Endovascular management of atherosclerotic renovascular disease: Early results following primary intervention
Article Outline
Objective
This retrospective review examines periprocedural morbidity and early functional responses to primary renal artery angioplasty and stenting (RA-PTAS) for patients with atherosclerotic renovascular disease (RVD).
Methods
Consecutive patients undergoing primary RA-PTAS for hemodynamically significant atherosclerotic RVD with hypertension and/or ischemic nephropathy were identified from a prospectively maintained registry. Hypertension responses were determined based on pre- and post-intervention blood pressure measurements and medication requirements. Estimated glomerular filtration rate (eGFR) was used to determine renal function responses. Both hypertension and renal function responses were assessed at least three weeks after RA-PTAS. Stepwise multivariable regression analysis was used to examine associations between blood pressure and renal function responses to RA-PTAS and select clinical variables.
Results
One-hundred ten primary RA-PTAS were performed on 99 patients with atherosclerotic RVD with a mean angiographic diameter-reducing stenosis of 79.2 ± 12.9%. All patients had hypertension (mean of 3.4 ± 1.3 antihypertensive agents). Mean pre-intervention eGFR was 49.9 ± 22.7 mL/min/1.73 m2, and 74 patients had a pre-intervention eGFR < 60 mL/min/1.73 m2. The technical success rate for RA-PTAS was 94.5%. The periprocedural complication rate was 5.5%; there were no periprocedural deaths. Statistically significant decreases in mean systolic blood pressure (161.3 ± 25.2 vs. 148.5 ± 25.2 post-intervention, P < .0001), diastolic blood pressure (78.6 ± 13.3 versus 72.5 ± 13.5 post-intervention, P < .0001), and number of antihypertensive agents (3.3 ± 1.2 versus 3.1± 1.3 post-intervention, P = .009) were observed. Assessed categorically, hypertension response to RA-PTAS was cured in 1.1%, improved in 20.5%, and unchanged in 78.4%. Categorical eGFR response to RA-PTAS was improved in 27.7%, unchanged in 65.1%, and worsened in 7.2%. Multivariable stepwise regression revealed associations between pre- and post-intervention systolic blood pressure (P < .0001), diastolic blood pressure (P < .0001), and eGFR (P < .0001), as well as a trend toward improved diastolic blood pressure response among patients managed with staged bilateral intervention (P = .0589).
Conclusion
Primary RA-PTAS for atherosclerotic RVD was associated with low peri-procedural morbidity and mortality but only modest early improvements in blood pressure and renal function. Results from ongoing prospective trials are needed to assess the long term outcomes associated with RA-PTAS and clarify its role in the management of atherosclerotic RVD.
Severe secondary hypertension and ischemic nephropathy due to atherosclerotic renovascular disease (RVD) are associated with increased risk for both adverse cardiovascular events and all-cause mortality.1, 2, 3, 4 Medical management of hypertension, hyperlipidemia, and associated risk factors is appropriate initial management of atherosclerotic RVD, but some patients exhibit uncontrolled hypertension and/or progressive decline in renal function despite medical therapy. Although several retrospective cohort series have reported favorable blood pressure and renal function outcomes associated with RA-PTAS,5 randomized trials published to date have been heterogeneous in terms of their procedural management and have reported mixed results that do not uniformly favor endovascular management of RVD.6, 7, 8 In spite of the limitations of existing evidence, percutaneous renal artery angioplasty and stenting (RA-PTAS) has become the most commonly utilized form of management for patients with atherosclerotic RVD requiring procedural intervention. Correspondingly, the frequency with which this procedure is performed in the United States has risen dramatically in recent years.9, 10 Increasing utilization of RA-PTAS has been accompanied by scrutiny of the evidence supporting its role in the management of atherosclerotic RVD. A comparative effectiveness review by the Agency for Healthcare Research and Quality concluded that there was insufficient evidence to support one treatment approach over another,11 prompting the Centers for Medicare and Medicaid Services to examine application of this procedure through both a national coverage analysis and an evidence development and coverage advisory committee.12, 13
While eagerly awaiting the results of ongoing clinical trials evaluating RA-PTAS,14 this retrospective report describes the results from our own center. The objectives of this retrospective study were: 1) to examine the periprocedural morbidity and mortality associated with primary RA-PTAS for atherosclerotic RVD; 2) to evaluate early blood pressure and renal function responses to RA-PTAS; and 3) to examine clinical and anatomic factors associated with procedural outcomes. Based on previous investigations, we hypothesized that completeness of repair (ie, treatment of all hemodynamically significant disease), increased pre-intervention serum creatinine, employment of distal renal artery balloon occlusion, and use of antiplatelet medications would influence blood pressure and/or renal function responses in a favorable fashion.15, 16, 17
Methods
Study population
This retrospective investigation was conducted with approval from the Wake Forest University Health Sciences Institutional Review Board. Consecutive patients undergoing primary RA-PTAS for hemodynamically significant atherosclerotic renovascular disease (defined pre-intervention as ≥60% diameter-reducing stenosis by duplex ultrasonography) performed by vascular surgeons at the Wake Forest University Baptist Medical Center from October 2003 through September 2007 were identified from a prospectively maintained database. All treated patients had hypertension with or without associated ischemic nephropathy. RA-PTAS performed for fibromuscular dysplasia or recurrent renal artery stenosis were excluded from analysis.
