Treatment of In-Stent Restenosis in Patients with Renal Artery Stenosis

Abstract

Purpose:

To determine clinical outcomes of patients treated for renal artery in-stent restenosis (ISR) with atherosclerotic renal artery stenosis.

Materials and Methods:

A retrospective review was performed of the clinical data of all patients who underwent renal artery stent placement for atherosclerotic renal artery stenosis from 1996 to 2009. Medical records of patients were reviewed for relevant clinical history, including blood pressure, antihypertensive medications, and renal function data before and after an intervention. In 1,052 patients, 1,090 renal artery stent placements were performed. Of these, 101 stents in 79 patients developed ISR, which was treated with either percutaneous transluminal angioplasty (PTA) or repeat stent placement. Procedural details, including modality of intervention, stent diameter, and time to restenosis, were recorded. Hypertensive agent and use of statins were recorded. Univariate analysis was performed to identify risk factors associated with restenosis after treatment of ISR.

Results:

Patients treated with repeat stent placement were 6.89 times more likely to lose patency after treatment than patients treated with PTA (P < .01). No additional clinical or procedural factor, including smoking history; presence of cardiac, renal, or metabolic disease; use of statin at time of ISR treatment; or diameter of treatment (stent or PTA), had a significant association with duration of stent or angioplasty patency.

Conclusions:

Treatment of renal artery ISR with PTA among patients with atherosclerotic renal artery stenosis has a lower rate of subsequent ISR compared with repeat stent placement.

Atherosclerotic renal artery stenosis (RAS) is one of the most common causes of secondary hypertension in adults and is an important cause of renal insufficiency (1,2). Treatment options for RAS include medical therapy, surgical reconstruction, and percutaneous revascularization. Stent placement is the preferred method of percutaneous intervention for atherosclerotic RAS (3).

There has been debate over the benefit of percutaneous revascularization for RAS since the Angioplasty and STent for Renal Artery Lesions (ASTRAL) and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trials (4,5). Neither of these randomized prospective studies demonstrated significant benefit when renal artery stent placement was added to medical therapy for RAS. Several limitations have been noted in each of these trials, particularly in terms of their patient enrollment (6-8). Despite the controversy, percutaneous renal artery stent placement should be considered for RAS in cases of unstable angina, pulmonary edema, abrupt congestive heart failure, deteriorating renal function, and hemodynamically significant RAS (9). In these circumstances, renal artery stent placement has been shown to improve hypertension and has a low periprocedural complication rate (10-12).

Major complications or setbacks related to stent placement include artery rupture, dissection, and in-stent restenosis (ISR). Several previously identified risk factors of ISR include smaller vessel diameter, prior treatment of ISR, stent type, and cigarette smoking (13). Understanding predictors and outcomes of ISR treatment is important when selecting the appropriate modality for revascularization. In this study, the clinical outcomes of ISR treatment in patients who initially received stents for atherosclerotic RAS were evaluated, including potential risk factors for additional restenosis events.

MATERIALS AND METHODS

Patient Population

Institutional review board approval was obtained for this retrospective, longitudinal follow-up study. The clinical data of all patients who underwent a procedure for renal artery stent insertion for atherosclerotic RAS between 1996 and 2009 were reviewed for development of restenosis with follow-up ending on December 20, 2015. After intervention, the medical record for each patient was reviewed up to the most recent follow-up visit for clinical history, including blood pressure, antihypertensive medications, use of statins, diabetes, vascular disease, dyslipidemia, smoking history, and renal function before and after the intervention. Procedural details, including modality of intervention, stent diameter, and time to restenosis, were recorded.

During the study period, 1,090 renal artery stents were placed in 1,052 patients. Average patient age was 73.6 years ± 8.3. In 79 patients, 101 stents developed ISR, and the patients underwent either repeat stent placement or percutaneous transluminal angioplasty (PTA). Repeat stent placement was performed with either a balloon-expandable bare metal stent (BMS) or a drug-eluting stent (DES). All 101 stents used in the index procedure were BMSs.

