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Cardiovascular Center, Kaohsiung Veterans General Hospital, Kaohsiung, TaiwanDepartment of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, TaiwanSchool of Medicine, National Yang-Ming University, Taipei, Taiwan
Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, TaiwanSchool of Medicine, National Yang-Ming University, Taipei, TaiwanDepartment of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
School of Medicine, National Yang-Ming University, Taipei, TaiwanDepartment of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
To explore the role of far infrared (FIR) radiation therapy for hemodialysis (HD) access maintenance after percutaneous transluminal angioplasties (PTA).
Methods
This was a prospective observational study. Eligible patients were those who received repeated PTA with the last PTA successfully performed within 1 week before the study enrollments. Consecutively enrolled patients undergoing successful HD treatments after PTA were randomly assigned to the FIR-radiated group or control group without radiation. FIR-radiated therapy meaning 40-minute radiation at the major lesion site or anastomosed site three times a week was continued until an end-point defined as dysfunction-driven re-PTA or the study end was reached.
Results
Of 216 participants analyzed, including 97 with arteriovenous grafts (AVG) (49 FIR-radiated participants and 48 control participants) and 119 with arteriovenous fistulas (AVF) (69 FIR-radiated participants and 50 control participants), the FIR-radiated therapy compared with free-radiated usual therapy significantly enhanced PTA-unassisted patency at 1 year in the AVG subgroup (16.3% vs. 2.1%; p < .01), but not the AVF subgroup (25.0% vs. 18.4%; p = .50), and this accounted for the overall improved patency rates (21.4% vs. 10.3%; p = .02).
Conclusions
This study suggests FIR-radiated therapy improves PTA-unassisted patency in patients with AVG who have undergone previous PTA.
The study provides data regarding far infrared (FIR) radiation therapy on recurrent hemodialysis (HD) access stenosis that has been treated with balloon angioplasty. The positive results obtained show that FIR radiation therapy following balloon angioplasty is beneficial in the case of recurrent HD access stenosis, especially arteriovenous graft stenosis, in terms of improving the angioplasty-free patency at 1 year. The data may be clinically valid for management of recurrent HD access stenosis and guidance of FIR radiation therapy.
Introduction
Vascular access plays an important role in hemodialysis (HD) treatment through two commonly used forms, an autogenous arteriovenous fistula (AVF) and a prosthetic arteriovenous graft (AVG). Vascular access stenosis, which probably emerges over time, is one of the major causes of HD access failure. Percutaneous transluminal angioplasty (PTA) has become a first-line modality for treating stenosis-related access dysfunctions.
Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis.
A few studies have been published that propose materials, devices, and techniques with the intention to retard the process of neointimal hyperplasia and improve HD access survival.
Among these, the novel therapy of far infrared (FIR) radiation has been documented to improve the unassisted patency at 1 year in the AVF population, possibly through thermal and non-thermal effects.
Reported beneficial effects of FIR radiation therapy include increased production of endothelial nitric oxide (eNO), inhibition of endothelial inflammation, improvement of impaired endothelial function, and increased skin microcirculation.
To the best of our knowledge, no literature has been published regarding the impact of post-PTA FIR radiation therapy on patency outcome. This study was therefore designed to investigate the effect of post-PTA FIR radiation therapy on unassisted patency outcome in HD patients who had undergone repeated PTA.
Materials and Methods
Patient selection
The study was primarily designed as a single-center, prospective, and randomized study. Eligible recruited patients were those who had received two or more PTA on the target lesions at upper extremities, with the last PTA successfully performed within the week before patient enrollment. After successful completion of at least 1 week of HD treatment, the patients with AVF or AVG were consecutively enrolled and randomly assigned to either a post-PTA FIR radiation group or a control group receiving the usual form radiation therapy at a 1:1 ratio. Excluded patients were those who received HD treatments other than three times a week, who had previously received FIR radiation therapy, who received implantation of an endovascular stent, who had multiple lesions that a single radiation field did not cover or the central lesion was considered too deep to be irradiated, who missed FIR radiation treatments exceeding 10%, who underwent renal transplantation or switched to peritoneal dialysis treatments, or who had any severe disease with an estimated life expectancy of less than 1 year. Data relevant to baseline characteristics and patency outcomes were accumulated between groups. The study was conducted in accordance with the Declaration of Helsinki and the local regulatory guidelines. The medical ethics committee of the hospital approved the study protocol (VGHKS098-CT4-12). Informed consent was obtained from all participants before beginning the study.
