Atherosclerotic renal artery stentosis (RAS) is a frequently recognised cause of secondary hypertension and chronic kidney disease.1–4 Revascularisation of RAS with angioplasty and stenting is often performed with the goals of improved blood pressure control and preserving or improving renal function.5 However, renal artery stenting is sometimes associated with acute worsening of renal function.6 Possible mechanisms of renal artery injury following stent placement include toxicity from iodinated contrast and distal embolisation. Atheroembolisation is well documented as a cause of renal disease, although definitive diagnosis requires a renal biopsy and therefore is rarely confirmed pathologically.7–10 The use of embolic protection devices (EPDs) has been shown to improve outcomes of percutaneous revascularisation procedures in saphenous vein grafts and carotid arteries.11–13 Although currently no EPDs are approved for use during renal artery stenting, data are emerging that suggest a role for these devices in this setting.
Atheroembolisation During Renal Artery Stenting
In an ex vivo study, Hiramoto et al. demonstrated that renal artery stenting is associated with the release of atheroembolic particles.14 In this study, explanted aorto-renal artery specimens from renal artery endarterectomy procedures were used, along with polytetrafluroethylene grafts, to create a model for renal artery stenting. This demonstrated that each step of the procedure, including passage of the guidewire, was associated with embolisation of thousands of particles, with the particle number inversely related to particle size. This ex vivo evidence of atheroembolisation is supported by several clinical studies that demonstrated the retrieval of embolic material following renal stenting with the adjunctive use of an EPD.15–24
Embolic Protection Devices
Currently, several EPDs are commercially available. These devices can be divided into three broad categories: proximal protection devices, distal occlusive devices and distal filter devices. Due to the fact that the overwhelming majority of atherosclerotic RAS lesions are ostial, proximal protection devices are not practical and will not be discussed here.
Distal Occlusion
The GuardWire® (Medtronic, Minneapolis, MN, US) is a system that utilises a temporary occlusion balloon to prevent antegrade flow during a stent procedure. Following stent deployment, an aspiration catheter is used to remove any embolised material before balloon deflation and the restoration of antegrade flow to the kidney. The use of the GuardWire in conjunction with renal artery stenting has been reported.16–19,22–24 A potential advantage of distal occlusion is its low crossing profile. Indeed, given that guidewire passage leads to the embolisation of large numbers of atheromatous particles, a lower profile may help to decrease this number, particularly in the case of high-grade stenoses.14 In addition, the technique of occlusion and aspiration prevents the embolisation of particles of all sizes. This may be important, given that the majority of embolised particles are smaller than 100μm.14,16 Although the clinical significance of the embolisation of small particles, particularly those smaller than 60μm, is unknown, particles in the size range of 20–40μm may be large enough to obstruct the afferent arteriole.14 Consistent with this possibility, it has been demonstrated that embolic particles smaller than 100μm may lead to cerebral injury.25,26
One potential disadvantage of distal occlusion is that imaging between procedural steps, such as balloon pre-dilatation and stent deployment, is limited due to the static column of contrast. A second potential disadvantage of distal occlusion is the induction of renal ischaemia. Henry et al. reported a mean renal artery occlusion time of 6.46 minutes.19 Whether this duration of ‘warm’ renal ischaemia may lead to a decline in renal function is not known.
