Short-Term Outcomes Using a Drug-Coated Balloon for Transplant Renal Artery Stenosis

Background

Transplant renal artery stenosis (TRAS), which is evidenced by refractory hypertension and graft dysfunction, has become an increasingly recognized cause of poor long-term patient and allograft survival [1]. It is reported that the incidence of TRAS ranges from 6% to 23%, depending on the diagnostic criteria, which shows wide variability among reports [2]. The commonly accepted definition of hemodynamically significant TRAS is arterial lumen stenosis greater than 50% and/or a peak systolic velocity (PSV) exceeding 200 cm/s as measured by ultrasound, computed tomography angiography (CTA), and digital subtraction angiography (DSA) [1–3].

The etiological mechanism of TRAS has not been determined. Apart from bend-kink, suture, and donor procurement, intimal hyperplasia, fibrosis or scarring, and immunological disorder are the main risk factors of TRAS [4]. Percutaneous transluminal angioplasty (PTA), alone or using a stent, was accepted as initial therapy for TRAS [4,5]. However, the incidence of restenosis for PTA alone ranges from 15% to 28% [3]. The rate after stenting is reported to be superior to PTA alone, but remains as high as 15% for bare-metal stents (BMS) and 15.7% for drug-eluting stents (DES) [3].

Use of a paclitaxel-coated balloon, inhibiting arterial smooth muscle cell proliferation and migration as well as extracellular matrix formation, has been shown to decrease the intimal hyperplasia and confer increased vessel patency in the treatment of femoral and popliteal arteries [6,7]. Few studies have evaluated the safety and efficiency of drug-coated balloon (DCB) use in patients who undergo endovascular intervention for TRAS. Thus, we present our short/mid-term clinical outcomes in patients with TRAS, using DCBs in transplanted renal arteries.

Material and Methods

OPERATIVE PROCEDURE:

All of the procedures were accomplished in our hybrid operation room by our endovascular team. Under local or general anesthesia, percutaneous access was obtained by femoral puncture. A nonselective angiography was performed preliminarily to confirm TRAS location and rule out iliac obstructive disease. Then, TRAS was crossed using a 0.035 or 0.018 guidewire and appropriate catheters. According to the transplanted renal artery, a DCB (orchid/dahlia, Acotec Scientific Co., Ltd., China) properly sized to cover the TRAS segment, was dilated and maintained for 60 s after pre-dilation with a standard balloon less than 1 mm smaller than the reference diameter of the target artery. Diluted contrast, digital subtraction, and roadmap allowed the minimum usage of iodinate contrast material. A completion angiography was performed to confirm technique success and femoral hemostasis was obtained by using the ProGlide closure system (Abbott, USA). Figure 1 illustrates the endovascular approach.

STATISTICAL ANALYSIS:

Data are expressed as means and ranges. Preoperative and postoperative levels of systolic blood pressure (SBP), Scr, and renal artery peak systolic velocities (PSV) were compared using the paired two-sample t test. Statistical analysis was performed using Prism 6.0 software (GraphPad Software Inc., San Diego, CA). A value of P<0.05 was considered significant.

Results

EARLY OUTCOMES:

The mean serum creatinine level at 1 month after endovascular treatment was 154 μmol/L (range, 89.1–301.2 μmol/L). There was a significant decrease in serum creatinine levels (t=8.9, p<0.0001), and similar results were found in SBP and PSV. The mean SBP at 1 month after the procedure was 144.8 mmHg (range, 136–154 mmHg), which was markedly decreased from the pre-intervention result (t=8.8, p<0.0001). PSV was measured by 2 ultrasound physicians. During the early follow-up, we observed a sharp decrease in PSV (t=7.6, p<0.0001), from 364.1 cm/s (range, 217.6–511.9 cm/s) to 134.9 cm/s (range, 79.8–184.2 cm/s). No acute restenoses or occlusions were detected.

MID-TERM OUTCOMES:

Eleven patients finished mid-term follow-up (>6 months) and the mean follow-up time was 10.1 months. No postoperative deaths occurred. The Scr level in the 11 patients was 135.4 μmol/L (range, 87.7–189.3 μmol/L) at latest follow-up. This result was not significant compared with the early outcome (t=2.2, p=0.06). Three patients had a slightly increased SBP, but the mean level remained at 143.5 mmHg (range, 136–152 mmHg), which was unchanged from the early result (t=1.0, p=032). Neither arterial occlusion nor restenosis needing re-intervention was found at latest follow-up. All of the patients who underwent DCB treatment maintained the patency of transplanted renal arteries. None of the treated patients developed a pseudoaneurysm at the site of treatment at latest follow-up. The mean renal artery PSV was 134.3 cm/s (range, 80.4–183.4 cm/s). Although the results were a bit lower than those of early outcomes, they were not significantly different (t=0, p>0.99 and t=1.6, p=0.13).

