real‐world effectiveness of Rheocarna in patients with advanced CLTI undergoing hemodialysis (HD) remains unclear. This study evaluated clinical outcomes of Rheocarna therapy in patients with CLTI undergoing HD.
Methods
We retrospectively reviewed 31 patients undergoing HD (mean [±SD] age 67 ± 11 years) with CLTI treated with Rheocarna at a single center. Primary outcomes were ulcer healing at 6 months and amputation‐free survival (AFS) at 1 year, with baseline characteristics compared between healed and non‐healed groups.
Results
At 6 months, the ulcer healing, major amputation, and mortality rates were 25.8%, 35.5%, and 22.6%, respectively. The 1‐year AFS rate was 40%. The mean ankle–brachial index significantly improved from 1.00 ± 0.17 to 1.07 ± 0.15 (p = 0.041).
Conclusion
Rheocarna may support wound healing and limb salvage in patients with CLTI undergoing HD; however, its clinical effectiveness appears limited in advanced disease stages.
Keywords: amputation‐free survival, chronic limb‐threatening ischemia, hemodialysis, LDL apheresis, Rheocarna
1. Introduction
Chronic limb‐threatening ischemia (CLTI) is the most severe manifestation of lower extremity artery disease (LEAD) and is associated with high risks of major amputation, poor quality of life, and premature mortality [1]. These risks are markedly high in patients undergoing maintenance hemodialysis (HD). Komaba et al. [2] provided the prevalence, risk factors, and clinical outcomes of CLTI in 2292 Japanese patients on maintenance HD. In that cohort, CLTI was 8.6%, and CLTI was considerably associated with poor clinical outcomes, including all‐cause mortality, cardiovascular events, and CLTI‐related interventions. A recent study from the BEST‐critical limb ischemia (CLI) trial revealed that more than half of the patients with CLTI undergoing HD die within 3 years [3].
In patients undergoing HD, CLTI is characterized by advanced arterial calcification, severe distal arterial involvement, and widespread microvascular dysfunction [4]. Microvascular involvement limits the efficacy of conventional revascularization strategies, including endovascular therapy (EVT) and surgical bypass.
Low‐density lipoprotein (LDL) apheresis improves microcirculatory impairment in patients with LEAD [5].
Rheocarna (Kaneka Corporation, Osaka, Japan), a novel direct LDL absorption column, was developed in Japan in 2020. Compared with conventional complicated LDL apheresis systems such as Liposorber (Kaneka Corporation, Osaka, Japan), Rheocarna enables a simple direct hemoperfusion system. In Japan, Rheocarna is clinically approved for lower‐extremity ischemic wounds refractory to conventional revascularization treatment. In addition to LDL cholesterol (LDL‐C) absorption, Rheocarna selectively removes high‐molecular‐weight substances, including fibrinogen. Proposed mechanisms of LDL apheresis in LEAD include improved hemorheology, endothelial function restoration, increased nitric oxide and bradykinin bioavailability, increased vascular endothelial growth factor levels, and reduced monocyte adhesion molecules [6, 7].
Although prior studies have shown the efficacy of LDL apheresis in LEAD in patients undergoing HD [8], the real‐world efficacy of Rheocarna in these patients with advanced CLTI, particularly Rutherford category 5 or 6 disease, remains unclear.
This study retrospectively evaluated clinical outcomes, including wound healing, major amputation, and amputation‐free survival (AFS), in patients with CLTI undergoing HD treated with Rheocarna.
2. Methods
2.1. Study Population
This was a single‐center retrospective cohort study, including 31 patients with CLTI undergoing HD who were hospitalized at Shonan Kamakura General Hospital and treated with Rheocarna (Kaneka Corporation, Osaka, Japan).
2.2. Clinical Data Collection Methods
Clinical data were extracted from electronic medical records with all patient identifiers removed prior to analysis. Collected variables included demographic characteristics, comorbidities, dialysis history, wound characteristics, prior revascularization, laboratory parameters, physiological assessments, and Rheocarna treatment details.
Clinical outcomes included wound healing, major lower limb amputation, AFS, and mortality at 6 and 12 months after Rheocarna therapy initiation.
Rheocarna is an adsorptive device for direct hemoperfusion consisting of a 250‐mL polypropylene column filled with cellulose beads on which dextran sulfate and L‐tryptophan are chemically immobilized. The negatively charged dextran sulfate and hydrophobic L‐tryptophan are bound to the surface of the cellulose beads. During hemoperfusion, LDL‐C, containing the positively charged apolipoprotein B, is selectively adsorbed via electrostatic interactions, while fibrinogen is adsorbed via hydrophobic interactions with L‐tryptophan.