Diagnosis of ISR after the index procedure was made with duplex ultrasound (91%), computed tomography angiography (1%), or conventional angiography (8%). ISR was defined as peak systolic velocity of > 300 cm/s or renal-to-aortic ratio > 3.5 on duplex ultrasound or luminal stenosis > 50% on computed tomography angiography or conventional angiography. All cases of significant ISR were treated with a repeat revascularization procedure. All such cases were diagnosed with duplex ultrasound using the same criteria used to diagnose the initial in-stent lesions. Baseline characteristics of patients are summarized in Table 1.

Table 1.

Patient Characteristics

Characteristic	PTA (n = 62)	BMS (n = 33)	DES (n = 6)	Total (N = 101)	P
Sex, no. (%)
Female	30 (48.4)	21 (63.6)	3 (50.0)	54 (53.5)	.383
Male	32 (51.6)	12 (36.4)	3 (50.0)	47 (46.5)
Age, y, mean (SD)	71.0 (8.3)	66.6 (8.3)	73.6 (8.3)	69.7 (8.5)	.029
Bilateral RAS, no. (%)	33 (56.9)	18 (62.1)	3 (60.0)	54 (58.7)	.935
GFR category, no. (%) (mL/min/1.73 m2)
GFR 1–3a (≥45)	25 (40.3)	15 (45.5)	1 (16.7)	41 (40.6)	.476
GFR 3b–4 (15–44)	37 (59.7)	18 (54.5)	5 (83.3)	60 (59.4)
Smoking status, no. (%)
Former	49 (84.5)	25 (78.1)	4 (66.7)	78 (81.3)	.151
Current	9 (15.5)	6 (18.8)	1 (16.7)	16 (16.7)
Diabetes, no. (%)	26 (41.9)	9 (27.3)	2 (33.3)	37 (36.6)	.401
Carotid artery disease, no. (%)	36 (58.1)	15 (45.5)	3 (50.0)	54 (53.5)	.510
Coronary artery disease, no. (%)	38 (61.3)	18 (54.5)	4 (66.7)	60 (59.4)	.797
Peripheral artery disease, no. (%)	50 (82.0)	25 (75.8)	5 (83.3)	80 (80.0)	.189
Hyperlipidemia, no. (%)	54 (87.1)	27 (84.4)	5 (83.3)	86 (86.0)	.901
Blood pressure medications, mean (SD)	3.0 (1.1)	2.6 (1.3)	3.3 (1.0)	2.9 (1.2)	.145

BMS = bare metal stent; DES = drug-eluting stent; GFR = glomerular filtration rate; RAS = renal artery stenosis.

PTA or Stent Placement

Three board-certified interventional radiologists (S.M., M.A.M., H.B.) performed renal artery PTA and/or stent placement. After initial treatment with PTA, if the patient did not have residual stenosis of > 30% on a follow-up angiogram or a mean pressure gradient of < 10 mm Hg measured simultaneously or pullback gradient, the patient received no further treatment. If there was an unsatisfactory PTA result, a bare metal balloon expandable stent such as a Herculink (Abbott Vascular, Abbott Park, Illinois) was used. In a small group of patients, a DES was used.

Blood pressure, creatinine, antihypertensives, and statin medications were documented before and after the procedure. Blood pressure medications were maintained until the day of the procedure. Stent and PTA diameters were recorded.

Measured Outcomes

The primary outcome was the need for reintervention for recurrent ISR. The duration of patency for the intervention was defined as the time between the first treatment for ISR and the date of the second reintervention. Secondary endpoints included changes in blood pressure, antihypertensive medication, and serum creatinine after treatment; time to restenosis by intervention; and duration of patency based on modality of intervention. Additionally, cardiac and metabolic disease and smoking history were analyzed as possible contributing factors for ISR. Mortality within 30 days of intervention was determined from the medical record.

Statistical Analysis

Statistical analysis was performed with SAS version 9.4 (SAS Institute Inc, Cary, North Carolina). Comparisons were made between normally distributed continuous variables with the Student paired t-test. Patient baseline characteristics were compared using Fisher exact and Kruskal-Wallis tests. Univariate Cox regression analysis was performed to identify risk factors associated with restenosis after treatment of ISR. Statistical significance was defined as P < .05. Kaplan-Meier analysis was used to determine the duration of renal artery stent patency after PTA or repeat stent placement for ISR.