Distal Filters
The Angioguard® (Cordis, Miami Lakes, FL, US) is a 0.014-inch guidewire with a polyurethane filter with 100μm pores supported by a basket made up of eight nitinol struts. The FilterWire EZ™ (Boston Scientific, Natick, MA, US) is also a 0.014-inch guidewire system; however, it utilises a single nitinol loop to support a polyurethane filter with 110μm pores. Use of both the Angioguard and the FilterWire EZ in conjunction with renal artery stenting has been reported.15,18–21 Only the Angioguard device has been evaluated in a randomised trial compared with the control of no EDP.15
The greatest potential advantage of distal filters is their ability to maintain renal perfusion during the procedure. This eliminates the theoretical concern of ischaemia induced by balloon occlusion. In addition, continuous antegrade flow makes it easier for the operator to visualise each step of the procedure, and this may also reduce total procedure time. Henry et al. reported a mean time of filter deployment of 4.25 minutes, which was shorter than the occlusion time with a distal occlusion balloon.19
Potential disadvantages of distal filters include incomplete protection of the renal parenchyma from embolised material, as any particles smaller than the pore size will not be filtered. In addition, it may be difficult to ensure that the filter device is completely opposed to the vessel wall. If the device is not adequately opposed, embolised material may simply slip past the device. Another potential disadvantage of these devices is that the initial crossing profile is larger, and this may lead to increased embolisation during initial deployment and difficulty with crossing a stenosis without use of pre-dilatation. One technique to facilitate crossing of the stenosis and filter deployment without pre-dilatation is the use of a ‘buddy wire’. Even if pre-dilatation is required to deploy the filter, there may still be a benefit, as subsequent procedural steps, including stenting, are associated with embolisation.14
In addition to device-specific advantages and disadvantages, there are limitations to the use of any EPD. First, there may be an early bifurcation of the main renal artery. This would prevent complete protection of the renal parenchyma during the stenting procedure (see Figure 1). Whether partial protection is beneficial has not been established. In some circumstances, vessel tortuosity precludes safe deployment of an EPD. In addition, the diameter of the renal artery in the ‘touchdown zone’ for the device may not accommodate an EPD. Although a vessel being too small for EPD use occurs less frequently – as is occasionally encountered during treatment of an accessory renal artery – it is not unusual for the artery to be in excess of 6mm, at which point use of some protection devices is precluded due to an inability to achieve adequate apposition to the vessel wall.
Finally, all EPDs are effective only after deployment, thus they do not help to protect the kidney from atheroembolism during initial engagement with a guide catheter, and certainly do not protect the contralateral kidney or other organ systems that may be affected by emboli liberated from the abdominal aorta. In order to minimise embolic complications with initial catheter engagement, a number of techniques are available, including the ‘telescoping catheter’ technique and the ‘no-touch’ technique.27
The telescoping catheter technique uses a 5–6Fr diagnostic catheter to initially engage the renal artery. A larger guide catheter is advanced in over the diagnostic catheter, which is then removed prior to performing the interventional procedure. Using the no-touch technique, a 0.035-inch J-tipped guidewire is advanced out of the guide catheter, in order to keep it away from the wall of the aorta. The guide catheter is then brought into proximity to the renal artery, and a 0.014-inch guidewire is directed into the distal renal artery. The interventional procedure is then performed following removal of the 0.035-inch J-tipped wire.27 In addition, aggressive aspiration of the catheter with the removal of at least 10ml of blood and subsequent flushing with heparinised saline prior to angiography can help to protect against distal embolisation.28
Clinical Reports of Embolic Protection Device Use in Renal Stenting
The use of EPDs in renal artery stenting has been reported in several case series.16–24 The primary outcome measure has been the change in renal function from baseline to follow-up, measured by serum creatinine and/or estimated glomerular filtration rate (eGFR). A summary of these results is shown in Table 1. Although these reports have suggested that EPD may prevent deterioration of renal function following renal stenting, they are limited by the lack of a control group.
The recently published RESIST trial15 compared renal artery stenting with and without the use of the Angioguard short-tip EPDs. In the RESIST trial, a total of 100 patients were treated, and 91 of these patients were evaluated for the prespecified primary end-point of renal function, as assessed by the eGFR calculated from the modified diet and renal disease equation.29 Among patients assigned to the Angioguard device, the change in eGFR was somewhat better at -1%, compared with -10% in patients who did not receive EPD, although this was not statistically significant (p=0.08). In addition, within the subgroup of patients treated with Angioguard alone (without concomitant use of abciximab), there was a statistically significant decline in eGFR.
