Gamma Brachytherapy for the Treatment of In-Stent Restenosis of Renal Arteries

Introduction

Percutaneous transluminal renal angioplasty (PTRA) followed by subsequent stent implantation is an efficient treatment of atherosclerotic renal artery stenosis and has been shown to be associated with improvement in renal function, control of refractory hypertension and/or stabilization.¹ However, the incidence of angiographic in-stent restenosis (ISR) at the stented segment has been reported at approximately 14–20%.^2–5 There is limited data on the available treatment options for renal ISR. Some preliminary data suggest that these treatments include balloon angioplasty, re-stenting and surgical revascularization. Cutting balloon (Boston Scientific Corporation, Maple Grove, MN), which is used in coronary in-stent restenosis mainly due to the lack of movement during inflation, should be considered as another modality, although there is only limited case report data available for the in-stent renal stenosis.⁶ While all conventional percutaneous transluminal revascularization modalities reported high rates of recurrence,⁷ surgical revascularization is associated with a comparably higher morbidity and mortality. Vascular brachytherapy is proven to be effective for the treatment of ISR in coronary arteries, and is approved by the Food and Drug Administration (FDA) for this indication. Off-label use of brachytherapy was extended to ISR in other vessels such as saphenous vein grafts, superficial femoral arteries and renal arteries. The present study was conducted to examine the safety and feasibility of endovascular gamma brachytherapy for the prevention of recurrent ISR in the renal arteries.

Materials and Methods

Patient selection. From January 2003 to March 2004, a total of 11 patients who previously received a unilateral stent to the renal artery, and presented with ISR defined as > 60% stenosis by duplex ultrasound or ? 50% by angiographic visual estimate, were identified and included in the present study. These patients, recruited from the general population at Washington Hospital Center, presented with a duplex ultrasound and/or clinical symptoms indicating angiographic evaluation of the renal arterial system. Clinical follow-up was conducted at 1, 3, 6, and 9 months, and duplex ultrasound was conducted at 9 months after successful treatment with PTRA (with or without additional stenting) and brachytherapy of renal arteries to assess peak systolic velocities of aorta and target renal artery, as described in earlier studies.⁸ All patients consented to undergo angioplasty followed by off-label brachytherapy of the renal artery.

Inclusion and exclusion criteria. For the purpose of the study, renal ISR was defined as > 60% stenosis by duplex ultrasound or > 50% stenosis at the angiographic examination. Patients were required to be hemodyanamically stable before the procedure. Other inclusion criteria included ISR lesions amenable to balloon angioplasty and a target vessel diameter of 4.0–8.0 mm, assessed by intravascular ultrasound (IVUS) before intervention. Patients were required to understand the risks and benefits of radiation therapy and available alternative treatment options. Patients were required to agree to return for 9-month follow-up which included a duplex ultrasound examination, and if it showed > 60% stenosis, undergo renal angiography with possible repeat intervention. Exclusion criteria included intolerance, contra-indication, or inability to commence and follow dual antiplatelet therapy with aspirin, ticlopidine or clopidogrel, serum creatinine > 4mg/dl, target lesion in a renal artery supplying a transplanted kidney or evidence of thrombus at the target site. Patients presenting with acute coronary syndrome or with acute myocardial infarction within the previous 48 hours, patients with left ventricular ejection fraction Radiation details. Gamma radiation was administered using the Checkmate system (Cordis Corporation, Miami, FL) with Ir-192 seeds (Best Industries, Richmond, VA) in the dedicated peripheral catheterization and intervention laboratory. A 3.4 Fr closed-end lumen catheter was advanced into the vessel. Based on the lesion length, a commercially available radioactive Ir-192 ribbon containing either 6, 10 or 14 seeds was chosen to deliver radiation dose via this catheter. These ribbons, when properly positioned, can cover lesions 13–45 mm in length with a 5 mm margin at each end. To deliver the prescription dose, the radioactive ribbon was left at the lesion site for 20–45 minutes, depending on the source activity and reference vessel diameter (RVD), assessed by intravascular ultrasound (IVUS). Dosimetry calculations for this study were based on a dose rate versus distance table generated and based on AAPM TG43 calculation.

