The three R's: radiation for restenotic renals?

Revascularization of renal artery stenosis in an effort to control hypertension and preserve renal function is becoming more widely accepted. Peripheral intervention of atherosclerotic renal arteries by balloon angioplasty with stenting is the preferred means of revascularization. Stenting induces a proliferative response, sometimes producing enough neointimal hyperplasia within the lumen of the stent to obstruct flow. The incidence of in-stent restenosis (ISR) in renal arteries is approximately 20%. (1) As equipment and techniques continue to improve, the number of patients diagnosed with and managed for ISR of renal arteries will increase.

In this issue of the Southern Medical Journal, Jahraus et al (2) describe a case series of five patients whom they treated with vascular brachytherapy (VBT) for ISR in renal arteries. VBT has been shown to reduce the risk of recurrent ISR in coronary arteries by approximately 50%. (3-5) Patients with recurrent ISR in coronary arteries have a risk of subsequent recurrence as high as 80% without VBT. (6) Diabetes and lesion length are highly predictive of the risk of ISR. Similarly, the pattern of ISR is predictive of recurrence: the more diffuse the proliferative response, the greater the risk of recurrence. (7) The patient and lesion characteristics that predict ISR of renal arteries are not well described, although Lederman et al (1) found that vessel diameter was a significant predictor of restenosis. Vessels smaller than 4.5 mm had a restenosis rate of 36.0% compared with a 6.5% risk of ISR in vessels larger than 6.0 mm (P < 0.01). (1) It is interesting to note that a coronary artery with a caliber of 4 mm has a risk of ISR of approximately 10 to 15% depending on length. (8) This difference between two rates of ISR for 4-mm vessels underlines the difference in biology between coronary and renal arteries. It remains to be proven whether VBT is more efficacious in renal arteries in reducing recurrent ISR than angioplasty alone, and the experience of Jahraus et al (2) is an important step in outlining the role of VBT.

The authors recognize the limitations of nonrandomized data, particularly with such a small number of patients. There is no angiographic core laboratory for the index procedure; indeed, there is no angiographic follow-up. Instead, surrogate markers for recurrent restenosis were used: recurrence of hypertension and elevation of serum creatinine, which are insensitive markers at best. Angiography remains the "gold standard" for the diagnosis of renal artery stenosis, and uniform angiographic follow-up after VBT would have been valuable. Two noninvasive means of evaluating renal artery stenosis and ISR are color duplex ultrasonography and multidetector computed tomographic angiography (MDCTA). Duplex ultrasound is limited by its inability to assess the renal arteries in some patients due to body habitus. MDCTA still requires administration of an IV contrast agent but is not associated with an increased risk of renal failure, although a larger volume of contrast is used when compared with digital subtraction angiography. (9) Although computed tomography and magnetic resonance imaging had previously faced the obstacle of stent-induced artifact, this hurdle has been overcome by MDCTA. At the Ochsner Clinic, after renal artery stenting, patients undergo Doppler ultrasound at 6 months, 12 months, and then annually as a screening test for ISR, in addition to following blood pressure and renal function.

The authors used the Novoste Beta-Cath (Novoste, Norcross, GA) to deliver a [.sup.90]SR/[.sup.90]Y source, a [beta]-emitter, to the renal artery. There have been no large-scale, head-to-head trials of [beta]-emitting versus [gamma]-emitting sources for the inhibition of ISR in coronary arteries. Both have demonstrated similar efficacy in risk reduction of recurrent ISR. (3), (5) [beta]-Emitting sources have a steep dose gradient related to distance and are easily shielded, (10), (11) explaining why [beta]-emitting systems were more widely adapted in cardiac catheterization laboratories. In theory, this steep dose decrease may make [beta]-emitting sources less desirable in larger-caliber vessels. The Novoste Beta-Cath system is calibrated to deliver approximately 18 Gy to a 2.7-mm artery. If a vessel is large enough, a [beta]-emitting source may be unable to deliver an adequate dose to the adventitial layer of the vessel wall. The Guidant Galileo system (Guidant Corp., Indianapolis, IN) uses a centering balloon catheter to deliver its [beta]-emitting source, and this feature may provide more uniform dosing of [beta]-radiation in larger caliber vessels. The Cordis Checkmate system (Cordis Corp., Miami Lakes, FL) administers [gamma]-emitting [.sup.192]Ir, which has a less steep dose decrease, (10), (11) theoretically making it a better source for treating ISR in large-caliber peripheral vessels.