PTA before FIR radiation therapy
The participants were referred to our center for angiography and PTA as appropriate when the access developed any of the following referral criteria: (a) dysfunctional access signs including abnormal symptoms or physical examination findings suggesting anatomic lesions; (b) presence of decreased flow signs when the inflow rate was set at 300 mL/min; (c) increased dynamic intra-access pressure by 25% from initial baseline; or (d) acutely thrombosed access. A significant lesion was defined as a lumen loss of 50% or more compared with adjacent normal vessel. In the study, the stenotic lesions were treated with balloon PTA using normal-pressure balloon catheters (Fox plus PTA catheter; Abbott, IL, USA) and/or high-pressure balloon catheters (Conquest PTA balloon dilatation catheter; Bard, Tempe, AZ, USA) on an outpatient basis. Patients who received vascular stents were excluded from the study. In general, high-pressure balloon PTA was reserved for lesions refractory to normal-pressure balloon PTA at the rated burst pressure. The inflated pressure was gradually increased until the lesion was totally dilated or the pressure reached the level of rated burst pressure. The double balloon occlusion technique, previously documented to be safe and effective for thrombectomy,
In addition, thromboaspiration and pharmacologic thrombolysis (urokinase) were permitted for rescuing acutely thrombosed accesses. Board-certified vascular interventionists with 2 to 7 years' experience performed all study-related procedures. Two independent and experienced physicians interpreted angiographic findings and determined procedural ends for minimization of interobserver bias.
Post-PTA FIR radiation therapy
The therapy was administered in three 40-minute sessions per week before, during, or after each HD treatment, either at the HD unit or at our center. The WS TY-101N emitters (WS Far Infrared Medical Technology Co., Ltd, Taipei, Taiwan) used for the FIR radiation therapy were positioned approximately 20 to 25 cm above the skin surface at the site of the major stenotic lesion or at the venous anastomosed site for the occluded type in which the major lesion was undetermined. Irradiating power densities are about 10 and 20 μWatt/cm2 when a radiator is set at a distance of 30 and 20 cm above the skin surface, respectively. Radiation therapy was continued every week until an end-point was reached.
Follow-up and endpoints
The target accesses were weekly assessed using the same criteria mentioned above during the 1-year follow-up. Once dysfunctional signs and any of referral criteria recurred in participants with the target accesses, angiography was done to confirm the need for repeat PTA. When a re-PTA was performed, the study ended and radiation therapy was discontinued. Unassisted access patency was defined as the period between the first re-intervention and the initial PTA. Participants who missed over 10% of radiation treatments, switched to peritoneal dialysis, received renal transplantation, or were lost to follow-up were excluded from analysis.
Statistical analysis
All variables were analyzed with SPSS software for Windows (Version 12.0; SPSS Inc., Chicago, IL, USA). All categorical data and rates are displayed as percentages and numbers, and the continuous data are shown as means ± standard deviation. Baseline characteristics and outcome data were compared between groups using chi-square test or Fisher exact test for categorical variables, independent Student t tests for continuous variables, and Mann–Whitney U test for non-normally distributed continuous variables. Kaplan–Meier survival analysis with log-rank test was used to detect differences in unassisted patency between groups. A p value <.05 with two-sided 95% confidence interval was considered statistically significant for all tests.
Results
Baseline characteristics
From March 2008 to March 2010, a total of 216 enrolled participants, 97 with AVG and 119 with AVF, were randomly assigned to post-PTA FIR radiation therapy or usual form of radiation therapy at a 1:1 ratio, to create four groups: (1) 49 with AVG receiving post-PTA FIR radiation therapy; (2) 48 with AVG receiving post-PTA usual therapy as control participants; (3) 60 with AVF receiving post-PTA FIR radiation therapy; and (4) 59 with AVF receiving post-PTA usual therapy as control participants. Unpredictably, nine AVF control participants asked to cross over to the FIR-radiated group after the assignments had been made (Fig. 1). During the follow-up period, one participant died from lung cancer and another died suddenly in the AVF population. Finally, 68 AVF participants in the FIR-radiated group (Group 3) and 49 AVF controls (Group 4) were analyzed. No patients missed FIR radiation treatments exceeding 10%, none underwent renal transplantation, and none switched to peritoneal dialysis treatment in the course of the study. As shown in Table 1, baseline characteristics were identical between groups in the AVF or AVG population.