Interventional management
All RA-PTAS were performed in an endovascular operating suite as previously described.18 All patients underwent pre-intervention intravenous hydration with normal saline (patients with pre-intervention eGFR > 30 mL/min/1.73 m2) or sodium bicarbonate (patients with pre-intervention eGFR ≤ 30 mL/min/1.73 m2) and received four 600 mg doses of N-acetylcysteine every twelve hours beginning 24 hours before RA-PTAS. Patients with bilateral RAS were managed according to clinical response to unilateral RA-PTAS (improved blood pressure control and/or eGFR). When logistically feasible within the overall clinical plan of care, patients requiring intervention for bilateral renal artery lesions were managed in a staged fashion to minimize contrast volume per procedure and to reduce the potential for bilateral ischemic renal complications.
Procedures were performed using percutaneous femoral or open brachial 6F sheath access followed by systemic heparin anticoagulation. Iodixanol (Visipaque, Amersham Health, Princeton, NJ) diluted 1:1 with normal saline was the arterial contrast medium of choice, and carbon dioxide utilized as an alternative or adjunct in the setting of severely compromised renal function and/or history of allergy to iodinated contrast media. Renal artery cannulation was performed using a minimal contact technique, with ostial engagement using an angled guide catheter. Lesion predilation prior to angioplasty and stenting was performed at the discretion of the operating surgeon. RA-PTAS were performed with balloon-mounted stents sized to match the renal artery distal to the stenotic lesion. Stents were positioned to completely cover the stenoses and, in the setting of ostial lesions, to extend 1-2 mm into the aortic lumen following deployment.
When distal renal artery balloon occlusion was utilized as a protective measure prior to RA-PTAS, initial crossing of the stenotic renal artery lesion was performed with a commercially available 0.014” balloon-tipped guidewire (Guardwire, Medtronic, Minneapolis, Minn). After passing the stenotic lesion, the distal occlusion balloon was inflated and distal renal artery occlusion confirmed by hand injection of contrast. Following RA-PTAS, the static column of blood between the treated lesion and occlusion balloon was evacuated using a rapid exchange catheter (Export Catheter, Medtronic, Minneapolis, Minn). After aspirating 40-60 ml of blood, the renal artery was then irrigated with 20-60 ml of heparinized saline prior to deflation of the occlusion balloon and completion angiography.
Patients were routinely treated with pre-operative aspirin and discharged within 24 hours following RA-PTAS on combinationoral antiplatelet therapy (aspirin plus clopidogrel). Post-intervention outpatient follow up (including clinical evaluation, renal artery duplex ultrasound, blood pressure measurement, and serum creatinine) was routinely performed at four weeks, six months, and then annually.
Data collection and management
Data were collected from the hospital, outpatient clinic, and clinical vascular laboratory records. Electronically archived renal angiography images were measured using computer software, and percent renal artery stenosis by angiography was determined by measuring the smallest luminal diameter of the point of maximal stenosis and comparing it with the lumen of the distal main renal artery. Blood pressure and renal function outcomes were assessed based on the first post-intervention data available at three or more weeks following RA-PTAS in order to minimize the influences of peri-procedural contrast administration and intravascular volume expansion.
Bilateral brachial systolic and diastolic blood pressures were recorded in the outpatient Vascular Clinic with patients in the seated position using an oscillometer (Vital Signs 300, Welch Allyn, Beaverton, Ore). Measured blood pressures from the outpatient visit prior to RA-PTAS and the first outpatient follow up visit three or more weeks following RA-PTAS were used for evaluation of early blood pressure response to intervention. Categorical hypertension response to RA-PTAS was graded as cured, improved, or failed using a combination of blood pressure and number of antihypertensive agents required for hypertension management before versus after intervention as previously described.19 Patients' self-reported highest known blood pressure was also recorded as a descriptive indicator of hypertension severity, but only measured blood pressure was used to evaluate clinical response to RA-PTAS. History of hypertensive emergency was defined as history of inpatient hospitalization for management of severe hypertension associated with target organ damage including pulmonary edema, hypertensive encephalopathy, acute coronary syndrome, and acute renal failure.20
Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula:21 eGFR/1.73 m2 = 186 × (Serum Creatinine)−1.154 × (Age)−0.203 × (0.742 if female) × (1.210 if African American). Post-intervention renal function was categorized as improved or worsened based on a ≥20% increase or decrease in eGFR, respectively, and otherwise categorized as unchanged.
