1

Case report

An 81-year-old patient suffering from hypercholesterolemia and diabetes from more than 15 years was admitted to our institution because of an acute coronary syndrome after a hypertensive crisis. The medical history of this patient was uneventful except for two previous percutaneous interventions to treat left renal artery stenosis with bare-metal stent implantation and subsequently to treat ISR by cutting balloon angioplasty.

Coronary angiography revealed distal collateralized occlusion of the left anterior descending artery and peripheral angiography showed a diffuse left renal artery subocclusive ISR ( Fig. 1 ), probably contributing to the poor blood pressure control in this patient. The diagnostic catheter was therefore exchanged with a Judkins Right 4 guiding catheter and a 0.014-workhorse guidewire was advanced through the ISR toward a distal branch. A 3/15-mm vascular imaging balloon catheter (VIBE, Volcano, San Diego, CA) was used to perform intravascular ultrasound (IVUS) assessment of the implanted stent that was well expanded and apposed with a diameter of 4.5 mm and significant neointimal proliferation ( Fig. 2 B ) and concurrently predilated the lesion ( Fig. 2 B). Predilation was then improved with a 4.5/15-mm non-compliant balloon. Finally, drug-eluting balloon (DEB) angioplasty was performed with a 4/25-mm DIOR II generation (Eurocor, Bonn, Germany) DEB inflated at 18 atm according to its compliance chart to reach the previously implanted stent diameter ( Fig. 3 ), yielding excellent final angiographic and IVUS results ( Fig. 4 A, B ). No significant increase in serum creatinine was registered. At 6-month follow-up the patient reported stable blood pressure control and renal artery angiography showed patency of the treated vessel ( Fig. 5 ).

Baseline left renal artery angiography showing a severe in-stent restenosis.

Vascular imaging balloon catheter allowing for intravascular ultrasound assessment of the in-stent restenosis showing a well-expanded and well-apposed 4.5-mm diameter stent with significant neointimal proliferation (A) and concurrently pre-dilating the lesion (B).

Drug-eluting balloon angioplasty performed with a 4/25-mm DIOR II generation (Eurocor, Bonn, Germany) balloon inflated at high pressure to reach the previously implanted stent diameter.

Excellent final angiographic (A) and intravascular ultrasound (B) results.

Six-month follow-up left renal artery angiography showing a persisting good result.

2

Discussion

Recurrent renal artery ISR occurs in about one third of cases posing major challenges to treatment . Indeed, in a cohort of 31 patients with a second or further ISR, regular balloon angioplasty and cutting balloon angioplasty were associated with restenosis rates of 71% and 100%, respectively . We report the first case of successful DEB angioplasty in the treatment of recurring renal artery ISR.

Based on positive results of clinical trials on the treatment of coronary ISR, DEB was endorsed as a class IIa (level of evidence B) recommendation for the treatment of ISR by the European Society of Cardiology (ESC) guidelines on myocardial revascularization . The ESC guidelines acknowledge the lack of a class effect and highlighted that the recommendation is valid only for specific devices with proven efficacy/safety profile according to published trials. More, specifically the efficacy of the DIOR balloon in the treatment of ISR has been previously assessed in the Spanish DIOR Registry, which enrolled 250 non-consecutive real-world patients from 10 Spanish centers. Of them, 126 underwent DEB treatment for restenosis of both bare-metal stents ( n = 65) and drug-eluting stents ( n = 61), providing a 12-month rate of major adverse events defined as the composite of cardiac death, myocardial infarction and target lesion revascularization of 9.2% and 14.8%, respectively . Angiographic follow-up was available at 6 months for patients from two centers and showed an overall late lumen loss of 0.31 ± 0.28 mm. Successively, the Valentines Trial showed a 11.1% cumulative rate of major adverse events in a truly real-world population of 250 patient treated with the second-generation DIOR for both bare-metal and drug-eluting stents restenosis .

With its efficacy in the treatment of coronary ISR, implementation of DEB technology for the treatment of renal artery ISR is extremely appealing. Certainly, differences in the local flow pattern and shear stress magnitude influence the ultrastructure of different arteries in the same individual and the progression and composition of atherosclerotic plaques . However, despite that ISR in renal artery continues to occur beyond the 6-month window typically characterizing bare-metal stent restenosis in the coronary circulation, in both vascular territories, ISR appears to depend on a common pathophysiologic mechanism leading to neointimal hypeplasia .

On the other hand, ISR in renal arteries may be characterized by a greater amount of neointima due to the generally larger diameter of these vessels compared to coronary arteries, potentially hampering the efficacy of DEB treatment in vessels with a caliber greater to the average diameter of coronary arteries where this technology has proved to be effective. However, ISR is associated with smaller renal artery diameters thus making this limitation virtually pointless . Also, the excellent results of DEB treatment of ISR involving femoral arteries further support the use of DEB in the treatment of ISR independently from the size of the artery .

The mechanism of action of DEB relies on the rapid and homogenous diffusion of the antiproliferative agent paclitaxel to the vessel wall during a 30- to 60-second inflation without the harm of a new metallic layer . A molecular binder on the surface of the DEB prevents paclitaxel loss during balloon tracking while enhancing drug transfer. The DIOR II generation implements Shellac as a binder, which is a natural bioadhesive polymer. Paclitaxel persists in the vessel wall at an effective concentration for a couple of weeks allowing inhibition of vascular smooth muscle cell proliferation during the period of the biological response to the barotrauma caused by balloon inflation . Precisely, paclitaxel acts by binding to cellular microtubules thus stabilizing their structure between the mitosis’ metaphase and anaphase thus inducing cellular death .

To pursue good long-lasting results, optimal lesion preparation prior to DEB angioplasty is considered crucial. To this aim we used a novel device, namely the VIBE catheter, consisting of a semi-compliant balloon mounted a few millimeters distally to a 20-MHz electronic ultrasound transducer, thus allowing for IVUS-targeted balloon inflation with a single catheter. Moreover, optimal imaging of the implanted stent was also crucial to allow effective DEB angioplasty, since no manufacturer had produced a DEB suitable for typical sizes of renal arteries at the time the case has been performed.