Comparison between the FIR-radiated group and control group by chi-square test for categorical variables and by independent Student t test for continuous variables.
Comparison between the FIR-radiated group and control group by chi-square test for categorical variables and by independent Student t test for continuous variables.
Age (years)
62.7 ± 10.9
63.1 ± 12.5
.86
67.8 ± 15.7
66.9 ± 9.7
.35
Male/female
32/37
24/26
1.00
18/31
12/36
.27
Hypertension (n)
48
38
.54
34
30
.53
Diabetes (n)
42
28
.71
20
16
.53
Hemodialysis time (years)
4.2 ± 3.5
4.9 ± 4.7
.37
5.7 ± 5.6
5.7 ± 5.1
.83
Duration of access (months)
21.8 ± 23.0
23.5 ± 22.6
.69
20.2 ± 19.1
21.1 ± 22.0
.56
No. of angioplasties at target access before study of
.46
.80
1
14
15
9
11
2
30
20
19
16
3 or more
25
15
21
21
Presentation:
Stenosis type
.39
.19
Elevated pressure ratio
15
6
5
7
.14
Low flow rate
36
29
30
27
.11
Mixed or uncertain
18
15
1
6
.98
Acute occlusion
8
8
.59
18
15
Lesion site:
.79
Vein-side lesions
32
26
30
35
.44
Artery-side lesions
17
12
2
2
.43
Multiple lesions
20
12
17
11
.26
Maximal balloon size
.14
NP: 4–10 mm (n)
4(5)/5(27)/6(17)/7(11)/8(8)/9(1)
5(23)/6(14)/7(5)/8(5)/9(0)/10(3)
5(3)/6(7)/7(21)/8(15)/9(0)/10(3)
6(3)/7(25)/8(16)/9(1)/10(3)
.41
HP: 5–8 mm (n)
5(8)/6(6)/7(4)/8(3)
5(6)/6(4)/7(2)/8(2)
6(3)/7(10)/8(8)
6(2)/7(13)/8(7)
.58
Angioplasty-related complication
2
1
1.00
1
1
1.00
FIR radiation-related complication
0
0
0
0
Death
1
1
1.00
0
0
–
Loss to follow-up
0
0
–
0
0
–
AVF = arteriovenous fistula; AVG = arteriovenous graft; FIR = far infrared radiation; HP = high pressure; NP = normal pressure.
a Comparison between the FIR-radiated group and control group by chi-square test for categorical variables and by independent Student t test for continuous variables.
The results are summarized in Table 2. The 118 participants in Groups 1 and 3, receiving post-PTA FIR radiation therapy, had significantly enhanced unassisted patency rates at 1 year (21.4%, 25/117 vs. 10.3%, 10/97, respectively; p = .04) compared with the 98 participants in Groups 2 and 4 receiving post-PTA usual therapy. The benefit of post-PTA FIR radiation therapy was also demonstrated by Kaplan–Meier survival analysis (p = .02) (Fig. 2).
Table 2PTA-unassisted patency rates in overall, AVF, and AVG populations during 1-year follow-up.
Figure 2One-year cumulative incidence of PTA-unassisted patency is shown overall. The Kaplan–Meier plot denotes a significant increase in 1-year cumulative incidence of PTA-unassisted patency in the group receiving FIR-radiated therapy (FIRT) compared with receiving free-radiation usual therapy after index PTA.