Stents that elute antiproliferative drugs, such as sirolimus and paclitaxel, have been shown to reduce the risk of ISR and are approved for use in coronary vessels in the United States and are already used in practice in Europe. (12), (13) The potential of sirolimus as an antirestenotic agent was discovered when its ability to inhibit neointimal proliferation in carotid arteries in animal balloon injury models was noted. (14) Although there may be initial enthusiasm for use of these stents in noncoronary arteries, the largest diameter stents available will be 3.5 mm. The SIRIUS trial suggested that sirolimus only inhibits ISR in the part of the vessel with which it is in contact (15); the dose of sirolimus on these coronary stents may be insufficient to inhibit ISR in a 5.0- or 6.0-mm-diameter vessel.

Stoeteknuel-Friedli et al (16) reported their experience with 13 patients treated for ISR with [.sup.192]Ir to deliver 12 Gy at 5.0 mm from the source. Eleven of the 13 patients were successfully irradiated, one of whom died as a result of an unrelated cause during follow-up. Patients had planned duplex ultrasonography at 1 year after angioplasty and high-dose-rate brachytherapy. Two of the 10 irradiated patients (20%) developed restenosis. Although this ISR rate is similar to historical controls for de novo stenting, these patients were most likely in a higher risk cohort, having had at least one prior episode of restenosis.

The Food and Drug Administration and the Nuclear Regulatory Commission have approved these endovascular brachytherapy devices for coronary use. Their use in noncoronary vessels is off-label. There are a few randomized trials suggesting that VBT is an effective means of inhibiting ISR in other peripheral beds, and the authors are to be commended for adding to our knowledge by tracking their outcomes and sharing their experience. We look forward to a large-scale, randomized, placebo-controlled trial of VBT for renal artery ISR.

Not the cry but the flight of the wild duck leads the flock to fly and follow.

--Chinese proverb

From the Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, New Orleans, LA, the Department of Radiology, Medical College of Georgia, Augusta, GA, and the Department of Radiology, University of South Alabama Medical Center, Mobile, AL.

Reprint requests to John P. Reilly, MD, Department of Cardiology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. Email: [e-mail]

Accepted April 23, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1094

References

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2. Jahraus CD, St Clair W, Gurley J, et al. Endovascular brachytherapy for the treatment of renal artery in-stent restenosis using a [beta]-emitting source: A report of five patients. South Med J 2003;96:1165-1168.

3. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary [gamma]-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250-256.

4. Suntharalingam M, Laskey W, Lansky AJ, et al. Clinical and angiographic outcomes after use of [.sup.90]strontium/[.sup.90] yttrium [beta] radiation for the treatment of in-stent restenosis: Results from the Stents and Radiation Therapy 40 (START 40) registry. Int J Radiat Oncol Biol Phys 2002;52:1075-1082.

5. Waksman R, Raizner AE, Yeung AC, et al. Use of localised intracoronary [beta] radiation in treatment of in-stent restenosis: The INHIBIT randomised controlled trial. Lancet 2002;359:551-557.

6. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697-1703.

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9. Lufft V, Hoogestraat-Lufft L, Fels LM, et al. Contrast media nephropathy: Intravenous CT angiography versus intraarterial digital subtraction angiography in renal artery stenosis-a prospective randomized trial. Am J Kidney Dis 2002;40:236-242.

10. Amols HI, Zaider M, Weinberger J, et al. Dosimetric considerations for catheter-based [beta] and [gamma] emitters in the therapy of neointimal hyperplasia in human coronary arteries. Int J Radiat Oncol Biol Phys 1996;36:913-921.

11. Hall EJ. The physics and chemistry of radiation absorption, in Hall EJ: Radiobiology for the Radiologist. Philadelphia, J.B. Lippincott Co., 1994, ed 4, pp 1-13.

12. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: Six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38-42.

13. Sousa JE, Costa MA, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24-27.

14. Gregory CR, Huie P, Billingham ME, et al. Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury: Its effect on cellular, growth factor, and cytokine response in injured vessels. Transplantation 1993;55:1409-1418.

15. Leon M, Moses J, Popma J, et al. A multicenter randomized clinical study of the sirolimus-eluting stent in native coronary lesions: Angiographic results. Circulation 2002;106(Suppl II):393 (abstract).

16. Stoeteknuel-Friedli S, Do DD, von Briel C, et al. Endovascular brachytherapy for prevention of recurrent renal in-stent restenosis. J Endovasc Ther 2002;9:350-353.

John P. Reilly, MD, Joseph Kaminski, MD, and James B. Summers, MD, MS