Preoperative identification of hemodynamically significant renal artery stenosis was performed with duplex ultrasound using previously described criteria.22 Procedural technical success was defined as RA-PTAS of the intended lesion with a residual diameter-reducing stenosis of ≤30% on completion angiography and absence of hemodynamically significant stenosis defined as main renal artery peak systolic velocity <180 cm/s on completion renal duplex ultrasonography. Staged bilateral RA-PTAS were treated as a single intervention for analysis of blood pressure and renal function outcomes, while both staged RA-PTAS procedures were analyzed individually for description of procedure-related technical success and complications. Distal renal artery balloon occlusion during RA-PTAS was defined as complete if no distal flow was identifiable on post-inflation angiography, incomplete if ongoing branch or accessory renal artery flow was observed, and failed if no significant renal artery occlusion was achieved. Treatment of renal artery stenosis was considered complete in patients with duplex-defined hemodynamically significant unilateral disease undergoing unilateral repair or patients with bilateral disease undergoing bilateral RA-PTAS, and incomplete in patients with bilateral disease treated with unilateral RA-PTAS. Peri-procedural complications were defined as procedure-related complications occurring within the first 30 days following RA-PTAS.
Statistical methods
Descriptive statistics are reported as mean ± standard deviation for continuous measures and count (percent) for categorical factors. Blood pressure, antihypertensive agent, and renal function outcomes following RA-PTAS were assessed with paired t tests; an alpha level of ≤.05 was considered statistically significant. Associations between clinical or procedural predictors of blood pressure and eGFR response to RA-PTAS were examined using multivariable linear regression models. A “best” model for each outcome was selected using a stepwise selection approach where candidate variables with P-values ≤.10 were entered one at a time in order of descending significance and retained if they remained significant in the multivariable model at the .10 level following entry. Model residuals were examined after the selection process to evaluate fit and examine influential observations. All statistical analyses were performed using SAS software, version 9 (SAS Institute, Cary, NC).
Results
From October 2003 through September 2007, 144 RA-PTAS were performed on 133 patients by the Vascular and Endovascular Surgery Section at our center. One-hundred ten primary RA-PTAS procedures performed for atherosclerotic renovascular disease on 99 of these patients form the basis this report (Table I). Mean patient age was 69 ± 10 years (range, 40-88 years). Of the patients, 87.9% were Caucasian, and 51.5% were female. All patients had hypertension (measured mean blood pressure 161.1 ± 26.0/78.3 ± 13.1) and were on a mean of 3.4 ± 1.3 antihypertensive medications prior to intervention. Fourteen patients (14.1%) had a previous inpatient hospitalization for management of a hypertensive emergency. Mean serum creatinine was 1.5 ± 0.6 mg/dL (range, 0.6-3.6 mg/dL) and mean eGFR was 49.9 ± 22.7 mL/min/1.73 m2 (range, 15.8-152.2 mL/min/1.73 m2). Seventy-four patients (74.7%) had a pre-intervention eGFR ≤ 60 mL/min/1.73 m2. No patients were dialysis dependent prior to intervention. Comorbid conditions included coronary artery disease (44.4%), cerebrovascular disease (31.3%), and diabetes (30.3%). Among patients with two kidneys, 33 (42%) had bilateral, hemodynamically significant renal artery stenosis by pre-intervention duplex ultrasound. Of the 99 patients, 74 were taking antiplatelet agents at the time of initial evaluation for RA-PTAS, including aspirin alone in 50 patients, clopidogrel alone in six patients, and aspirin plus clopidogrel in 18 patients.
