Endovascular brachytherapy for the treatment of renal artery in-stent restenosis using a [beta]-emitting source: a report of five patients.

Abstract: We report five cases of renal artery in-stent restenosis treated with endovascular brachytherapy. This procedure has been previously used extensively for the treatment of coronary artery in-stent restenosis with successful results. Therefore, it follows logically that noncoronary in-stent restenoses would also be successfully treated in this manner. Though our experience is limited, we feel that this report provides adequate data to justify the formation of a prospective trial for a more adequate evaluation of the potential utility of this intriguing approach.

Key Words: angioplasty, endovascular brachytherapy, radiotherapy, renal artery stenosis, stent

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Restenosis of vessels treated by percutaneous transluminal coronary angioplasty (PTCA) is one of the greatest limitations of this procedure's effective use. Research into the pharmacologic treatment of restenosis has been pursued with agents such as heparin; however, success has been limited. (1) Metallic stents were introduced with great enthusiasm and it was initially thought that these would eliminate the problem of restenosis. However, intimal hyperplasia with growth through the metallic mesh still proved problematic. (2), (3) Within the past few years, numerous trials have been conducted, and many reports have been published demonstrating the efficacy of endovascular brachytherapy for in-stent coronary restenosis. (1), (3) In this procedure, the restenosed stented vessel is opened by balloon angioplasty and then irradiated with an intraluminal radioactive source to prevent intimal hyperplasia and repeat restenosis. More recently, interest has developed in the application of endovascular brachytherapy to restenosed stents outside of the coronary vessels. Restenosis of stents placed in renal arteries is one such area of this treatment's potential utility. The application of endovascular brachytherapy to renal artery restenosis has been demonstrated safe and effective in a French study using a rabbit model, (4) and single-patient reports have previously been published. (5) Furthermore, a Swiss study was recently published describing a small group of patients treated with renal artery endovascular brachytherapy. (6) In this study, however, the source of radiation used was fundamentally different from the source used in our patients. Our system has both unique challenges and potential advantages that are discussed later. We present a series of five patients seen at the University of Kentucky and treated for renal artery in-stent restenosis by endovascular brachytherapy with a [beta]-emitting source.

Discussion

Much debate over the utility of endovascular brachytherapy has ensued since its introduction several years ago. While it has demonstrated efficacy in treating in-stent restenosis of coronary artery stents, its potential for use in noncoronary vessels has been both lauded and questioned. The available basic science research and experience with treatment of coronary restenosis justifies the treatment of restenosis in non-coronary stents. With the exception of our transplant patient, the results presented here demonstrate an overall improvement in clinical measures of disease.

While limited in number, our experience demonstrates a potential for preventing renal artery restenosis in patients not previously transplanted. We note, with interest, the fact that our transplant patient did not experience a significant reduction in pharmacologic regimen or representative SBP and ultimately required repeat angioplasty. Whether this lack of response is a result of the prior surgical intervention or the severity of the underlying pathology is not clear. We feel that, based on this single case, no conclusion can be made with regard to transplant patients. Furthermore, it should be noted that the interval to target vessel failure and degree of failure was similar both poststenting and postbrachytherapy, suggesting that brachytherapy did not have a detrimental effect.

The Swiss pilot study mentioned earlier used [.sup.192]Ir, a [gamma]-emitting radioisotope, as the source of radioactivity. Conversely, our system uses [.sup.90]Sr, a [beta]-emitter. While there may be dosimetric advantages to [.sup.192]Ir, we have described our method of calculating the proper dose for renal vessels and feel that this is a feasible approach. In addition, [beta]-radiation requires less extensive shielding and results in lower radiation exposure to personnel and to the patient. (9)

[FIGURE 1 OMITTED]

It has been observed that the Novoste [beta]-Cath system does not have a centering device to ensure that the source train is continuously at the center of the vessel. Irregularities of the vessel wall or even the source itself may create a turbulent flow. However, as radiotherapy from this system is delivered over minutes, it is our feeling that the minimal oscillations of the source train within the vessel are likely self-compensating. While the Novoste system was the only device available to us, a self-centering source may reduce the potential for error and thus may be more desirable.

All patients tolerated the procedure with no untoward side effects and, in the ensuing period of follow-up, no complications or toxicities have been realized. Postprocedurally, our patients are maintained on a 6- to 12-month regimen of clopidogrel. At the University of Kentucky, close coordination between the cardiology and radiation medicine departments minimizes the amount of extra time spent in the catheterization procedure. The endovascular brachytherapy process adds approximately 15 to 20 minutes to the time normally spent in the catheterization laboratory.

Clearly, additional follow-up is needed for all patients discussed. We acknowledge the limitations of our small case series and realize the durability of response in the nontransplanted patients could change with extended follow-up. Nonetheless, we feel that our experience, the available basic science data, and other case reports justify a larger prospective trial of this potentially lifesaving treatment. Ideally, such a trial would include follow-up with repeat catheterization to quantify stent patency, a procedure not medically justifiable in the present series.