Discussion

The findings of this retrospective study indicate that angioplasty of TRAS with DCB is safe and effective. The Scr level, SBP, and renal artery PSV were decreased significantly after the therapy, and the restenosis was maintained at a low rate during follow-up. Our results also demonstrate the DCB can offer a reasonable approach to treating TRAS of ISR, decreasing the need for repeat revascularization.

The etiology of TRAS is not fully understood; however, intimal hyperplasia, fibrosis or scarring, and immunological disorder are thought to be the main risk factors of TRAS [8,9]. In our study, most stenoses were located at the anastomosis or in the proximal portion of the transplant artery, suggesting that intimal hyperplasia caused by intimal injury during suturing or an immune-mediated reaction with donor tissue are the main features of TRAS. An important milestone in percutaneous revascularization was the discovery that local delivery of an antiproliferative agent at the site of the lesion is the most important factor in reducing intimal hyperplasia. For this purpose, attention has turned to the use of DES due to the incidence of restenosis associated with BMS placement. Recent studies have reported that primary stenting with either DES or BMS was a safe and effective therapy for TRAS, but DES conferred no significant advantage in terms of rate of restenosis compared to BMS [4].

Several disadvantages in using a stent as a vehicle were inferred theoretically according to the mechanism of DES. Firstly, drug distribution from stent to arterial wall is inhomogeneous. DES do not cover a large area (75% to 85%) of the vessel wall between stent struts, resulting in low tissue levels of the antiproliferative agent in these areas and incomplete suppression of neointimal hyperplasia [10]. Polymeric matrices on the DES, which control drug release kinetics, can lead to chronic inflammation and thrombosis and these materials can cause delayed and incomplete reendothelialization. Patients are usually required to take long-term dual antiplatelet agents, which is potentially harmful to their transplanted kidneys. In addition, DES is a permanent implant, which can induce neointimal hyperplasia by itself.

In this study, single DCB was used in each patient instead of DES, and satisfactory early and mid-term outcomes were observed. Importantly, the renal artery PSV remained at a reasonable level as shown by the ultrasound examination, which proved the sustained antiproliferative effect of DCB at the stenosis site.

When compared to a DES, a DCB offers several advantages able to overcome all of the drawbacks related to a DES. DCBs can cover the entire lesion site during inflation and homogeneously provide rapid release of a high concentration of drug to the transplanted renal artery wall. At the same time, no polymer-related chronic inflammation is induced by DCB, which potentially decreases the incidence of late thrombosis. Without the presence of a permanent implant stent, the overdependence on antiplatelet therapy, especially dual antiplatelet therapy, can be avoided. In addition, the original arterial anatomy and flow pattern are better maintained using DCB.

Another obviously better beneficial effect offered by DCB is the unique advantage in treating ISR. The lumen re-narrowing continues to occur and represents a challenging clinical problem despite the widespread use of either DES or BMS. Multiple treatment options such as balloon angioplasty, repeat stenting, and debulking have been investigated in patients with femoropopliteal ISR [6,7]. However, there is no established optimal treatment strategy because no single therapy is particularly more effective or superior to others. Fortunately, the DCB has been proved to have superior efficacy in comparison to plain balloon angioplasty with femoropopliteal ISR, providing a new therapy for these patients [6,7]. Instead of atherosclerotic diseases, the mechanism of ISR in the transplanted renal arteries is intimal hyperplasia, which is the direct target of antiproliferative agents. Thus, the DCB theoretically has better clinical results in treating ISR of transplanted renal arteries. In the present study, the 3 ISR cases were all successfully treated and had follow-up periods of 11, 9, and 4 months. Compared to the early results, renal artery PSV were not statistical changed, suggesting that the antiproliferative effect of DCB is a main feature of ISR therapy.

Our study is limited by the small number of included patients, the retrospective process, and the absence of a control group of TRAS patients treated with plain balloons. The small number of subjects is a common problem in most TRAS investigations and is a large obstacle to any potential retrospective or prospective study.

Conclusions

We found the endovascular approach to TRAS with DCB was safe and had a high rate of success. It was an effective treatment to restore and maintain the artery flow and renal function in short-term follow-up. A study with longer follow-up is required to demonstrate the long-term performance of DCB.