The impact on patency outcome obviously varied between the AVG and AVF subgroups. In the AVG population, post-PTA FIR radiation therapy (Group 1) significantly augmented the unassisted patency rates at 9 months (28.6%, 14/49 vs. 8.3%, 4/48, respectively; p = .01) and at 1 year (16.3%, 8/49 vs. 2.1%, 1/48, respectively; p = .02) compared with the usual therapy (Group 2). Kaplan–Meier survival analysis also confirmed the benefit of post-PTA FIR radiation therapy in terms of improved cumulative incidence of unassisted patency at 1 year (p = .01) (Fig. 3). In addition, Table 3 shows the results of subgroup analysis of the AVG population. In the AVF population, post-PTA FIR radiation therapy (Group 3) did not produce a statistical difference in unassisted patency rate at 1 year compared with the usual therapy (Group 4) (25.0%, 17/68 vs. 18.4%, 9/49, respectively; p = .50). The similarity of patency outcome was also demonstrated by Kaplan–Meier analysis (p = .45) (Fig. 4).
Figure 3One-year cumulative incidence of PTA-unassisted patency is demonstrated using Kaplan–Meier analysis in participants with AVG. The cumulative 1-year incidence of PTA-unassisted patency is significantly higher in the FIRT group compared with the free-radiation control group after index PTA.
Comparison between the FIR-radiated group and the control group by chi-square test.
Male
135.6 (n = 18)
106.3 (n = 12)
.53
Age > 70 years
163.0 (n = 27)
70.6 (n = 18)
<.01
Age > 65 years
165.9 (n = 35)
70.6 (n = 23)
.07
Diabetes mellitus
133.9 (n = 20)
129.6 (n = 16)
.92
Non-diabetes mellitus
172.8 (n = 29)
93.0 (n = 32)
.01
Hypertension
167.6 (n = 34)
113.5 (n = 30)
.09
Non-hypertension
132.7 (n = 15)
91.3 (n = 18)
.23
1 previous PTA
244.7 (n = 9)
96.3 (n = 11)
<.01
2 previous PTA
159.4 (n = 19)
138.4 (n = 16)
.66
3 previous PTA
117.0 (n = 21)
84.6 (n = 21)
.23
Presentation with elevated VP
154.8 (n = 30)
108.6 (n = 27)
.10
Presentation with mixture of elevated VP and low flow
145.8 (n = 18)
111.9 (n = 15)
.48
Vein-side lesion
158.1 (n = 30)
110.1 (n = 35)
.10
Multiple lesions
137.9 (n = 17)
107.6 (n = 11)
.51
Occlusion type
176.8 (n = 5)
115.7 (n = 7)
.56
Non-occlusion (stenosis) type
154.6 (n = 44)
103.4 (n = 41)
.03
Presented as the mean of patency days and number of subgroups. AVG = arteriovenous graft; FIR = far infrared radiation; PTA = percutaneous transluminal angioplasty; VP: venous pressure.
a Comparison between the FIR-radiated group and the control group by chi-square test.
Figure 4One-year cumulative incidence of PTA-unassisted patency is expressed using Kaplan–Meier analysis in participants with AVF. The cumulative 1-year incidences of PTA-unassisted patency are equal between the FIRT group and the free-radiation control group (p = .45).
Unassisted patency rates significantly differed between the AVG control participants (Group 2) and AVF control participants (Group 4). The AVF control participants were associated with a significantly higher rate of unassisted patency at 1 year compared with the AVG control participants (18.4%, 9/49 vs. 2.1%, 1/48, respectively; p = .01) despite a potential difference in baseline characteristics. In contrast with the control groups, no difference in unassisted patency rate at 1 year was observed between the AVG FIR-radiated group (Group 1) and the AVF FIR-radiated group (Group 3) (16.3%, 8/49, vs. 25.0%, 17/68, respectively; p = .36 by Fisher exact test).
Complications
No patients suffered from radiation-related complications such as skin burn injuries or allergies.
Discussion
FIR radiation therapy has been reported to improve access blood flow and unassisted patency in patients with functioning AVFs.
To the best of our knowledge, this is the first study to investigate the impact of post-PTA FIR radiation therapy on unassisted patency in HD patients who had received repeat PTA on recurrent lesions. The study generates four major findings: (a) AVF and AVG that have required more than two PTAs have very poor unassisted 1-year patency rates; (b) post-PTA FIR radiation therapy significantly improves the unassisted patency at 1 year compared with the usual form of radiation therapy; (c) the use of FIR radiation improves the unassisted patency rate in patients with AVG but not in patients with AVF who have previously undergone more than two PTA; (d) post-PTA FIR radiation therapy particularly benefits AVG patients with age exceeding 70 years, no diabetes, fewer previous PTA, and non-occlusion type.