The decline in renal function seen with EPD use in randomised patients from RESIST differs significantly from prior non-random case series where improved renal function has often been reported and worsened renal function has rarely been described.16–21 One potential reason for this discrepancy is patient selection. In previously published studies, all patients received complete embolic protection; however, in RESIST, 25 of 44 (56%) patients received complete protection and 19 of 44 (44%) received partial protection. A second possible reason for the lack of benefit seen with EPD use in RESIST is that worsening renal function following stent placement is multifactorial, and other variables are not affected by EPD.
The Role of Platelets During Renal Artery Stenting
The importance of platelet inhibition during stenting procedures in native coronary arteries has been well established, with benefit seen with the use of aspirin, thienopyridines and glycoprotein (GP) IIb/IIIa inhibitors.30–33 The data on the combined use of GPIIb/IIIa inhibitors in saphenous vein graft interventions are less clear.34 Whether there is a role for adjunctive platelet inhibition during renal stent procedures has yet to be established; however, there are animal model data to suggest that platelet activation contributes to glomerular injury and that platelet inhibition reduces this injury.35–37
Currently, there is a lack of consensus among physicians about the use of antiplatelet agents during renal artery stenting. Aspirin is used routinely; however, the use of thienopyridines or GPIIb/IIIa inhibitors is not standardised. In addition, the use of thienopyridines and GPIIb/IIIa inhibitors in this setting would represent an off-label use. Given the potential benefits of utilising these agents, trials evaluating their use are needed.
The Use of Abciximab in RESIST
In addition to randomising patients to receive EPD, the RESIST trial also randomised patients to the use of abciximab versus placebo in a doubleblind fashion using a two-by-two factorial design. Among patients receiving placebo, the percentage change in eGFR was -10%, compared with 0% in patients receiving abciximab (p < 0.05).15 Notably, an excess of bleeding complications was not seen.
Embolic Protection Device and Abciximab Interaction in RESIST
The results discussed previously look at the effects of EPD or abciximab without consideration of whether the patient received one or both therapies. In RESIST, patients may have been allocated to one of four treatment groups: control (no Angioguard and placebo), Angioguard alone, abciximab alone or Angioguard and abciximab.15 Although dividing the patients into smaller groups decreases statistical power, it provides important insights as well. When each therapy was looked at in isolation, the eGFR declined significantly in a manner similar to that seen among patients assigned to the control group. Conversely, the patients treated with both EPD and platelet inhibition were noted to have a slight increase in eGFR.
Analysis of Captured Embolic Debris
The role of platelets in renal injury following renal artery stenting is also supported by analysis of the captured embolic debris. Most studies comment on the presence of macroscopic embolic material; however, a limited number of case studies have performed pathological analysis of captured material. The rate of capture of embolic debris varies between 44 and 100% of cases analysed.15–17,19–21 Analysis of the embolic material reveals that thrombi – both acute and chronic – are captured along with atheromatous material.15,21 Analysis of data from the RESIST trial revealed that material was captured in 47% of cases and that capture of platelet emboli – either alone or with atheromatous material – was more common than the capture of atheromatous material.15 The prevalence of platelet-rich thrombi suggests that platelet inhibition may have an important role in improving outcomes of renal artery stent procedures.
Summary
Deterioration of renal function following renal artery stent placement is an important challenge. Several factors may contribute to the post-procedure decline in renal function, and all must be addressed if the problem is to be solved. The use of peri-procedural hydration to help prevent contrast-induced nephropathy has become routine, as has the meticulous catheter manipulation to prevent excessive scraping of plaque while engaging the renal artery. Preliminary data suggest that EPD and adjunctive platelet inhibition may each have a role in limiting renal injury post-stenting. In addition, there seems to be an interaction between EPD and GPIIb/IIIa blockade that results in an increased and unexpected benefit.
Current data do not provide a definitive answer regarding the role of EPD or platelet inhibition in renal artery stenting. Enrolment of patients in clinical trials will be essential to answering these questions. Until these questions are answered, it seems that physicians can use these devices safely with the possibility of some benefit.