Table I. Descriptive statistics for patients undergoing primary renal artery angioplasty and stenting (N = 99)
| N (%) | Mean ± SD | |
|---|---|---|
| Age (years) | 69.1 ±10.0 | |
| Caucasian race | 87(87.9) | |
| Female gender | 51(51.5) | |
| Weight (kg) | 76.1±15.4 | |
| Highest known SBP (mm Hg)† | 201.3±28.3 | |
| Highest known DBP (mm Hg)† | 101.7±22.2 | |
| Renal artery PSV (cm/s) | 268.3±99.6 | |
| Significant contralateral RAS⁎ | 33(41.8) | |
| Antihypertensive agents | 3.4±1. | |
| Serum creatinine (mg/dL) | 1.5±0.6 | |
| eGFR⁎⁎ (mL/min/1.73 m2) | 49.9±22.7 | |
| Renal insufficiency (eGFR) | ||
| None (eGFR > 60) | 25(25.3) | |
| Moderate (eGFR 30-60) | 59(59.6) | |
| Severe (eGFR < 30) | 15(15.2) | |
| Ischemic nephropathy (Cr ≥ 1.8) | 34(34.3) | |
| Diabetes | 30(30.3) | |
| Any cerebrovascular disease | 31(31.3) | |
| Stroke | 27(27.3) | |
| TIA | 4(4.0) | |
| Any cardiac disease | 60(60.6) | |
| Coronary artery disease | 44(44.4) | |
| Angina | 5(5.1) | |
| Coronary intervention | 26(26.3) | |
| LVH | 35(35.4) | |
| COPD | 14(14.1) | |
| Smoking | ||
| Current | 25(25.2) | |
| Former | 46(46.5) | |
| Hypertensive emergency | 14(14.1) | |
| Resistive Index⁎⁎ | 0.75±0.08 | |
| Resistive Index ≥ 0.8⁎⁎ | 23(24.7) | |
| Abdominal aortic aneurysm | 6(6.1) | |
| Preoperative medications | ||
| Aspirin | 68(68.7) | |
| Clopidogrel | 24(24.2) | |
| Statin | 58(58.6) | |
| Fibrate | 5(5.1) |
⁎Significant contralateral renal artery stenosis defined as peak systolic velocity ≥180 cm/s on preoperative duplex ultrasound. |
⁎⁎Resistive Index from the side with the higher B-Segment primary renal artery angioplasty and stenting. |
†Highest known blood pressure values prior to intervention. |
Table II summarizes procedural data (N = 110). The technical success rate for RA-PTAS was 94.5%. Six technical failures occurred in five patients and were related to inability to establish ostial engagement in one case, and a residual post-intervention stenosis in five cases. All patients designated as technical failures due to residual stenosis were identified by completion duplex ultrasonography; in contrast, completion angiography identified residual stenosis greater than 10% in only three patients, none of whom had residual lesions >30% by angiography. Prior to RA-PTAS the mean diameter-reducing renal artery stenosis was 79.2 ± 12.9%, and stents were placed in 108 procedures (98.1%). Eighty-six (86.9%) RA-PTAS were unilateral, while 11 (11.1%) of 99 were staged bilateral interventions; two patients (2.0%) underwent bilateral RA-PTAS at the same procedural setting. Renal artery stenosis was treated in an incomplete fashion (unilateral intervention in the setting of bilateral disease) in 21 patients (21.2%) and a complete fashion in 73 patients (73.7%); five patients whose contralateral renal artery was not adequately assessed on pre-intervention duplex ultrasound due to technical limitations could not be categorized in terms of completeness of treatment. Fifteen patients had RA-PTAS performed to a single functioning kidney with either contralateral renal artery occlusion or previous nephrectomy. A mean volume of 58.4 ± 34.1 mL of arterial contrast was used per procedure, and mean fluoroscopy time was 9.5 ± 7.3 minutes. One hundred RA-PTAS (90.9%) had distal renal artery balloon occlusion attempted for protection from procedure-related atheroembolism. Among these, renal artery occlusion was complete in 74, partial in 22, and failed in four.
Table II. Descriptive statistics for RA-PTAS procedures (N=110)
| N (%) | Mean ± SD | Minimum | Maximum | |
|---|---|---|---|---|
| Pre-intervention stenosis (%) | 79.2±12.9 | 55.0 | 98.0 | |
| Renal artery diameter (mm) | 5.6±1.3 | 3.3 | 8.8 | |
| Stent diameter (mm) | 5.7±0.8 | 4.0 | 7.0 | |
| Stent length (mm) | 16.2±3.1 | 12.0 | 24.0 | |
| Renal stent/artery diameter ratio (%) | 105.7±21.5 | 69.0 | 181.8 | |
| Stent placed | 108(99.1) | |||
| Predilation prior to stenting | 14(12.7) | |||
| Distal Protection | ||||
| Attempted | 100(90.9) | |||
| Complete (% of attempted) | 74(74.0) | |||
| Partial (% of attempted) | 22(22.0) | |||
| Failed (% of attempted) | 4(4.0) | |||
| Balloon occlusion time (minutes) | 15.1±5.9 | 8.0 | 35.0 | |
| Staged treatment of bilateral RAS⁎ | 11(11.1) | |||
| Contrast volume (mL) | 58.4±34.1 | 9.0 | 156.0 | |
| Fluoroscopy time (minutes) | 9.5±7.3 | 2.7 | 41.6 |
⁎RAS, renal artery stenosis defined as peak systolic velocity >180 cm/s: denominator for staged treatment is 99 (complete procedures). |
There were no peri-procedural deaths. Peri-procedural complications were associated with six out of 110 procedures (5.5%). Four of six peri-procedural complications were access site-related: one retroperitoneal hematoma, one inguinal hematoma associated with hypotension, one brachial hematoma, and one femoral artery pseudoaneurysm. One peri-procedural myocardial infarction occurred in a patient who required coronary artery bypass and subsequently developed acute renal failure requiring hemodialysis. An additional patient experienced post-intervention hypotension attributed to a protamine reaction and required overnight observation in the intensive care unit.