The proposed thermal and non-thermal effects of FIR radiation therapy may delay the progression of vascular restenosis and prolong the intervention-free survival time.
FIR radiation emitters generate electromagnetic waves with wavelengths in the spectral range of 3 to 25 μm (most of 5 to 12 μm and peak at 8.2 μm), which are sufficient for producing both thermal and non-thermal effects.
The thermal effects of FIR radiation therapy are generated by the transfer of heat energy to a depth of 1 to 3 cm in subcutaneous tissue and by an increase in skin temperature of up to 4 °C.
Data from animal models have shown that FIR radiation therapy improves vascular endothelial function through thermal effects which lead to up-regulation of endothelial NO synthase (eNOS).
Furthermore, non-thermal effects considered unique to FIR radiation therapy have been proven to inhibit vascular inflammation by inducing heme oxygenase-1,
These beneficial effects may partially account for the superiority of FIR radiation therapy over the usual therapy with regard to patency outcome, particularly in the AVG population. Subgroup analysis also provides us with clues to undergo further investigation.
The prior study by Lin et al. included 145 participants with functioning AVF who had not received PTA exceeding 3 months before recruitment.
Most of them (72.4%, 105/145) had not received a PTA previously. The difference in study populations may explain the inconsistent results in unassisted patency at 1 year. It is not surprising that the recurrent AVF lesions treated with repeat PTAs responded poorly to the FIR radiation therapy. The beneficial effects on vascular access provided by this therapy may have been partially attenuated or neutralized in the current series. The findings imply that the impact of FIR radiation therapy on unassisted patency varies among groups with functioning AVF and recurrently PTA-treated AVF. We consider that the PTA-treated lesions are more likely to accelerate neointimal hyperplasia and develop access vascular restenosis requiring re-intervention.
For the AVF population, the data, compared with those from the landmark study, demonstrated the apparently lower rate of unassisted patency at 1 year for both the FIR-radiated group (25%, 17/68 vs. 85.9%, 55/64; p < .01) and the control group (14.3%, 7/49 vs. 67.6%, 46/68; p < .01), although the baseline characteristics were potentially different.
These findings indicate that FIR radiation therapy may be applied earlier to AVF which function well or have not received repeat PTA yet, with the consideration of improving unassisted patency.
On the other hand, the unassisted patency rate at 1 year unsurprisingly appeared higher in the AVF control participants than in the AVG control participants who received PTA alone.
Nevertheless, our data show that the patency rates were the same for the AVF and AVG groups receiving post-PTA FIR radiation therapy. The findings reveal that post-PTA FIR radiation therapy may narrow the gap in patency outcomes between the AVF and AVG groups. The mechanism of the findings is not clear. We infer that variations in vessel size, capacity for producing NO, or susceptibility to NO may potentially have contributed to the results. At the least, we can conclude that the application of non-invasive FIR radiation therapy to HD patients with functioning AVF and even with recurrently PTA-treated AVG is safe and clinically beneficial. Although it should be noted that the low mortality rate in the study may be caused by patient selection excluding severe diseases.
Limitations
A few limitations should be emphasized in the study. (a) Dysfunction-driven referral is not the ideal or even the most accurate model for selecting patients with target access restenosis. For example, a non-radiated lesion may occur. (b) It is very difficult to quantify, standardize, and formalize the FIR radiation therapy. This may lead to inequality of the therapy among groups. (c) Detailed lesion properties, HD parameters, and PTA procedures were not considered in the study. They potentially affected the patency outcomes. (d) The study is limited to a small number of participants undergoing repeat PTA at a single center. The results are not generalized to all kinds of HD patients.
Conclusion
The data show that post-PTA FIR radiation therapy is safe and effective, and improves PTA-free HD access patency, especially in the AVG series. This study suggests that this form of radiation therapy may be regarded as a helpful tool after PTA in terms of prolonged unassisted patency.
Acknowledgements
We appreciate the assistance of Ms. Ya-Ting Wu, Yu Shin, Lu, and Hsiu-Chieh Chang for their statistical, secretarial, and illustration work.
Conflict of Interest
None.
Funding
This study was supported by a grant from Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C. (VGHKS 098-016, 099-013, 099-016).
Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis.
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