Conclusions

Endovascular brachytherapy for the restenosis of renal artery stents is a feasible procedure with the potential to significantly alleviate clinical measures of disease. We have demonstrated that the technology used to treat coronary instent restenosis can be adapted to treat restenosed renal artery stents and that proper dosimetry, adjusted to the larger renal artery diameter, can be performed. Furthermore, we provide evidence of the safety of this procedure, as demonstrated by animal studies and widespread experience with coronary brachytherapy and renal artery angioplasty. We think that renal artery brachytherapy plays an important role in the treatment of restenosis at this site. However, a prospective trial is necessary to evaluate its efficacy adequately.

One of the greatest necessities in America is to discover creative solitude.

-Carl Sandburg

Key Points

* Endovascular brachytherapy treatment of renal artery in-stent restenosis is feasible and practical.

* Significant reductions in pharmacologic regimens and systolic blood pressure were seen in patients treated with endovascular brachytherapy.

* Such advantages may not be realized in renal transplant patients with in-stent restenosis.

Table 1. Patient and treatment characteristics of the five patients
described in this report

Patient  Age  Pre SBP  Post SBP  Side    Dose    Mo F/U

   1     65     130      120     Right  2070cGy    7

   2     65     150      129     Right  2070cGy    5

   3     71     190      145     Right  1690cGy    3

   4     70     190      190     Right  2215cGy    1

   5     62     138      132     Right  2100cGy    5

From the Departments of Radiation Medicine and Cardiology, University of Kentucky College of Medicine, Lexington, KY.

This study was financially supported by the University of Kentucky.

The authors have no proprietary interest in the systems described in this report.

Reprint requests to Christopher D. Jahraus, MD, Department of Radiation Medicine, University of Kentucky College of Medicine, 800 Rose Street, Room C-1, Lexington, KY 40536. Email: [e-mail]

Accepted February 27, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1165

References

1. Kotzerke J, Hanke H, Hoher M. Endovascular brachytherapy for the prevention of restenosis after angioplasty. Eur J Nucl Med 2000;27:223-236.

2. King SB. Restenosis following angioplasty, in Waksman R (ed): Vascular Brachytherapy. Armonk, NY, Futura Publishing Co., 2002, ed 3, pp 3-11.

3. Popma JJ, Suntharalingam M, Lansky AJ, Heuser RR, Speiser B, Teirstein PS, et al. Randomized trial of [.sup.90]Sr/[.sup.90]Y [beta]-radiation versus placebo control for treatment of in-stent restenosis. Circulation 2002;106:1090-1096.

4. Le Blanche AF, Bonneau M, Wassef M, Farres MT, Gabez L, Aubert B, et al. Histomorphometric evaluation of [.sup.198]Au endovascular brachytherapy in a renal artery restenosis model in rabbits. AJR Am J Roentgenol 2002;179:611-618.

5. Stuckle CA, Laufer U, Kirchner J, Muller H, Adams S, Adamietz IA, et al. Successful treatment of intimal hyperplasia in renal arteries by endovascular brachytherapy. Cardiovasc Radiat Med 2001;2:114-118.

6. Stoeteknuel-Friedli S, Do DD, von Briel C, Triller J, Mahler F, Baumgartner I. Endovascular brachytherapy for prevention of recurrent renal in-stent restenosis. J Endovasc Ther 2002;9:350-353.

7. Novoste Corp. Beta-Cath System User's Manual. Norcross, GA, Novoste Corp., 2002, pp 51-52.

8. Soares CG, Halpern DG, Wang CK. Calibration and characterization of [beta]-particle sources for intravascular brachytherapy. Med Phys 1998;25:339-346.

9. French MH, Faxon DP. Update on radiation for restenosis. Rev Cardiovasc Med 2002;3:1-6.

RELATED ARTICLE: Case Reports

All patients had undergone prior renal artery stenting due to renal artery stenosis. These patients returned with worsening symptoms, and angiography demonstrated in-stent restenosis. The patients underwent angioplasty followed by endovascular brachytherapy using the Novoste [beta]-Cath system (Novoste Corp., Norcross, GA). A 30- to 40-mm source train was used to cover the entire length of the stented portion of the vessel with at least 5-mm proximal and distal margins. In all cases, a single dwell position was used for the radiotherapy and the stated dose was delivered to the intima. For a patient with a 5-mm artery, the dose was prescribed to 2.5 mm; for a patient with a 6-mm artery, the dose was prescribed to 3 mm.