RESULTS

Of 1,090 renal artery stents placed between 1996 and 2009 for atherosclerotic RAS, 101 stents developed ISR. Median follow-up duration was 5.1 years. Bilateral ISR was identified and treated in 27.8% of patients. New stents were placed in 39 renal arteries with ISR; 6 of the arteries received a DES. PTA was performed on the remaining 62 renal arteries. Stent size and ISR rates are shown in Table 2.

Table 2.

Number of Interventions Performed for First ISR Event after Index Procedure and Rate of Subsequent ISR Requiring a Third Procedure

	No. Treated ISR Cases (N = 101)	Rate of Second ISR, no. (%)
PTA*	62	3 (4.8)
PTA diameter ≤ 5 mm	35	2 (5.7)
PTA diameter > 5 mm	25	1 (4.0)
BMS*	33	10 (30.3)
Stent diameter ≤ 5 mm	13	6 (46.2)
Stent diameter > 5 mm	17	4 (23.5)
DES	6	0
Stent diameter ≤ 5 mm	5	0
Stent diameter > 5 mm	1	0

BMS = bare metal stent; DES = drug-eluting stent; ISR = in-stent restenosis.

^*Diameter not available for all procedures.

Renal arteries with ISR treated with repeat stent placement were 6.89 times more likely to develop restenosis requiring a repeat procedure compared with arteries treated with PTA (P < .01). None of the arteries that received a DES during repeat stent placement developed significant restenosis. The 2-year patency rate of the second stent was 72% and of the PTA was 94% (SE < 0.1). The Figure shows the Kaplan-Meier event-free survival curves for the 3 treatment groups.

Figure.

Kaplan-Meier reintervention-free survival curves for the 3 treatment groups. No restenosis events occurred in the DES group. Stent = bare metal stent.

The mean systolic blood pressure (SBP) among patients who developed ISR before reintervention was 149.3 mm Hg ± 22.9. After ISR treatment, the mean SBP within 1 month decreased to 133.7 mm Hg ± 22.5. The mean diastolic blood pressure before and after ISR intervention was 70.5 mm Hg ± 12.9 and 63.1 mm Hg ± 13.8, respectively. There was a statistically significant decrease in both SBP and diastolic blood pressure after reintervention (P < .001 and P < .001).

No statistically significant change in the number of blood pressure medications was seen after ISR treatment (P = .959). Similarly, no statistically significant change in serum creatinine was seen before (1.7 mg/dL ± 0.8) or after (1.6 mg/dL ± 0.6) renal artery revascularization (P = .126).

Of the 101 (12.9%) renal arteries treated for ISR, 13 developed a secondary ISR. Univariate analyses of predictors of recurrent ISR are shown in Table 3. No significant difference was observed in baseline renal function, blood pressure, or medications. Two patients had bilateral recurrent ISR: 1 patient with prior bilateral stents in arteries and 1 patient with prior PTA on 1 side and stent on the other. In the latter patient, the side treated with PTA developed recurrent ISR after 14.7 months, whereas the side with a stent developed restenosis after 119.9 months.

Table 3.

Univariate Analysis of Predictors of Recurrent ISR after Initial Treatment of ISR

	Hazard Ratio	Lower 95% CI	Upper 95% CI	P
Male sex	0.53	0.16	1.74	.296
Current smoker	0.95	0.21	4.35	.945
Diabetes	0.36	0.08	1.63	.184
Coronary artery disease	0.61	0.20	1.82	.375
Peripheral artery disease	1.38	0.31	6.25	.675
Chronic renal insufficiency	0.86	0.19	3.86	.838
Hyperlipidemia	1.95	0.25	15.17	.523
Statin use	3.82	0.50	29.42	.200
Stent diameter > 5 mm	0.85	0.27	2.51	.776
BMS	6.89	1.89	25.21	.004

BMS = bare metal stent; CI = confidence interval; ISR = in-stent restenosis.