Rheocarna sessions were performed for 2 h once or twice weekly. Blood flow was initiated at 30–50 mL/min and increased to 50–100 mL/min if hemodynamically tolerated (maximum 200 mL/min). Heparin was administered at 500–1500 U/h following a 2000–3000 U bolus; nafamostat was used when heparin was contraindicated. EVT was performed when clinically indicated.
2.3. Statistical Analyses
Data are presented as the mean ± standard deviation, median (interquartile range [IQR]), or number (percentage). Comparisons before and after treatment were performed using the Wilcoxon signed‐rank test. AFS was analyzed using the Kaplan–Meier method. Statistical analyses were conducted using JMP version 10 (SAS Institute, Japan). A p value < 0.05 was considered statistically significant.
3. Results
3.1. Baseline Characteristics of Patients
Baseline characteristics are summarized in Table 1. The mean age was 67 ± 11 years, and 74% of patients were male. Diabetes mellitus was present in 80.6% of patients. Rutherford category 5 and 6 accounted for 80.6% and 19.4% of patients, respectively. EVT was performed in 93.5% of patients, with approximately 80% comprising below‐knee lesions. All patients underwent Rheocarna treatment after EVT, with a median interval of 1.1 months [IQR 0.5–2.2 months]. The median number of Rheocarna treatments was 7 (IQR 4–12).
TABLE 1.
Baseline characteristics of the study participants (n = 31).
| Age (years) | 67 ± 11 |
| Male, n (%) | 23 (74.2) |
| Dialysis vintage (years) | 8.9 ± 6.3 |
| Underlying disease | |
| Diabetic nephropathy, n (%) | 25 (80.6) |
| Chronic glomerular nephritis, n (%) | 2 (6.5) |
| Others, n (%) | 4 (13.0) |
| Ischemic heart disease, n (%) | 20 (64.5) |
| Cerebrovascular disease, n (%) | 13 (41.9) |
| Rutherford category 5, n (%) | 25 (80.6) |
| Rutherford category 6, n (%) | 6 (19.4) |
| TP (g/dL) | 6.3 ± 0.7 |
| Albumin (g/dL) | 3.1 ± 0.6 |
| Creatinine (mg/dL) | 7.9 ± 2.1 |
| T. chol (mg/dL) | 131 ± 42 |
| TG (mg/dL) | 106 ± 54 |
| HDL‐C (mg/dL) | 43.2 ± 14.5 |
| LDL‐C (mg/dL) | 67 ± 32 |
| WBC (/μL) | 7300 ± 3000 |
| Hemoglobin (g/dL) | 10.4 ± 1.6 |
| Platelet (/μL) | 19.7 ± 7.8 |
| ABI | 1.0 ± 0.17 |
| SPP (mmHg) | 46 ± 22 |
Note: Data are presented as the mean ± standard deviation or n (%).
Abbreviations: ABI, ankle–brachial index; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; PAD, peripheral artery disease; SPP, skin perfusion pressure; T. chol, total cholesterol; TG, triglycerides; TP, total protein; WBC, white blood cell.
3.2. Clinical Outcome
At 6 months, ulcer healing, major amputation, and mortality rates were 25.8%, 35.5%, and 22.6%, respectively (Table 2). The ankle–brachial index (ABI) significantly improved at 3 months after Rheocarna treatment (1.0 ± 0.17 vs. 1.07 ± 0.15, p = 0.041). Skin perfusion pressure (SPP) showed a nonsignificant improving tendency (46 ± 22 vs. 66 ± 28 mmHg, p = 0.15) (Figure 1).
TABLE 2.
Clinical outcomes following Rheocarna treatment.
| Outcome | 1 month | 3 months | 6 months | |||
|---|---|---|---|---|---|---|
| Wound healing rate | 1 | 3.2% | 5 | 16.1% | 8 | 25.8% |
| Major amputation rate | 6 | 19.4% | 11 | 35.5% | 11 | 35.5% |
| Mortality rate | 3 | 9.7% | 5 | 16.1% | 7 | 22.6% |
Note: Clinical outcomes at 1, 3, and 6 months following Rheocarna therapy. Evaluated outcomes included wound healing, major amputation, and all‐cause mortality. Results are expressed as the number of patients and percentages relative to the total study population at each time point.
FIGURE 1.