Novoste provides FDA-approved prescription data for irradiation of vessels up to 4 mm in diameter on the source certificate. In addition, the system manual provides tabulated data for determining dose falloff as a function of the distance from the source. (7), (8) The appropriate dwell time for each patient and the size of the angioplasty balloon the treating cardiologist anticipated he would use to reexpand the stent before irradiation were calculated on the basis of these data. Due to physical and practical constraints inherent in the process, the anticipated dose could not always be delivered precisely. Thus, the dose referenced for each patient is the actual dose delivered, recalculated postprocedurally.

Evaluation of therapy was measured with an endpoint of target vessel failure. Three surrogate clinical criteria were identified to determine target vessel failure: loss of blood pressure control as evidenced by a sustained elevation in systolic blood pressure (SBP), intensification of antihypertensive medical regimen, and elevation of serum creatinine greater than 0.5 mg/dl.

Patient 4 did not have a follow-up measure of creatinine available. However, none of the remaining patients (Patients 1-3 and 5) experienced an elevation in creatinine. Thus, no patient experienced target vessel failure based on a rise in creatinine. Medical regimens and representative blood pressure measurements for each patient are discussed below. Table 1 summarizes pertinent patient and treatment characteristics for each of the cases described, and Figure 1 demonstrates graphically the pre- and postprocedural changes in SBP. It should be noted that the SBP measurements shown in the graph are representative measurements deemed consistent with the overall trend of each patient's SBP.

Patient 1

Patient 1 was a 65-year-old man previously treated with stenting for right-sided renal artery stenosis. His presenting feature was worsening hypertension. At the time of presentation, his hypertension was managed with a daily regimen of 400 mg labetalol, 300 mg irbesartan, 360 mg diltiazem, and 10 mg torsemide. Despite this aggressive pharmacologic management, his SBP was 130 mm Hg. Before the institution of the pharmacologic regimen noted, his SBP was 180 mm Hg. The patient was treated with endovascular brachytherapy of the affected artery to a dose of 2070 cGy using a [.sup.90]Sr source. After 7 months of follow-up, the patient was maintained on a daily regimen of 200 mg of labetalol and 20 mg of furosemide. His SBP on this regimen was 120 mm Hg.

Patient 2

Patient 2 was a 65-year-old man previously treated with stenting for right-sided renal artery stenosis. His presenting feature was worsening hypertension. At the time of presentation, his hypertension was managed with a daily regimen of 1,200 mg of labetalol, 32 mg of candesartan, and 0.9 mg of clonidine. On this regimen, his SBP was 150 mm Hg. The patient was treated with endovascular brachytherapy of the affected artery to a dose of 2070 cGy using a [.sup.90]Sr source. After 5 months of follow-up, the patient was maintained on a daily regimen of 1,200 mg of labetalol, 1.8 mg of clonidine, and 5 mg of amlodipine. His SBP on this regimen was 129 mm Hg.

Patient 3

Patient 3 was a 71-year-old man previously treated with stenting for right-sided renal artery stenosis. He presented with worsening hypertension, on a daily regimen of 50 mg of metoprolol, 0.4 mg of clonidine, 180 mg of diltiazem, and 40 mg of furosemide. Preprocedural SBP on this regimen was 190 mm Hg. A dose of 1,690 cGy was administered via a [.sup.90]Sr source. Three months after treatment, the patient was on the same medical regimen, with the exception of a 50% reduction in his clonidine dose. However, his SBP was 145 mm Hg.

Patient 4

Patient 4 was a 70-year-old woman previously treated with bilateral stenting for renal artery stenosis. A dose of 2,215 cGy was administered via a [.sup.90]Sr source. Preprocedurally, the patient's daily medical regimen included 2.5 mg lisinopril, 25 mg metoprolol, 40 mg furosemide, and 25 mg spironolactone; and her SBP was 190 mm Hg. One month after treatment, her lisinopril was maintained at 2.5 mg/d, her metoprolol was reduced by 50% to 12.5 mg/d, her furosemide was maintained at 40 mg/d, and her spironolactone was discontinued. She did not experience a drop in SBP.

Patient 5

Patient 5 was a 62-year-old man who had a prior renal transplant followed by stenosis of the vessel supplying the graft, subsequent stenting of the artery supplying the donor organ, and restenosis of the stent. His antirejection regimen consisted of cyclosporine, mycophenolate mofetil, and prednisone. The patient's vessel was treated with a dose of 2,100 cGy. His antihypertensive pharmacotherapy could not be adjusted 1 month posttreatment and his blood pressure did not change significantly. Five months later, the patient presented with sustained hypertension and renal insufficiency and required repeat angioplasty of the transplant renal artery for restenosis after brachytherapy. Over this 5-month interval, an 80% restenosis developed, based on angiography at the time of repeat angioplasty. This compares with 90% restenosis that developed in the 4-month interval between stenting and brachytherapy.

Christopher D. Jahraus, MD, William St. Clair, MD, PHD, John Gurley, MD, and Ali S. Meigooni, PHD