Table III shows mean blood pressure and renal function responses following RA-PTAS. Eighty-eight patients had post-intervention blood pressure data and 83 patients had serum creatinine data available for analysis at three or more weeks following RA-PTAS, and the median interval between intervention and early follow up was 9.4 weeks. Statistically significant decreases in mean systolic blood pressure (161.3 ± 25.2 pre-versus 148.5 ± 25.2 post-intervention, P < .0001), diastolic blood pressure (78.6 ± 13.3 pre-versus 72.5 ± 13.5 post-intervention, P < .0001), and number of antihypertensive agents (3.3 ± 1.2 pre-versus 3.1 ± 1.3 post-intervention, P = .009) were observed. Categorical hypertension response to RA-PTAS was cured in one patient (1.1%), improved in 18 (20.5%), and unchanged in 69 (78.4%). Serum creatinine decreased from 1.6 ± 0.6 pre-intervention to 1.5 ± 0.6 post-intervention (P = .0113). A corresponding statistically significant increase in eGFR was also observed (46.8 ± 17.3 pre-intervention versus 50.2 ± 19.7 post-intervention P = .0114). Based on a ≥20% change in eGFR, renal function was improved in 27.7%, unchanged in 65.1%, and worsened in 7.2%. Unadjusted percent changes in systolic blood pressure, diastolic blood pressure, and eGFR relative to pre-intervention values stratified by complete versus incomplete treatment are shown in the Figure. Among patients undergoing complete repair, post-intervention increases in eGFR were +11.8% for patients with two kidneys and unilateral stenosis, +7.4% among patients with bilateral disease undergoing bilateral intervention, and +2.6% for patients with stenosis affecting their single functioning kidney.
Table III. Renal function and blood pressure responses following RA-PTAS
| Pre-intervention⁎ | Post-intervention | Difference | P⁎⁎ | |
|---|---|---|---|---|
| Blood pressure | ||||
| Systolic (mmHg) | 161.3±25.2 | 148.5±25.2 | −12.8 | <0.0001 |
| Diastolic (mmHg) | 78.6±13.3 | 72.5±13.5 | −6.1 | <0.0001 |
| Antihypertensive agents | 3.3±1.2 | 3.1±1.3 | −0.2 | 0.0090 |
| Renal function | ||||
| Serum creatinine (mg/dL) | 1.6±0.6 | 1.5±0.6 | −0.08 | 0.0113 |
| eGFR (mL/min/1.73 m2) | 46.8±17.3 | 50.2±19.7 | 3.5 | 0.0114 |
⁎Pre-operative values from patients on whom paired post-operative values were also available. |
⁎⁎P value from paired samples t-test. |
Fig.
Mean percent change in outcome variables following RA-PTAS: complete versus incomplete treatment. Unadjusted data displayed for patients with post-intervention blood pressure (N = 88) and serum creatinine (N = 83) data available at ≥3 weeks following RA-PTAS. SBP, systolic blood pressure (mmHg); DBP, diastolic blood pressure (mmHg); eGFR, estimated glomerular filtration rate as calculated using abbreviated Modification of Diet in Renal Disease formula. Incomplete treatment is defined as unilateral intervention in the setting of bilateral hemodynamically significant renal artery stenosis as determined by pre-intervention duplex ultrasound.
Multivariable linear regression models derived using stepwise selection are summarized in Table IV. We observed a significant positive association between post-intervention systolic blood pressure and pre-intervention systolic blood pressure (P < .0001). A similar positive association with pre-intervention values was observed for diastolic blood pressure (P < .0001), while a trend toward lower diastolic blood pressure was associated with staged bilateral repair status (as opposed to unilateral repair or bilateral repair in a single procedural setting) (P = .0589). A significant positive association between pre-intervention eGFR and post-intervention eGFR was also observed (P < .0001). All covariates assessed are included in Table I, Table II.