To be consistent with previous intravascular brachytherapy studies, the dose prescription point, taken as 2 mm from the source center, was kept. Since centering was not an option with this catheter, radiation treatment was given prior to intervention so the vessel lumen could be kept at a minimum and the dose uniformity optimized. Dosage for this protocol was designed to be within the range of 8 Gy, which is known to be the minimum effective dose, and a maximum tolerated dose that would prescribe 100 Gy or more to the lumen. Furthermore, treatment time per lesion was kept to ? 45 minutes by using a source with seed activity ? 30 mCi each. Output from all sources was measured using the intravascular brachytherapy well chamber calibrated by ADCL prior to first clinical usage. In-house values were used for calculating dwell times for sources confirmed with deviations more than +5% of the vendor’s value. Doppler ultrasonography. Doppler ultrasonography was performed utilizing a 3.5 MHz transducer with longitudinal anterior, lateral and oblique approach. All patients were studied taking ? 3 samples of parameters along the artery. Patients were examined while lying in the supine position for the examination of the abdominal aorta and the origin of the renal arteries. After that, patients were turned on either side for the study of the renal arteries at the hilum and of parenchymal perfusion. Standard criteria for the diagnosis of significant renal artery stenosis (? 60%) are: 1) Systolic peak velocity > 180 cm/sec (sensitivity ~= 94% or 98% when peak velocity > 200 cm/sec); and 2) Renal aortic ratio, defined as the ratio between systolic peak velocity in the renal artery and systolic peak velocity in the abdominal aorta in the suprarenal tract, with a normal value of 8.

 PTRA protocol. All patients were pretreated with aspirin and clopidogrel (loading dose of ? 300 mg if patients were not currently on a maintenance therapy). After canulation of the involved renal artery with a 7.0 Fr IMA guiding catheter, the lesion was crossed with a cardiac 0.014-inch guidewire, and assessment of the target lesion and target vessel was undertaken using IVUS with the Galaxy-I system (Boston Scientific Corp.). The dosimetry calculations were made from the vessel diameter measured by IVUS, and radiation treatment was accomplished. Upon completion of the radiation procedure, angioplasty with a balloon sized 5–7 mm in diameter and up to 30 mm in length, with or without adjunctive laser ablation, was done to achieve an optimal angiographic result, defined as residual diameter stenosis of 250 seconds. After the procedure, patients were observed for 24 hours when post procedure serum creatinine, blood urea nitrogen and packed cell volume were assessed. Serial blood pressure measurements were recorded and patients were discharged the next day with advice to continue aspirin indefinitely and clopidogrel for a minimum period of 1 year, which is the practice adopted at our institution for patients who receive vascular brachytherapy.

Follow-up. Patients returned to the hospital for 6-month follow-up assessment of blood pressure, renal function, angina and congestive heart failure classification, and medication regimes. Renal function was assessed by serum creatinine and blood urea nitrogen. A 9-month follow-up duplex ultrasound examination was conducted to check the kidney size and aortic and renal peak systolic velocities.

Study endpoints. The primary endpoint of the study was primary patency of the treated renal artery at 9 months. The secondary endpoints were clinical composite endpoints, including mortality, morbidity, nephrectomy, significant embolic events resulting in end organ damage, worsening renal function, target lesion revascularization (TLR) at 9 months, quality of life as measured by reduction in blood pressure and medications, and the stabilization or improvement of renal function.

Definitions. Death was defined as all-cause mortality. Primary patency was defined as 1 mg/dL over the baseline creatinine. Stabilization or improvement in renal function was defined as stable serum creatinine or improvement in serum creatinine at follow-up. Target lesion revascularization was defined as clinically driven repeat revascularization of the treated vessel.

Statistics. Data are presented as mean ± 1 standard deviation. The 3 dependent variables (pre-procedure, post-procedure, and follow-up data) were analyzed by ANOVA procedure using SAS version 8.2 (SAS Institute, Cary, NC). The mean age of the patients was 64 ± 8.68 years with 45.5% (n = 5) male patients. Traditional risk factors for atherosclerosis in the study patients were as follows: hypertension (100%), hyperlipidemia (91%), diabetes mellitus (36.4%) and history of smoking (64%). Procedural success was 100%. The mean RVD was 5.4 ± 0.58 mm. The mean dose of radiation was 22.8 ± 0.6 Gy and the dwell time was 30.25 ± 1.92 minutes. The mean total radioactivity for the procedure was 270.64 ± 15.86 mCi.

During intervention, balloon and stent were used in 45.5%, balloon alone in 27.3%, balloon and laser in 18.18%, and laser, balloon and stent in 9.09%. Follow-up data is available for all patients with a mean follow-up duration of 9.0 ± 3.00 months. There were no significant differences in follow-up between pre-procedure, post-procedure, and follow-up in biochemical renal parameters or number of antihypertensive medications.