Changes in physiological blood flow parameters from baseline to 3 months after Rheocarna treatment. (A) ABI levels significantly increased after 3 months compared with those at baseline (1.0 ± 0.17 vs. 1.07 ± 0.15, p = 0.041). (B) SPP showed an upward trend at 3 months, although the change was not statistically significant (45.6 ± 21.6 mmHg vs. 65.9 ± 27.6 mmHg, p = 0.15). Data are presented as the mean ± standard deviation. Statistical significance was determined using a Wilcoxon signed‐rank test. Abbreviations: ABI, ankle–brachial index; SPP, skin perfusion pressure.
The Kaplan–Meier life‐table analysis demonstrated a 1‐year AFS rate of 40% (Figure 2). Almost half of the patients died or amputated within 1 month after Rheocarna treatment. The wound healing group had a significantly lower prevalence of Rutherford category 6 disease than the non‐healing group (12.5% vs. 21.7%, p < 0.01) (Table 3). Dialysis duration, diabetes mellitus, duration since wound onset, nutritional status, inflammation, and rheological parameters (represented by fibrinogen) were not associated with wound healing status after Rheocarna therapy.
FIGURE 2.
Kaplan–Meier curve for amputation‐free survival (AFS). The 1‐year AFS rate was 40% in this cohort (N = 31). The vertical axis represents the probability of survival without major amputation. The horizontal axis shows the time after Rheocarna therapy in months.
TABLE 3.
Comparison of the wound healing and the non‐healing groups.
| Healed (n = 8) | Non‐healed (n = 23) | p | |
|---|---|---|---|
| Age (years) | 65.9 ± 11.2 | 66.8 ± 10.4 | 0.83 |
| Male, n (%) | 7 (87.5%) | 16 (69.6%) | 0.68 |
| Duration of dialysis (months) | 114.9 ± 48.3 | 104.2 ± 83.7 | 0.74 |
| Diabetes mellitus, n (%) | 7 (87.5%) | 18 (78.3%) | 0.78 |
| Ischemic heart disease, n (%) | 4 (50.0%) | 16 (69.6%) | 0.56 |
| Rutherford category 6 | 1 (12.5%) | 5 (21.7%) | < 0.01 |
| Number of Rheocarna sessions | 8.0 ± 5.6 | 7.0 ± 5.7 | 0.69 |
| Duration since wound onset (days) | 176.6 ± 232.6 | 72.0 ± 72.3 | 0.08 |
| Time from EVT to first session (days) | 14.1 ± 12.9 | 12.3 ± 23.4 | 0.83 |
| ABI | 0.95 ± 0.13 | 1.01 ± 0.19 | 0.47 |
| SPP (mmHg) | 45.3 ± 28.2 | 45.8 ± 19.5 | 0.95 |
| Total protein (g/dL) | 6.42 ± 0.75 | 6.33 ± 0.69 | 0.79 |
| Albumin (g/dL) | 3.5 ± 0.5 | 3.0 ± 0.6 | 0.16 |
| CRP (mg/dL) | 2.26 ± 2.20 | 4.28 ± 5.67 | 0.34 |
| Fibrinogen (mg/dL) | 375.8 ± 43.6 | 428.2 ± 145.8 | 0.49 |
| Total cholesterol (mg/dL) | 129.3 ± 16.8 | 130.8 ± 47.9 | 0.94 |
| HDL cholesterol (mg/dL) | 50.5 ± 11.0 | 40.9 ± 14.9 | 0.16 |
| Hemoglobin (g/dL) | 10.1 ± 1.4 | 10.5 ± 1.7 | 0.48 |
Note: Comparison of the wound healing and the non‐healing groups. Data are presented as the mean ± standard deviation or number (percentage). Statistical significance was defined as p < 0.05.
Abbreviations: ABI, ankle–brachial index; CRP, C‐reactive protein; EVT, endovascular therapy; HDL, high‐density lipoprotein; SPP, skin perfusion pressure.
4. Discussion
In this retrospective study, Rheocarna therapy in patients with CLTI undergoing HD produced modest improvement in physiological perfusion parameters and wound healing in approximately 25% of patients. However, limb salvage rates and AFS rates were lower than those reported in prior multicenter studies [9]. In contrast to previous studies, all patients in this study cohort were patients on HD, and the patients had a high prevalence of below‐knee lesions, reflecting the advanced stage of CLTI in the study population.
Previous studies have reported favorable outcomes of Rheocarna therapy in patients with CLTI. Kobayashi et al. [10] evaluated 61 patients with CLTI, 90% on HD, and reported an ulcer healing rate of 45.9%. Similarly, Soga et al. [9] demonstrated a 60.7% 1‐year ulcer healing rate in a multicenter cohort of 221 patients with CLTI, 88% of whom were on dialysis, with corresponding survival and AFS rates of 70.2% and 61.3%, respectively. In addition, Fujii et al. [11] reported a 75% major AFS rate among 32 CLTI patients treated with Rheocarna, despite a high overall amputation rate of 78.1% including minor amputations. Collectively, these studies suggest that Rheocarna may promote wound healing and limb preservation, with outcomes varying by patient characteristics and disease severity.