Table IV. Multivariable linear regression models derived using stepwise selection
| Outcome | Variable | Estimate | Standard error | P |
|---|---|---|---|---|
| Postoperative SBP | Preoperative SBP | 0.406 | 0.099 | <0.0001 |
| Postoperative DBP | Preoperative DBP | 0.604 | 0.089 | <0.0001 |
| Staged bilateral intervention | −7.06 | 3.687 | 0.0589 | |
| Postoperative eGFR | Preoperative eGFR | 0.904 | 0.077 | <0.0001 |
Discussion
Primary RA-PTAS for atherosclerotic RVD was associated with no peri-procedural mortality, a low incidence of complications, and early improvements in blood pressure and renal function in this retrospective series of patients treated at our center. While these improvements in blood pressure and renal function following RA-PTAS were statistically significant when considered as continuous measures, the magnitude of the observed changes was generally modest. The clinical relevance of these early changes appeared limited when assessed in a categorical fashion: cure or improvement of hypertension was achieved in a minority of patients (1% and 21%, respectively) and eGFR improved in 28% of patients when defined by an increase of ≥20% of pre-intervention eGFR. Apart from pre-intervention measures of outcome variables (SBP, DBP, or eGFR, respectively), an association between staged bilateral intervention and improved post-intervention diastolic blood pressure was the only other significant relationship we observed between clinical and/or procedural factors and functional outcomes using stepwise selection. Stepwise selection therefore produced either simple (for SBP and eGFR) or bivariate (for DBP) linear models. Contrary to earlier observations, we did not identify an association between aspirin use and post-intervention eGFR response in this study,16 although our ability to identify such an association may have been impaired by a relative paucity of patients (25%) not taking an antiplatelet medication preoperatively. Otherwise, these results are consistent with prior RA-PTAS results reported by our group.16, 18
The favorable influence of staged bilateral repair on early diastolic blood pressure response to RA-PTAS is consistent with other results observed after open renal artery revascularization.17 This observed association between staged bilateral intervention and improved blood pressure response may be related to complete treatment in all patients managed in this fashion; conversely, residual contralateral disease in patients undergoing unilateral intervention could potentially impair blood pressure responses. Fig 1 displays mean percent change in post-intervention measures stratified by complete (ie, treatment of all hemodynamically significant disease identified on pre-intervention duplex ultrasonography) versus incomplete treatment. While a mean improvement in both groups was observed for both systolic and diastolic blood pressures, postoperative mean eGFR was increased by mean of 9.7 mL/min/1.73 m2 in the complete treatment group versus a mean decrease of decrease of 2.8 mL/min/1.73 m2 among patients treated in an incomplete fashion. Such incomplete treatment is not an uncommon occurrence in our current management algorithm; following initial intervention, a contralateral procedure may not be performed if hypertension and/or ischemic nephropathy prompting the first procedure have improved.
Distal renal artery balloon occlusion at the initiation of RA-PTAS was attempted in the majority of patients (90.9%) and produced complete renal artery occlusion distal to the stenotic lesion in 74% of attempts. Incomplete balloon occlusion of arterial flow was most often attributable to either ongoing renal perfusion through branch vessels (either unprotected accessory renal arteries or main renal artery branches with proximal origins) or size mismatch between the fully inflated balloon and renal artery. These cases reflect size limitations of currently available balloon occlusion devices when renal artery diameter exceeds 6 mm. The commercially available device we currently utilize for balloon occlusion “off label” under an investigational device exemption from the United States Food and Drug administration was originally designed for use in coronary saphenous vein grafts, and currently available filter protection devices are also susceptible to similar size mismatch issues when used in the renal circulation. It is therefore possible that technical success rates with balloon occlusion during RA-PTAS might improve if renal-specific devices compatible with larger diameter distal vessels become available in the future. Nonetheless, the 7% frequency of worsened post-intervention eGFR in this study compares favorably with functional deterioration rates ranging from 8-27% in retrospective series of RA-PTAS5, 23, 24, 25, 26, 27 performed without distal renal artery balloon occlusion and is consistent with other reports uniformly employing distal protection.18, 28, 29, 30, 31 We did not detect an association between either use or completeness of protective distal renal artery balloon occlusion and eGFR response to RA-PTAS, but our power to detect such an effect was limited by the small proportion of patients managed without balloon occlusion (9.1%). Use of distal renal artery balloon occlusion did not appreciably impact morbidity rates in this study group, and no observed complications were directly attributable to use of the balloon occlusion device. A prospective trial designed to evaluate the utility of renal artery balloon occlusion during RA-PTAS is currently enrolling at our center and will provide data that may define the utility of balloon occlusion for embolic protection.