We observed a statistically significant decrease in both systolic and diastolic blood pressure immediately after the procedure (systolic blood pressure p = 0.04; diastolic blood pressure: p = 0.01), which is a common phenomenon observed after renovascular angioplasty. At follow-up, however, this effect had subsided and there was no difference in systolic (p = 0.71) or diastolic blood pressure (p = 0.65) between pretreatment levels and follow-up.

Discussion

The principal findings of the present study are that gamma radiation treatment for ISR of renal arteries is safe and feasible, and is not associated with clinical adverse events up to 9 months with low rates of repeat revascularization. In-stent restenosis affecting atherosclerotic renal arteries is a significant problem with reported incidences ranging from 14–20%, yet there is no effective treatment option.^2–5 Available methods, including repeat balloon angioplasty and repeat stenting, are associated with high recurrence rates. Vascular brachytherapy has been shown to be an effective and FDA-approved strategy to treat ISR in coronary arteries. Experience with the application of gamma radiation using Ir-192 to treat renal ISR has been reported by some investigators as case reports^9–11 and a single-center experience that included 11 patients.¹² In all reports, renal ISR has been treated with initial balloon angioplasty or cutting balloon angioplasty followed by radiation treatment. Follow-up was obtained by angiography at 4 months,¹⁰ by digital subtraction angiography at 6 months and 1 year,¹¹ and by angiography or duplex sonography.¹² On the other hand, experience with beta radiation is much less — with one case report¹³ and a small series of 5 patients subsequently updated to 15 patients.^14,15 While the case report did not mention any follow-up, the case series had surrogate clinical markers as endpoints. Thus, we could find in the literature a total of 30 patients (gamma = 14 patients and beta = 16 patients). While all the patients described in the case reports had sustained benefit on follow-up, in the studies with gamma radiation there were two recurrences, and in the studies with beta radiation there were three recurrences on follow-up. The present study adds additional experience to the field of treatment for renal ISR using gamma radiation. Here, we found 100% procedural success and no immediate complications. The major difference between other published reports and the present study is administration of gamma radiation before pretreatment of the lesion with any device. This approach helps to overcome the centering problems of the radiation catheter and enables uniform distribution of the radiation dose to the vessel wall. Radiation was followed by balloon angioplasty and/or debulking devices to optimize vessel lumen diameter. Clinical and duplex ultrasound follow-up demonstrated no evidence of restenosis in 10 patients. There was 1 patient who presented with restenosis and was treated with repeat balloon angioplasty with good results. There was no adverse impact on the renal function parameters including blood urea nitrogen, serum creatinine and creatinine clearance on follow-up. The follow-up systolic and diastolic blood pressures were not decreased when compared to the baseline, which is also reflected by the lack of reduction in the antihypertensive medications required to control the blood pressure. Data on the impact of PTRA and stenting on control of hypertension conflicts with favorable¹⁶ and unfavorable¹⁷ reports. The present study deals with patients who presented with ISR and may represent a difficult subgroup of patients with refractory hypertension. The reported data on management of renal artery ISR is limited – with preliminary re-interventional conventional therapy demonstrating up to 25% restenosis at 11 months.¹⁸ Although the recurrence rate in our series was only 9.1%, it is premature to state that brachytherapy is more efficacious. Based on this limited data, a randomized clinical trial against conventional therapy is warranted. With the evolution of drug-eluting stents (DES), there is the possibility of reduction in renal ISR similar to the experience with coronary vascular brachytherapy. Currently, however, the maximum available diameter of DES is only 3.5 mm, and it is not known whether it is an effective option to implant them in larger-sized renal arteries. Further, downstream effects of the eluted drug on renal parenchyma are not known. Therefore, currently brachytherapy appears to be a viable option for the treatment of renal ISR. Our experience with gamma brachytherapy shows the potential of the technology, its safety, and mid-term durable beneficial effects. Unfortunately, out of the three commercially available radiation systems, namely, Novoste Beta Cath system (Novoste Corporation, Norcross, GA), Galileo Beta radiation system (Guidant Corporation, Santa Clara, CA), and Checkmate gamma system (Cordis Corporation, Miami, FL), we are left with only the Novoste Beta Cath system in the United States, which uses the Sr/Yr isotope. Whether to continue utilization of vascular brachytherapy technology with the Novoste system remains to be addressed.

Study Limitations

The present study is a prospective clinical observational analysis of a small number of patients without a control group. Furthermore, follow-up was limited to a 9-month period, thus the possibility of a late catch-up phenomenon cannot be entirely ruled out.

Conclusion

Gamma radiation treatment for ISR of renal arteries appears to be safe and feasible, and is not associated with clinical adverse events up to 9 months with low rates of repeat revascularization. However, the future of this intervention remains unclear.