Complications related to ISR treatment occurred in 6 patients. There were 3 cases of renal artery dissection, 1 case of femoral artery dissection, and 2 cases of renal artery rupture. Both cases of artery rupture occurred in the PTA group. Four patients died within 1 year of ISR revascularization. Of these, 1 patient died within 30 days of intervention secondary to renal artery rupture with retroperitoneal hemorrhage. The remaining 3 patients died of causes unrelated to their procedures.

DISCUSSION

ISR is a serious potential setback with renal artery stent placement in patients with atherosclerotic RAS. When a stent is inserted in an artery, the internal elastic lamina becomes disrupted. This results in smooth muscle cell migration and intimal hyperplasia. These intimal lesions incorporate atherosclerotic elements leading to ISR (9,13,14). Intractable hypertension and renal insufficiency may arise secondary to ISR (15). Therefore, understanding the potential benefits and complications of ISR treatment is important for good clinical outcomes. Hypertension associated with ISR in the present cohort was effectively treated with revascularization. The average SBP was reduced to < 140 mm Hg after treatment of ISR. However, no significant change in the number of blood pressure medications was observed. Other studies demonstrated a significant reduction in the mean number of antihypertensive medications (16), including a study by Stone et al (17) in which 30% of patients who underwent percutaneous ISR treatment had a reduction in the number of blood pressure medications. Although speculative, a change in the number of blood pressure medications in the present cohort would be unlikely once blood pressure control was achieved after revascularization, unless subsequent hypotension were to develop.

RAS, including ISR, is an important cause of renal insufficiency. After ISR treatment, serum creatinine levels did improve, but by a statistically nonsignificant degree. There is no consensus regarding renal function outcomes after ISR revascularization. Prior studies have demonstrated varying results with improved, unchanged, or worsened renal function. Generally, similar nonsignificant improvements in creatinine or glomerular filtration rate were seen (18-21), whereas patients with poor initial renal function tended to progress to end-stage renal disease (22,23). With a nonsignificant decrease in the mean creatinine level during follow-up, it is suggested that revascularization halted the progression of renal insufficiency.

Although PTA can effectively treat ISR in most cases, previous studies have reported higher rates of ISR recurrence with PTA versus BMS with rates of 37% among PTA groups (17,24,25). Furthermore, patients who underwent PTA tended to develop restenosis more quickly than patients treated with BMS (26,27). In contrast, patients in the present study who were treated with BMS were nearly 7 times more likely to develop a secondary ISR compared with patients who underwent PTA. No additional significant risk factor for recurrent ISR was identified. The cause of the lower success rate with BMS is unclear. However, one could postulate that patients who developed ISR may have a propensity for restenosis with subsequent stent placement. Also, despite higher restenosis rates in the BMS cohort, the overall rate of recurrent ISR in this group was approximately 10% (10 of 101), lower than what was reported in other studies (16,17,25,27). Similar to the prior studies, renal arteries that received PTA developed ISR earlier than arteries that received a stent.

The need for repeat revascularization has significantly decreased with the advent of DESs, which are coated with drugs such as sirolimus or paclitaxel to counteract the progression of vessel remodeling and intimal hyperplasia (28,29). However, according to the literature, 42% of DESs placed for atherosclerotic RAS developed restenosis out to 58 months of follow-up with 25% requiring reintervention (17,26). The Palmaz Genesis Peripheral Stainless Steel Balloon Expandable Stent, Comparing a Sirolimus Coated Versus an Uncoated Stent in REnal Artery Treatment (GREAT) trial compared the outcomes of the sirolimus-eluting stent (SES) with BMS. In the study, 105 subjects were randomly assigned to SES and BMS treatment groups. The patients in the SES group had greater systolic and diastolic blood pressure reduction at 6 months (P < .01). The 6-month and 1-year target lesion revascularization rates were not significantly different with rates of 7.7% and 11.5%, respectively, in the BMS group versus 1.9% in the SES group at both time points (30,31). None of the patients treated with DES developed a secondary ISR requiring revascularization. However, with only 6 patients receiving DES, the subgroup analysis is limited.