Renal artery revascularization using open operative techniques in our center has been associated with cure of hypertension in 10-12% of patients and improvement in 70-85%; renal function improvement was noted in 45-55% of patients compared with a 5-15% incidence of decline.15, 17, 32, 33 Although RA-PTAS has not duplicated these functional results in a durable fashion to date, it is important to note that the no peri-procedural deaths occurred in this cohort (vs reported perioperative mortality rates of 2-8% in large series of open repair15, 17, 32). This lower procedure-associated mortality makes RA-PTAS an attractive method for renal artery intervention in patients who would be considered high risk for open revascularization, and it is our perception that we do offer RA-PTAS to some patients who would not be offered open renal artery repair. Compared with our center's previous report on a cohort undergoing open renal artery revascularization for atherosclerotic RVD,15 the current series of patients had higher prevalence of diabetes, lower prevalence of ischemic nephropathy, and a greater frequency of incomplete treatment of RVD. These factors may have contributed the comparatively reduced blood pressure and renal function response rates following RA-PTAS. However, the 5.5% incidence of complications in this series of RA-PTAS compares favorably with morbidity associated with open renal revascularization in terms of both incidence (15-30% with open management) and severity (2/3 of complications in the current series were access-site related). While modest blood pressure and renal function responses to RA-PTAS have been demonstrated in most recent series, retrospective comparisons have not demonstrated a survival benefit associated with RA-PTAS.34 RA-PTAS appears to provide less robust blood pressure and renal function responses than open revascularization but lower risk for post-procedure death or complications. Recent trends in relative frequency of RA-PTAS and open operative repair indicate that the majority of patients and providers find this trade acceptable.9, 10 Ultimately, the value of endovascular renal artery repair will require analysis of long-term adverse events and dialysis-free survival relative to the natural history of medically treated RVD.
Benefits of endovascular treatment over the natural disease history in patients who cannot be managed medically are presumed by those utilizing RA-PTAS but remain to be proven. Results from several randomized trials comparing RA-PTAS with medical management are expected in the near future and may help to answer this question in the context of current medical therapy. The Angioplasty and Stent for Renal Artery Lesions (ASTRAL) trial is a multicenter, randomized trial of primary renal artery revascularization versus medical management designed to evaluate the effects of RA-PTAS on the rate of renal dysfunction progression; secondary endpoints include blood pressure control, renal events, vascular events, and mortality.35 Initial results from ASTRAL are anticipated in 2008. The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial is an ongoing multicenter, randomized trial evaluating the effects of RA-PTAS with distal embolic protection in patients with systolic hypertension; the primary composite endpoint includes event-free survival from a composite of cardiovascular and renal outcomes (cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, stroke, doubling of serum creatinine, and need for renal replacement therapy).14 The Renal Atherosclerotic Revascularization Evaluation (RAVE) study is a single center randomized trial designed as a pilot study to compare renal revascularization with medical therapy alone in patients with atherosclerotic renal vascular disease in whom revascularization is indicated; the primary endpoint for this study is a composite of death, dialysis, and doubling of creatinine, with subsequent plans for a larger multicenter trial designed based on the pilot study outcomes. The Benefit of Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Stenosis of the Renal Artery (STAR) study is a randomized trial evaluating RA-PTAS in the setting of renal failure; this study plans to randomize 140 participants with the primary outcome of reduction in creatinine clearance at two and five years.36 These studies and the results of other investigator-initiated randomized clinical trials will help to clarify the role of RA-PTAS.
This retrospective study has several limitations that deserve discussion. Incomplete post-intervention renal function and blood pressure data may have decreased our ability to detect associations between covariates and these outcomes or introduced bias resulting in overestimation of responses to RA-PTAS. Conversely, this study's relatively short follow-up interval (median interval of 9.4 weeks) may have resulted in an underestimation of the ultimate responses to RA-PTAS due to assessment of post-intervention outcomes earlier than the six month post-intervention interval previously used by others for assessment of procedural outcomes.6, 8 Sensitivity for detecting early single kidney changes in renal function and/or flow following RA-PTAS likely would have been increased by routine use of functional studies (such as nuclear medicine flow and GFR scanning). While these studies are impractical for routine clinical follow up due to cost, they are included as components of post-intervention follow-up in the randomized clinical trial of distal balloon occlusion during RA-PTAS being conducted at our institution. Blood pressure response to RA-PTAS may have been better characterized using ambulatory blood pressure monitoring, but this data was not obtainable given the retrospective nature of this study. Finally, we were unable to reliably ascertain patients' medication compliance during clinic visits where blood pressure measurements were obtained. We routinely instruct patients anticipating renal artery duplex ultrasound to be nothing prescribed orally (NPO) on the morning of the study, but patients are also advised to take their blood pressure medications. Conceivably, however, some patients may have held their blood pressure medications prior to clinic visits, especially when renal duplex ultrasonography was planned on the same day. Because renal duplex ultrasounds were routinely performed at both pre-and post-intervention visits, however, this phenomenon likely would have introduced bias favoring the null hypothesis rather than a type I error.