Treatment strategies for CLTI are broadly classified into revascularization procedures, such as EVT and surgical bypass, and adjunctive therapies, including LDL apheresis with devices such as Rheocarna. Comparable clinical outcomes are observed between EVT and surgical bypass in patients with CLI [12], including those on HD [13, 14]. However, restenosis after EVT remains a major clinical challenge, particularly for infrapopliteal lesions. Notably, the 1‐year restenosis rates following EVT for below‐knee arterial lesions in patients with CLI have been reported to reach 82% [15]. In the present study, more than 80% of patients underwent EVT targeting below‐knee lesions, which may partly account for the relatively low wound healing and AFS rates observed.
In patients with CLI undergoing HD, 1‐year AFS rates after EVT for below‐knee arteries and distal bypass surgery are approximately 65% [16] and 60%, respectively [17]. In contrast, the 1‐year AFS rate in this study was 40%, which was lower than rates reported in previous revascularization studies and the 61.3% reported by Soga et al. [9]. These findings indicated that Rheocarna should be regarded as an adjunctive therapy rather than a substitute for revascularization. Further investigation is warranted to clarify the clinical benefit of Rheocarna in patients with CLTI undergoing HD, particularly regarding optimal timing and patient selection.
The proposed mechanism of Rheocarna involves removing LDL cholesterol and fibrinogen, thereby reducing blood viscosity and systemic inflammation. Lower fibrinogen levels may improve capillary blood flow, while suppression of inflammatory mediators could facilitate granulation tissue formation during wound healing. However, once extensive tissue necrosis and microvascular loss have occurred, such pathological changes are largely irreversible. Consequently, improvements in physiological parameters may not translate into limb salvage in advanced disease stages. In this study, wound healing was particularly limited in patients with Rutherford category 6 disease, suggesting greater benefit with Rheocarna when is introduced earlier, before extensive tissue destruction or endovascular intervention. Furthermore, almost half of the patients died or underwent amputation within 1 month after Rheocarna initiation. The therapeutic effects of Rheocarna may need considerable time to improve pathophysiological abnormalities in CLTI. Therefore, its true efficacy may depend on r treatments repeated treatments and sufficient time to achieve wound healing and limb salvage.
In this study, the interval between EVT and the initiation of Rheocarna therapy varied. However, wound healing and clinical prognosis did not differ significantly between patients who started Rheocarna within 10 days of EVT and those who started Rheocarna after more than 10 days of EVT.
Furthermore, the number of Rheocarna sessions also varied among patients. Although the median number of treatments was higher in the wound‐healing group than in the non‐healing group, this difference was not statistically significant. These results suggest that only a limited portion of patients completed a full course of therapy.
In this study, although patients experienced significant improvements in the ABI, the improvements in the SPP values and clinical outcomes were modest. Given that severe vascular calcification is prevalent among patients on HD, these findings suggest that an increase in the ABI does not necessarily reflect improved microcirculation or accelerated wound healing.
Currently, Rheocarna treatment cannot be administered concurrently with HD and requires additional treatment sessions separate from HD, resulting in prolonged therapeutic burden, particularly for older patients undergoing HD. Such practical limitations may restrict its real‐world applicability and delay optimal intervention timing. Enabling earlier use of Rheocarna, potentially in combination with routine HD or at less advanced CLTI stages, may improve its clinical impact and prevent disease progression.
Several limitations should be acknowledged, including its retrospective design, small sample size, absence of a control group, and potential selection bias. The results of this study demonstrate the real‐world outcomes of Rheocarna use in a cohort of patients on HD with severe CLTI. However, as this study was an observational study, it was unable to assess the effectiveness of Rheocarna. Prospective randomized studies are warranted to clarify the optimal timing and patient selection for Rheocarna therapy in CLTI.
5. Conclusion
Rheocarna therapy may support wound healing in patients with CLTI undergoing HD; however, its effectiveness in improving limb salvage and survival appears limited in advanced CLTI disease stage. Appropriate selection of patients with CLTI and early‐stage intervention may offer greater clinical benefit.
Funding
The authors have nothing to report.
Ethics Statement
This study was approved by The Tokushukai Group Ethics Committee (TGE02730‐024) and conducted in accordance with the Declaration of Helsinki. Written informed consent was waived owing to the retrospective nature of the study, employing an opt‐out approach.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors have nothing to report.
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