Endovascular brachytherapy (EVBT) may also significantly reduce the rate of ISR. Although EVBT was not used in the study, a retrospective report by Silverman et al (32) demonstrated that 22 of 23 renal stents treated with EVBT for ISR remained patent with an average follow-up time of 43.9 months. Furthermore, SBP significantly improved at follow-up.

The stent or PTA diameter did not have a statistically significant association with renal artery patency. However, there tended to be fewer cases of restenosis with stents or PTA diameters > 5.0 mm. Other studies also found that stent diameter was not a significant predictor of recurrent ISR events, although a similar trend can be seen with increasing vessel diameter related to decreased ISR (22,26,33). One study by Lederman et al (34) found a significant decrease in ISR among renal arteries with diameters > 6.0 mm compared with diameters < 4.5 mm, but no significant difference between vessel diameters > 6.0 mm versus 4.5–6.0 mm.

In the present study, the overall rates of initial and secondary interventions for ISR were similar (9.3% vs 12.9%). Simone et al (16) demonstrated comparable findings with a nonsignificant difference between primary and subsequent intervention rates. However, other studies showed that patients who were treated for ISR required a repeat procedure approximately 21%–33% of the time (17,25). Ndoye Diop et al (33) showed that the overall rates of restenosis requiring reintervention were 25% at 6 months, 38.8% at 1 year, and 55.6% after 1 year.

Corriere et al (35) investigated the influence of use of statins at the time of initial treatment of de novo RAS on outcomes of restenosis. They observed that patients who were taking statins before renal artery stent placement had decreased restenosis rates compared with patients who were not taking statins. In the present study, the role of statins before the ISR treatment procedure in reducing a subsequent restenosis was determined. There were 80 stent or PTA procedures in patients who were taking statins when treatment of ISR occurred. Compared with patients not receiving statins, there were no differences in outcomes of repeat ISR.

Complications related to ISR revascularization occurred in 6 patients, including 2 cases of renal artery rupture. There is a paucity of data in the literature on renal artery rupture rates after ISR treatment. Both cases of rupture occurred in the PTA cohort, but an analysis of contributing factors is limited given the small sample size. There were 2 ruptures. Both patients were treated with 2-cm-long balloons. There was no “watermelon seed” effect observed in either procedure. One patient was treated with a balloon 5 mm × 2 cm long. This patient developed a retroperitoneal hematoma, which was treated the same day using a Jomed stent (Abbott Vascular) under a human investigational device exemption. The patient was doing fine after the procedure; however, she died 2 days later while in the hospital. The second patient had a rupture after using a 7-mm balloon. This was treated with prolonged inflation, and the patient recovered. This patient died 4 years later. In the present study, the rate of renal artery dissection is similar to the reported literature (16).

This study has a few limitations. The study was nonrandomized and retrospective. As a result, follow-up did not occur at regular intervals, medical therapy was not standardized, and data collection was incomplete resulting in the exclusion of a few patients. Moreover, patient selection and interventions were performed by several different operators, which may have resulted in introduction of unforeseen bias. Lastly, only a small subset of patients developed a second ISR across the 3 different treatment methods. Thus, identification of factors that influence restenosis in these patients is limited. However, the present article consists of all cases of percutaneous interventions for atherosclerotic RAS over a 13-year period, and this population size is one of the largest published to date with regard to recurrent renal artery ISR. A larger prospective trial following a standard protocol with longer consistent follow-up could be beneficial for validating these results.

In conclusion, patients treated with BMS for renal artery ISR were 6.89 times more likely to develop restenosis requiring reintervention compared with patients who underwent PTA. No patient treated with DES developed restenosis during follow-up, although there were only 6 cases in this cohort. Multiple factors may influence the treatment choice for ISR. Risks and benefits should be taken into account when considering BMS for ISR interventions; however, newer technologies such as DES may reduce subsequent restenosis rates.

ABBREVIATIONS

BMS

bare metal stent

DES

drug-eluting stent

EVBT

endovascular brachytherapy

ISR

in-stent restenosis

RAS

renal artery stenosis

SBP

systolic blood pressure

SES

sirolimus-eluting stent