As ongoing assessment RA-PTAS continues, further investigation should seek to improve functional responses of percutaneous therapy while maintaining low complication rates. Active investigations into embolic protection, drug-eluting stents, and medical management strategies all have the potential to improve future RA-PTAS outcomes. Results from ongoing prospective studies are needed to evaluate the durability of endovascular treatment for atherosclerotic renovascular disease, to establish the value of distal renal artery balloon occlusion for protection from atheroembolism, to assess outcomes following intervention for recurrent disease and fibromuscular dysplasia, and to identify predictors of both functional responses and disease recurrence.
Author contributions
References
- . Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. Arch Intern Med. 2005;165:207–213
- Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol. 2003;41:1364–1372
- . Increased cardiovascular mortality in hypertensive patients with renal artery stenosis (Relation to sympathetic activation, renal function and treatment regimens). J Hypertens. 1999;17(12 Pt 1):1743–1750
- Cardiovascular disease risk status in elderly persons with renal insufficiency. Kidney Int. 2002;62:997–1004
- Stent placement for renal arterial stenosis: where do we stand? (A meta-analysis). Radiology. 2000;216:78–85
- . Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis - A randomized trial. Hypertension. 1998;31:823–829
- The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. New England Journal of Medicine. 2000;342:1007–1014
- Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Journal of Human Hypertension. 1998;12:329–335
- Diffusion of new technology for the treatment of renovascular hypertension in the United States: surgical revascularization versus catheter-based therapy, 1988-2001. J Vasc Surg. 2004;40:717–723
- . Increase in utilization of percutaneous renal artery interventions by Medicare beneficiaries, 1996-2000. American Journal of Roentgenology. 2004;183:561–568
- Effectiveness of management strategies for renal artery stenosis: a systematic review. Ann Intern Med. 2006;145:901–912
- . NCA Tracking Sheet for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries. 2007;(CAG-00085R4)
- . Proposed Decision Memo for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries. 2007;(CAG-00085R4)
- Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial. Am Heart J. 2006;152:59–66
- Surgical management of atherosclerotic renovascular disease. J Vasc Surg. 2002;35:236–245
- Atheroembolism during percutaneous renal artery revascularization. J Vasc Surg. 2007;46:55–61
- Management of ischemic nephropathy: dialysis-free survival after surgical repair. J Vasc Surg. 2000;32:472–481
- Distal embolic protection during renal artery angioplasty and stenting. J Vasc Surg. 2006;44:128–135
- . Evolution of renal insufficiency in ischemic nephropathy. Ann Surg. 1991;213:446–455
- . Hypertensive crises: challenges and management. Chest. 2007;131:1949–1962
- . A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation (Modification of Diet in Renal Disease Study Group). Ann Intern Med. 1999;130:461–470
- Renal duplex sonography: evaluation of clinical utility. J Vasc Surg. 1990;12:227–236
- . Stent placement in ostial and nonostial atherosclerotic renal arterial stenoses: a prospective follow-up study. Radiology. 2000;216:498–505
- Stents in the treatment of renal artery stenosis: long-term follow-up. J Endovasc Surg. 1999;6:42–51
- . Primary renal artery stenting: characteristics and outcomes after 363 procedures. Am Heart J. 2001;142:314–323
- Treatment of atherosclerotic ostial renal artery stenosis with the intravascular stent. Am J Kidney Dis. 1998;32:611–622
- Stent-supported angioplasty of severe atherosclerotic renal artery stenosis preserves renal function and improves blood pressure control: long-term results from a prospective registry of 456 lesions. J Endovasc Ther. 2004;11:95–106
- Protected renal stenting with the PercuSurge GuardWire device: a pilot study. J Endovasc Ther. 2001;8:227–237
- Renal angioplasty and stenting under protection: the way for the future?. Catheter Cardiovasc Interv. 2003;60:299–312
- . Renal angioplasty and stenting with distal protection of the main renal artery in ischemic nephropathy: early experience. J Vasc Surg. 2003;38:962–968
- . Renal artery stent revascularization with embolic protection in patients with ischemic nephropathy. Kidney Int. 2006;70:948–955
- Renal artery reconstruction for the preservation of renal function. J Vasc Surg. 1996;24:371–380
- . Surgical revascularization for renal artery disease: current status. BJU Int. 2005;95(Suppl 2):75–77
- . Renal artery stenting slows the rate of renal function decline. J Vasc Surg. 2007;45:726–731
- Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far. J Hum Hypertens. 2007;21:511–515
- The benefit of STent placement and blood pressure and lipid-lowering for the prevention of progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery (The STAR-study: rationale and study design). J Nephrol. 2003;16:807–812
Competition of interest: none.
PII: S0741-5214(08)00670-8
doi:10.1016/j.jvs.2008.04.050
© 2008 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
